Cytotoxic Impact of Fluorinated Ligands in Equatorial Position of Trans-Configured Diam(m)inetetracarboxylatoplatinum(IV) Complexes

Abstract

A series of thirty novel tetracarboxylatoplatinum(IV) complexes in trans-configuration featuring combinations of mixed ammine, methylamine, dimethylamine, and cyclopentylamine ligands as well as acetato/propanoato and trifluoropropanoato ligands was synthesised. The platinum(IV) complexes were characterised by one- and two-dimensional multinuclear NMR spectroscopy (¹H, ¹³C, ¹⁵N, ¹⁹F, ¹⁹⁵Pt), ESI-MS, elemental analysis, and X-ray diffraction. Additional parameters such as reduction behaviour and lipophilicity were measured via NMR spectroscopy and RP-HPLC, revealing slow reduction and a broad spectrum of log k_w values in line with the respective ligand combination. In order to determine structure–activity relationships, cytotoxic activity was evaluated via the MTT assay in three human cancer cell lines (CH1/PA-1, ovarian teratocarcinoma, SW480, colon adenocarcinoma, A549, non-small-cell lung carcinoma). The induction of apoptosis and necrosis was determined in SW480 cells via the flow-cytometric annexin V/PI assay. In general, a tendency of higher lipophilicity leading to higher cytotoxicity was noticed. In contrast, lipophilicity alone plays a subordinate role for the induction of apoptosis, which strongly depends on the combination of am(m)ine and trifluoropropanoato ligands.

1. Introduction

The discovery of the anticancer activity of cisplatin, (SP-4-2)-diamminedichloridoplatinum(II), in 1965 [1] was also the beginning of a new era of intensive research in the field of bioinorganic chemistry. As a result of absent cytotoxic properties of diverse trans-configured compounds including transplatin, (SP-4-1)-diamminedichloridoplatinum(II), the cis-configuration of platinum complexes was supposed to be a prerequisite for their antiproliferative properties [2,3]. The inactivity of transplatin was related to two major reasons: On the one hand, two chlorido ligands in trans position result in fast reactivity due to kinetic instability [4,5]. Additionally, their higher affinity to serum proteins leads to biodegradation and deactivation [4,6]. Based on its stereochemistry, transplatin generates DNA-adducts different from those of its cis-congener [4]. Cisplatin mainly forms cytotoxic 1,2-intrastrand cross-links with purine bases of DNA, leading to the inhibition of the transcription and induction of apoptosis, whereas transplatin forms either weak monoadducts or a series of interstrand cross-links associated with rapid DNA repair [7,8]. However, the informal rule of a required cis-configuration for anticancer activity was broken by the discovery of trans-configured platinum compounds featuring higher cytotoxic potency than their cis-counterparts [2]. In the 1990s, the replacement of one ammine ligand with bulky planar amine ligands in the trans position of platinum(II) complexes led to enhanced antiproliferative properties, even in cisplatin-resistant tumour cells [9,10]. This might be explained by kinetic stability due to steric hindrance and the resulting deceleration of ligand substitution. In some cases, the preferentially formed 1,3-intrastrand and interstrand cross-links are more stable than those induced by transplatin. As these cross-links are less readily recognised by high mobility group (HMG) proteins, DNA repair may be prevented, an aspect playing an important role in drug resistance processes [4,7]. Based on this promising possibility of overcoming resistance by ligand variation, different types of trans-platinum compounds with low IC₅₀ values and low resistance factors were developed [11,12,13,14,15,16].

Besides the frequent occurrence of intrinsic and acquired resistances of diverse tumours to cisplatin, as well as the other classic cis-configured platinum(II) complexes carboplatin and oxaliplatin used in clinical practice worldwide, platinum(II)-based anticancer treatment is accompanied by serious adverse effects such as nephrotoxicity and neurotoxicity [17,18]. These dose-limiting effects are caused by kinetic lability and a lack of selectivity for cancerous tissue, followed by indiscriminate reactions with different biomolecules [19]. Based on these severe disadvantages of common platinum(II) compounds, intensive research has been devoted to the design of kinetically more inert platinum(IV) complexes in order to reduce adverse effects and improve selectivity for cancer cells [20]. Platinum(IV) complexes are considered as prodrugs and consequently follow the “activation by reduction” principle, unfolding their cytotoxic activity after the release of the two ligands in an axial position, preferentially in the acidic and oxygen-deficient milieu of tumour tissue [21]. In addition, the introduction of the axial ligands enables excellent possibilities for fine-tuning pharmacokinetic properties such as reduction behaviour and lipophilicity [22].

Here, we report on a novel series of trans-configured tetracarboxylatoplatinum(IV) complexes featuring acetato/propanoato and trifluoropropanoato ligands. The introduction of fluorine-based ligands not only has an influence on the physicochemical properties of the complexes, but it also enables the use of highly sensitive ¹⁹F NMR spectroscopy in biological matrices for future studies. Based on enhanced stability and cytotoxic activity [4,23], we integrated different mixed a(m)mine ligands with varying bulkiness and lipophilicity. Characterisation was performed via multinuclear NMR spectroscopy, electrospray ionisation mass spectrometry (ESI-MS), elemental analysis, and X-ray diffraction. Additionally, reduction behaviour and lipophilicity were determined via NMR spectroscopic and RP-HPLC studies, respectively. Finally, structure–activity relationships were studied based on the cytotoxicity in three human cancer cell lines (CH1/PA-1, SW480, and A549) as well as on the induction of apoptosis and necrosis in SW480 cells via the flow-cytometric annexin V/PI assay.

2. Results and Discussion

2.1. Synthesis

The synthesis of a series of compounds 1 and 2 was adapted from procedures previously published by our group (Scheme 1) [16]. The trans-configured complexes 1a–1e were obtained via the reaction of (SP-4-2)-diamminedichloridoplatinum(II), (SP-4-2)-dichloridobis(methylamine)platinum(II), or (SP-4-2)-dichloridobis(dimethylamine)platinum(II) with methylamine, dimethylamine, or cyclopentylamine (cpa) under moderate heating in aqueous solution. Afterwards, concentrated HCl was added to the intermediately formed tetraamine complexes and refluxed overnight, forming substances 1a–1e based on the trans effect [24]. Subsequently, ligand exchange via reaction with potassium iodide led to complexes 2a–2e. The further reaction with Ag₂SO₄ and the removal of the formed AgI resulted in the corresponding aqua complexes, which were added to an aqueous solution of Ba(OH)₂ and acetic acid, propionic anhydride, or CF₃CH₂COOH. This approach was adapted from a previously published procedure [25]. Subsequently, formed BaSO₄ was filtered off and compounds 3a–3e, 5b, 7a–7e, 8a–7e could be obtained as crude products and were used without purification. The following oxidation with hydrogen peroxide led to platinum(IV) complexes 4a–4e, 6b, 9a–9e, 10a–10e. As a last step, carboxylation was achieved by the reaction of the crude dihydroxidoplatinum(IV) complexes with acetic or propionic anhydride under an argon atmosphere. The final products 11a–16e were obtained after purification via RP-HPLC (Scheme 1).

The crucial reaction step was the introduction of the trifluoropropanoato ligands in equatorial position in order to produce complexes 4a–4e. However, this reaction step did not work in every case; monocarboxylatoplatinum(II) complexes and analogues with no carboxylato ligand at all were isolated. Consequently, mono(trifluoropropanoato) (13a–13e, 14a–14e) and tetracarboxylato complexes (15a–15e, 16a–16e) were obtained as side products of substances 11a–11e and 12a–12e.

Furthermore, configurational isomers (11c*–11e*, 12c*–12e*) of 11c–11e and 12c–12e were detected with mixed axial and equatorial carboxylato ligands via RP-HPLC and NMR spectroscopy (Scheme 2). Most likely, the switching of the ligands occurred during the oxidation process, which has already been reported in the literature [26], and may have been caused by steric hindrance. In particular, isomeric reactions were observed by complexes featuring the bulky cyclopentylamine ligand. Isomers of complexes 11c–11e could be separated via RP-HPLC, and pure substances of 11c–11e were used for further characterization and analysis. On the other hand, the separation of 12c–12e was difficult to achieve and would have caused drastically reduced yields and extremely long RP-HPLC runs. Therefore, only a very small amount of complexes 12c–12e was purified and used for NMR measurements, lipophilicity studies, ESI-MS, and X-ray crystallography. However, the mixtures 12c/12c*–12e/12e* were used for the MTT assay and the flow-cytometric annexin V/PI assay.

2.2. Analysis

Trans-configured platinum(II) complexes 1 and 2 were characterised by NMR spectroscopy (Supplementary Materials Figures S1–S11) as well as X-ray diffraction in the case of 1a, 1d, 1e, 2a, 2c, 2e (Supplementary Materials Figures S122–S127 and Tables S1–S18). As a reference and prime example, the cis-analogue of compound 2c (SP-4-2)-amminecyclopentylaminediiodidoplatinum(II) was synthesised and analysed (Supplementary Materials, Figure S1). Based on ¹H NMR spectra measured in d₆-acetone, significant changes in the chemical shifts from 4.50 to 3.98 ppm (NH₂), respectively, and from 3.94 to 3.46 ppm (NH₃) between the cis- and trans-isomer were detected, proving the successful synthetic pathway of the trans-configured complex 2c. In the case of iodidoplatinum(II) complexes 2a–2e, a significant difference in ¹⁹⁵Pt resonances was detected. Whereas complexes 2a, 2c and 2d had signals at around −1730 ppm, the resonances of complexes 2b and 2e were found at −1595 and −1575 ppm, respectively. Since complexes 2b and 2e both feature a secondary dimethylamine ligand, this downfield shift is most probably caused due to electronic and/or steric reasons.

The final tetracarboxylatoplatinum(IV) compounds 11–16 were characterised in detail via elemental analysis, electrospray ionisation mass spectrometry (ESI-MS), multinuclear one- and two-dimensional NMR spectroscopy (¹H, ¹³C, ¹⁵N, ¹⁹F, ¹⁹⁵Pt) (Supplementary Materials Figures S12–S121), and X-ray diffraction in the case of 12e, 13c, and 15e (Supplementary Materials Figures S128–S130 and Tables S19–S27).

For all products, ¹⁹⁵Pt signals between 3925 and 3987 ppm were detected, indicating a PtN₂O₄ coordination sphere. As expected, and already reported in the literature [27], no significant changes in ¹⁹⁵Pt chemical shifts between the different chain lengths of acetato (11, 13, 15) and propanoato (12, 14, 16) complexes were observed. On the contrary, differences between bis(trifluoropropanoato) (11, 12) and mono(trifluoropropanoato) (13, 14) complexes could be found in ¹H and ¹³C NMR spectra. Complexes 13 displayed an additional acetato signal between 1.95 and 1.91 ppm of the acetato ligand in the equatorial position in comparison to ¹H NMR spectra in d₆-DMSO of compounds 11. Consequently, a second signal for the CH₃ group could be also detected in the ¹³C NMR spectra between 22.5 and 22.2 ppm. Similarly, an additional overlapping quartet of the CH₂CH₃ group between 2.26 and 2.23 ppm as well as a second triplet of the CH₂CH₃ group between 0.95 and 0.94 ppm describe the difference between axial and equatorial propanoato ligands of complexes 14 in ¹H NMR spectra. Furthermore, additional signals of the carbonyl (180.7–180.3 ppm), CH₂CH₃ (28.9–28.4 ppm), and CH₂CH₃ groups (10.2–10.1 ppm) of the equatorial propanoato ligand could be identified in ¹³C NMR. Moreover, the isomers 11c–11e and 11c*–11e* as well as 12c–12e and 12c*–12e* were separated via RP-HPLC and analysed via NMR spectroscopy. The respective NMR data for 11c–11e and 12c–12e can be found in Materials and Methods. Besides the separate analyses of complexes 11c–11e and 11c*–11e* as well as 12c–12e and 12c*–12e*, the respective mixtures 11c/11c*–11e/11e* and 12c/12c*–12e/12e* were measured using NMR spectroscopy in order to clearly verify the presence of isomers. As expected, the 12c/12c*–12e/12e* mixtures displayed two overlapping quartets of the CH₂CF₃ group (3.51–3.42 ppm), two quartets of the CH₂CH₃ group (2.33–2.27 ppm), and two triplets of the CH₂CH₃ group (0.99–1.02 ppm) in the ¹H NMR spectra in d₇-DMF. Consequently, additional signals were also observed in the ¹³C NMR spectra for the two carbonyl groups of the propanoato and trifluoropropanoato ligands between 181.6 and 181.7 ppm, and two quartets between 171.0 and 171.1 ppm, respectively. Additionally, overlapping quartets were detected for the CF₃ and CH₂CF₃ group at 124.9 ppm and between 39.6 and 39.8 ppm, respectively. Furthermore, additional peaks between 29.0 and 29.3 ppm and at 10.1 ppm were found for the CH₂CH₃ and CH₂CH₃ group. Finally, two overlapping triplets of the CF₃ group between −63.7 and −63.4 ppm were found in the ¹⁹F NMR spectra. In contrast, the position of the fluorinated ligand in the equatorial (12c–12e) or axial position (12c*–12e*) did not affect the platinum(IV) core, proven by only one ¹⁹⁵Pt signal. Corresponding signals were also observed in ¹H, ¹³C, ¹⁹F, and ¹⁹⁵Pt NMR spectra for 11c/11c*–11e/11e* mixtures. Finally, the composition of isomers 11c–11e and 11c*–11e* as well as 12c–12e and 12c*–12e* was further verified by the same molecular weights measured via ESI-MS.

2.3. Crystallography

The trans-configuration of platinum(II) and (IV) complexes was further proven by X-ray diffraction analysis. Single crystals of precursor platinum(II) complexes 1a, 1d, 1e, 2a, 2c and 2e as well as of final platinum(IV) products 12e, 13c and 15e were received from a tetrahydrofuran (1a, 2a, 2c, 2e, 13c, 15e), an acetone (1d, 1e), or a DMSO (12e) solution by slow evaporation at room temperature. Details of the X-ray diffraction analysis, ORTEP views of the complexes, as well as tables with crystal data, data collection, structure refinement, bond lengths, and angles can be found in the Supplementary Materials (Figures S122–S130 and Tables S1–S27).

2.4. Reduction Behaviour

The reduction behaviours of selected complexes 11b, 11d, 11e, 12b, 14e, 15a, 15c, and 16e were investigated with NMR spectroscopy using ascorbic acid as a reducing agent. ¹H and ¹⁹F NMR spectra were measured for three days. In general, all measured complexes displayed a very slow reduction. After 2.5 days, between 2 and 11% of the respective complex was reduced (

Table 1. Overview of the reduction half-times of selected trans-platinum(IV) complexes at ambient temperature (ratio complex/ascorbic acid = 1:25). Based on the slow reduction, measurements were stopped after around 2.5 days, and the reduction status reached is mentioned in brackets.

Sample	Reduction Half-Time [h]
11b	>61 (~8%)
11d	>62 (~2%)
11e	>60 (~4%)
12b	>61 (~11%)
14e	>64 (~5%)
15a	>63 (~3%)
15c	>65 (~2%)
16e	>61 (~6%)

). These observations are consistent with previously published findings on comparable platinum(IV) complexes. Ten days after the addition of ascorbic acid, only around 10% of reduced tetracarboxylato(ethane-1,2-diamine)platinum(IV) complexes were detected [28]. In line with these results, 50% of carboxylated platinum(IV) analogues of carboplatin were still intact three weeks after the incubation with ascorbic acid [29]. A possible explanation for the slow reduction could be the limited ability of coordinated carboxylate acting as an electron transporter since analogous bis- and tris(carboxylato)platinum(IV) complexes with mixed am(m)ine ligands in the trans position, but with two or one hydroxido ligands, showed comparable, fast reduction [16].

2.5. Lipophilicity

Lipophilicity expressed by the parameter log k_w is an important factor for the bioavailability and/or cellular accumulation, and is therefore connected to cytotoxicity [29]. The log k_w values for all substances were determined via isocratic RP-HPLC runs of different methanol/water compositions and are summarised in

Table 2. IC₅₀ values [in µM] of platinum(IV) complexes in human cancer cell lines A549, CH1/PA-1, and SW480 (means ± standard deviations from at least three independent experiments, 96 h exposure), as well as their corresponding lipophilicity parameter log k_w.

Sample	A549	SW480	CH1/PA-1	log kw
11a	>200	42 ± 2	26 ± 8	2.12
11b	100 ± 14	29 ± 4	18 ± 1	2.90
11c	49 ± 5	14 ± 1	5.6 ± 1.5	4.07
11d	30 ± 2	11 ± 1	5.2 ± 1.2	4.24
11d/11d*	42 ± 3	15 ± 1	6.8 ± 0.8	-
11e	44 ± 4	11 ± 1	7.6 ± 0.8	4.44
12a	130 ± 1	45 ± 3	8.5 ± 2.0	2.92
12b	58 ± 8	25 ± 2	8.7 ± 2.5	3.77
12c/12c*	16 ± 1	7.7 ± 1.1	2.5 ± 0.2	4.94
12d/12d*	24 ± 2	11 ± 1	2.6 ± 0.1	5.15
12e/12e*	28 ± 2	8.9 ± 0.8	4.1 ± 0.8	5.04
13a	>200	115 ± 17	60 ± 7	1.92
13b	>200	~200	86 ± 10	2.26
13c	124 ± 18	48 ± 9	9.6 ± 0.6	3.22
13d	121 ± 29	42 ± 2	7.0 ± 0.9	3.57
13e	113 ± 24	31 ± 1	12 ± 3	3.37
14a	>200	108 ± 11	22 ± 6	2.48
14b	>200	82 ± 12	17 ± 3	3.37
14c	83 ± 5	31 ± 6	3.5 ± 0.8	4.47
14d	29 ± 4	15 ± 1	1.1 ± 0.1	4.07
14e	44 ± 4	16 ± 1	2.6 ± 0.5	4.80
15a	>200	>200	>200	-
15b	>200	>200	~200	2.07
15c	>200	84 ± 15	22 ± 5	2.62
15d	156 ± 8	73 ± 8	13 ± 4	2.81
15e	169 ± 4	55 ± 10	19 ± 3	2.97
16a	>200	>200	134 ± 30	2.36
16b	>200	~200	41 ± 10	3.01
16c	120 ± 35	57 ± 12	4.3 ± 1.0	3.63
16d	90 ± 19	47 ± 13	4.6 ± 0.6	4.21
16e	154 ± 23	42 ± 6	20 ± 4	4.33

. The compounds strongly differ by their lipophilicity, displaying log k_w values ranging from 1.92 for the second most hydrophilic substance 13a to 5.15 for the most lipophilic compound 12d. Complex 15a was the most hydrophilic complex; however, it was not possible to determine the log k_w value via RP-HPLC because the measurement would have been outside of the linear range.

As expected, complexes bearing ammine and methylamine (a) or dimethylamine ligands (b) are the most and second-most hydrophilic compounds within their corresponding series, respectively. Substances featuring cyclopentylamine combined with ammine (c), methylamine (d), or dimethylamine ligands (e) displayed partially similar log k_w values (e.g., 12c–e) and followed the general tendency of complexes e being more lipophilic than d and c, with some deviations. Furthermore, the following trend could be observed (from the highest to the lowest lipophilicity), 12 > 14 > 16 ≈ 11 > 13 > 15, with the only major exception being 14d. Remarkably, bis(trifluoropropanoato) complexes (12, 11) were more lipophilic than their corresponding mono(trifluoropropanoato) (14, 13) and tetracarboxylato counterparts (16, 15). As further expected, the longer chain length of propanoato ligands (12, 14, 16) led to more lipophilic substances compared to their acetato analogues (11, 13, 15).

2.6. Cytotoxicity

Cytotoxic potencies of the compounds were determined via MTT assays in adherent cultures of three human cancer cell lines: broadly chemosensitive CH1/PA-1 ovarian teratocarcinoma cells, SW480 colon carcinoma cells with moderate chemosensitivity, and highly multidrug-resistant A549 non-small-cell lung cancer cells. This sensitivity pattern is also consistently reflected in the results obtained here (Table 2, Supplementary Materials Figures S131–S136), with IC₅₀ values ranging over two orders of magnitude from 1 µM (compound 14d in CH1/PA-1 cells) to >200 µM.

Corresponding to their higher lipophilicity, complexes with a cyclopentylamine ligand (c–e) displayed higher cytotoxic potencies than analogues with an ammine ligand in the same (equatorial) position (a, b). In many cases, this difference roughly amounts to an order of magnitude. Otherwise, there is no overall correlation with log k_w values within series of analogues. Whereas the lowest cytotoxicity mostly corresponds to the minimum lipophilicity (with the exception of 13b vs. 13a), the optimum in terms of cytotoxicity (if identical in all three cell lines at all) does not (at least not entirely) correspond to the maximum lipophilicity in the majority of cases (e.g., 11d vs. 11e, 12c/12c* vs. 12d/12d*, 14d vs. 14e).

With only minor exceptions (cf. 14d with 12d/12d* and 14e with 12e/12e* in CH1/PA-1 cells), introducing and increasing the number of trifluoropropanoato ligands is advantageous for cytotoxicity and may convey moderate activity even to an almost non-cytotoxic basic structure (cf. 15a with 11a and 15b with 11b). Likewise, propanoato ligands are (at least slightly) advantageous for cytotoxicity compared to acetato ligands overall (cf. series 12 with 11, 14 with 13, and 16 with 15), but this effect does not increase with an increasing number of these ligands.

Due to the difficult separation of isomers of complexes 12c–12e, only the corresponding mixtures 12c/12c*–12e/12e* could be tested. In order to investigate the influence of the isomers, the effects of the axial/equatorial position of the trifluoropropanoato ligand on the cytotoxicity, pure complex 11d, as well as the mixture 11d/11d* were analysed. Based on the IC₅₀ values (compare 30 vs. 42 µM in A549, 11 vs. 15 µM in SW480, 5.2 vs. 6.8 µM in CH1/PA-1 cells), it could be assumed that equatorial trifluoropropanoato ligands probably lead to slightly higher cytotoxic activity.

2.7. Apoptosis/Necrosis Induction

The induction of apoptosis and necrosis was investigated by using a flow-cytometric annexin V-FITC/propidium iodide (PI) double staining assay in the colon cancer cell line SW480. Four different concentrations (2.5, 10, 40, and 160 µM) (

Table 3. Determination of apoptosis and necrosis induction by means of flow-cytometric annexin V/PI assays in SW480 colon cancer cells of selected platinum(IV) complexes (results from three independent experiments, 24 h exposure).

Sample	Concentration [µM]	Viable Cells [%]	Early Apoptotic Cells [%]	Late Apoptotic Cells [%]	Necrotic Cells [%]
11a	40	95.9 ± 0.4	1.1 ± 0.5	1.8 ± 0.7	1.3 ± 0.6
	160	96.2 ± 0.4	0.7 ± 0.1	2.0 ± 0.2	1.2 ± 0.5
11b	40	94.2 ± 3.4	1.5 ± 1.0	3.0 ± 2.1	1.2 ± 0.4
	160	91.9 ± 5.7	0.9 ± 0.5	5.8 ± 4.8	1.5 ± 0.7
11e	40	96.0 ± 0.2	0.7 ± 0.1	2.3 ± 0.5	1.0 ± 0.5
	160	88.8 ± 0.9	1.1 ± 0.3	8.1 ± 1.3	2.0 ± 0.5
12b	40	96.6 ± 0.5	1.2 ± 0.3	1.6 ± 0.1	0.6 ± 0.5
	160	93.8 ± 0.2	1.0 ± 0.2	3.8 ± 0.5	1.4 ± 0.4
12c/12c*	40	97.7 ± 0.4	0.5 ± 0.1	1.3 ± 0.3	0.5 ± 0.1
	160	60.4 ± 18.1	0.9 ± 0.4	35.2 ± 18.3	3.5 ± 0.2
12d/12d*	40	98.0 ± 0.2	0.4 ± 0.2	1.2 ± 0.1	0.4 ± 0.1
	160	40.0 ± 17.2	0.6 ± 0.1	54.1 ± 16.9	5.3 ± 2.1
12e/12e*	40	96.7 ± 0.7	0.6 ± 0.1	1.9 ± 0.5	0.8 ± 0.1
	160	21.1 ± 8.2	0.8 ± 0.4	71.1 ± 9.6	6.9 ± 1.8
13d	40	96.1 ± 0.3	1.3 ± 0.1	1.9 ± 0.4	0.7 ± 0.2
	160	96.0 ± 0.6	0.9 ± 0.3	2.2 ± 0.3	0.8 ± 0.1
14c	40	94.4 ± 3.0	1.5 ± 0.9	3.1 ± 2.0	1.1 ± 0.3
	160	72.7 ± 7.5	2.0 ± 0.5	22.6 ± 7.3	2.6 ± 1.0
14d	40	94.9 ± 1.6	1.3 ± 0.3	2.8 ± 0.9	1.0 ± 0.7
	160	79.8 ± 4.1	1.3 ± 0.3	16.4 ± 4.6	2.4 ± 0.6
14e	40	81.1 ± 6.1	3.6 ± 0.8	12.3 ± 4.6	3.0 ± 0.9
	160	80.5 ± 1.7	2.1 ± 0.3	15.3 ± 2.4	2.1 ± 0.7
15d	40	98.4 ± 0.2	0.4 ± 0.0	0.8 ± 0.1	0.4 ± 0.1
	160	98.4 ± 0.1	0.3 ± 0.0	0.7 ± 0.1	0.5 ± 0.1
16d	40	90.6 ± 1.5	1.0 ± 0.1	4.6 ± 0.7	3.8 ± 0.9
	160	85.4 ± 6.3	1.1 ± 0.4	8.5 ± 4.0	5.0 ± 2.8

, Supplementary Materials Table S28 and Figures S137–S141) of a diverse selection of complexes representing a broad range of cytotoxic activities (cf. Table 2) were chosen for studying apoptosis induction.

Comparing lipophilicity and the induction of apoptosis, the same overall trend was observable for the late apoptotic fraction of the chosen compounds, especially for the highest tested concentration: 12 > 14 > 16 ≈ 11 > 13 > 15. Additionally, the obtained results suggest structure–activity relationships of the combination of am(m)ine and trifluoropropanoato as well as acetato and propanoato ligands.

Furthermore, the diversity in cytotoxic potencies is reflected in the results of this assay: whereas compounds 11a, 12b, 13d and 15d showed no apoptotic or necrotic effects at all compared to untreated SW480 cells, marginally increased late apoptotic (<10%) or necrotic cells (up to 5%) could be demonstrated for 11b and 11e as well as for 16d. Intriguingly, 12c/12c*–12e/12e* and 14c–14e markedly enhanced the number of apoptotic cells, accompanied by minor necrosis induction (between 2% and 7%). A high incidence of late apoptotic cells (ranging from 35% up to 71% for the highest concentration tested) could be observed for 12c/12c*–12e/12e*, while 15% to 23% late apoptosis was induced by 160 µM of 14c-e, strongly suggesting a superior impact of the former compound series. These complexes differ by comprising either one (14c–14e) or two trifluoropropanoato ligands (12c/12c*–12e/12e*) in equatorial trans positions. Structures within each of these series differ by the grade of methylation on the amine ligand trans to cyclopentylamine. The higher the methylation grade, the higher the number of apoptotic cells induced by the former series: 12c/12c* < 12d/12d* < 12e/12e*. For the latter series, rather, the opposite trend can be observed: while the complex with a dimethylated amine (14e) resulted in levels of 15% late apoptotic cells, the non-methylated analogue (14c) induced 23% late apoptosis.

The following trends can be discerned from this set of complexes: for axial positions, propanoato ligands seem to be preferable to acetato ligands (16d > 15d). For equatorial positions, cyclopentylamine together with an am(m)ine may result in stronger effects than two single am(m)ine ligands (acetato complexes: 11e ≈ 11b, propanoato complexes: 12e/12e* > 12b). Furthermore, increasing amounts of trifluoropropanoato ligands seem to be favourable (12d/12d* > 14d > 16d), and the effects of the methylation of one am(m)ine ligand strongly depend on the other ligands (12e/12e* > 12d > 12c but 14e < 14d < 14c).

3. Materials and Methods

3.1. Materials

All chemicals were obtained from commercial suppliers and used as received. The following chemicals were used for the synthesis: K₂[PtCl₄] (Assay: 46.69% Pt) (Johnson Matthey, Zurich, Switzerland), methylamine (40% in water) (Merck, Hohenbrunn, Germany), dimethylamine (40% in water) (Sigma Aldrich, Steinheim, Germany), cyclopentylamine (99%) (Sigma Aldrich, Steinheim, Germany), potassium iodide (99%) (Fisher Scientific, Loughborough, UK), Ag₂SO₄ (≥99.5%) (Sigma Aldrich, Steinheim, Germany), Ba(OH)₂∙8H₂O (Emsure^®) (Merck, Darmstadt, Germany), acetic acid (99%) (Acros Organics, Geel, Belgium), acetic anhydride (≥97.0%) (Fisher Scientific, Schwerte, Germany), propionic anhydride (>98.0%) (TCI, Zwijndrecht, Belgium), CF₃CH₂COOH (98%) (Sigma Aldrich, Steinheim, Germany), and hydrogen peroxide (30% in water) (VWR Chemicals, Leuven, Belgium).

Aqueous solutions and RP-HPLC runs were conducted with Milli-Q water (18.2 MΩ cm, Milli-Q Advantage). Reactions containing platinum complexes were performed under the absence of light and with glass-coated magnetic stirring bars.

3.2. NMR Spectroscopy

NMR measurements were conducted with a Bruker Avance NEO 500 MHz NMR spectrometer or Bruker Avance III HD 700 MHz NMR spectrometer at 500.32 (¹H), 125.81 (¹³C), 50.70 (¹⁵N), 470.56 or 659.03 (¹⁹F), and 107.55 MHz (¹⁹⁵Pt) in d₆-acetone, d₆-DMSO, or d₇-DMF at 298 K. ¹H and ¹³C NMR spectra were measured relative to the solvent resonances (d₆-acetone: δ = 2.05 ppm (¹H), δ = 29.92(¹³C); d₆-DMSO: δ = 2.50 ppm (¹H), δ = 39.51 ppm (¹³C); d₇-DMF: 2.75 ppm (high field signal, ¹H), 29.8 ppm (high field signal, ¹³C). ¹⁵N, ¹⁹F, and ¹⁹⁵Pt NMR spectra were measured relative to NH₄Cl, CCl₃F, and K₂[PtCl₄], respectively.

3.3. Preparative RP-HPLC

Preparative RP-HPLC was performed with an Agilent 1200 Series system using an XBridge^® Prep C18 10 µm OBD^TM Column (19 mm × 250 mm) from Waters. Different mixtures of Milli-Q water and acetonitrile adding 0.1% formic acid were used as solvents.

3.4. Elemental Analysis

The Microanalytical Laboratory of the Faculty of Chemistry of the University of Vienna performed the elemental analysis (C, H, N) of all platinum(IV) complexes with a Eurovector EA3000 elemental analyser.

3.5. ESI-MS

High-resolution electrospray ionisation mass spectra were collected with a Bruker maXis ESI-QqTOF (electrospray ionisation quadrupole-quadrupole-time-of-flight) spectrometer in the positive mode, using a mixture of acetonitrile, methanol, and 1% H₂O as solvent.

3.6. Lipophilicity

The lipophilicity parameter log k_w of all substances was determined by means of reversed-phase UHPLC using three different isocratic runs. Different mixtures of methanol and Milli-Q water with 0.1% formic acid added (range between 10% and 65% methanol) served as solvents, whereas a reversed-phase Acquity BEH C18 column from Waters was used as a stationary phase. The dead volume was detected by a potassium iodide solution (0.3 mM), and 0.5 mM solutions of samples in a methanol/water mixture (1:9) were prepared and filtered through 0.45 µm nylon filters (Minisart RC 25, Sartorius AG, Göttingen, Germany). The runs were conducted with a flow rate of 0.6 mL/min, 10 µL injection volume at a column temperature of 25 °C, and UV-vis detection at 210, 230, 252, and 318 nm. The following equation was used for the calculation:

k′ = (t_R − t₀)/t₀

(1)

k′ is the capacity factor which is the partition of a substance between the stationary and mobile phase, t_R is the retention time of the sample, t₀ is the retention time of the dead volume sample. The linear range of k′ factors is 0.5 < log k′ < 1.5. The lipophilicity factor log k_w is the y-intercept of the linear graph of log k′ (x-axis) and methanol concentration (y-axis) [30].

3.7. Reduction Behaviour

The reduction behaviour of selected platinum(IV) complexes was observed by ¹H NMR spectroscopy at 298 K. The compounds (1 mM) were dissolved in a D₂O phosphate-buffered solution (50 mM) at a pD of 7.4. Afterwards, ascorbic acid was added (25 mM) and ¹H NMR spectra were measured for three days. For compounds 11b, 11d, 11e, 15a, and 15c, the decreased intensity of the acetato signal was analysed, whereas for 12b, 14e, and 16e, the change in the quartet of the propanoato and/or CH₂CF₃ ligand was monitored.

3.8. Cytotoxicity Tests

The MTT assay (96 h exposure time) was conducted as described in [25]. The following three human cancer cell lines were used: adherent CH1/PA-1 ovarian teratocarcinoma cells (provided by L. R. Kelland, CRC Centre for Cancer Therapeutics, Institute of Cancer Research, Sutton, UK; confirmed by STR profiling as PA-1 cells at Multiplexion, Heidelberg, Germany), SW480 colon carcinoma, and A549 non-small-cell lung cancer cells (both provided by the Institute of Cancer Research, Department of Medicine I, Medical University of Vienna, Austria).

3.9. Apoptosis/Necrosis Induction

Apoptosis and necrosis were quantitatively analysed via flow cytometry using double staining with FITC-conjugated annexin V (eBioscience, San Diego, CA, USA) and propidium iodide (PI, 1.0 mg/mL). SW480 cells were seeded into 48-well plates (7 × 10⁴ cells/well) in 600 µL aliquots and allowed to settle for 24 h. Then, cells were incubated with different concentrations (prepared from 100% DMSO stock solutions) of the respective compound for 24 h. After treatment, the supernatant was removed, and cells were washed once with PBS. The washing solution was collected, and cells were trypsinized for 5 min at 37 °C. Trypsinization was stopped by adding supplemented MEM, and the cell suspension was added to the PBS previously collected. Cells were centrifuged for 3 min at 300× g. Afterwards, the supernatant was removed, and the cell pellet was resuspended in 150 µL binding buffer (10 mM HEPES/NaOH pH 7.4, 140 mM NaCl and 2.5 mM CaCl₂ × 2H₂O) with 1.5 µL FITC-conjugated annexin V and incubated for 15 min at 37 °C. A total of 1 µL of propidium iodide in 150 µL binding buffer was added shortly before flow-cytometric analysis using a Guava easyCyte 8HT (Merck Millipore, Burlington, MA, USA) instrument with the InCyte module of guavaSoft 3.1.1. software. The results of at least three independent experiments were evaluated by using FlowJo software 10.6.1 (TreeStar, Ashland, OR, USA).

3.10. Synthesis

3.10.1. General Procedure 1: Synthesis of Trans-Configured Diaminedichloridoplatinum(II) Complexes

The synthesis was adapted from a previously published procedure from our group [16]. (SP-4-2)-diamminedichloridoplatinum(II), (SP-4-2)-dichloridobis(methylamine)platinum(II), or (SP-4-2)-dichloridobis(dimethylamine)platinum(II) were suspended in H₂O and the corresponding methylamine, dimethylamine, or cyclopentylamine was added. The reaction mixture was stirred at 50 °C until complete dissolution. Afterwards, concentrated HCl was added, and the solution was refluxed overnight. The precipitates were collected via filtration and dried under reduced pressure.

1.

(SP-4-1)-Amminedichloridomethylamineplatinum(II) (1a)

General procedure 1. (SP-4-2)-diamminedichloridoplatinum(II) (909 mg, 3.03 mmol, 1 eq) in H₂O (25 mL), methylamine (40%, 1.073 mL, 12.72 mmol, 4.2 eq), concentrated HCl (6.5 mL). Yield: 635 mg (67%). ¹H NMR (d₆-acetone): δ = 3.98 (b, 2H, NH₂), 3.38 (b, 3H, NH₃), 2.43 (t, ³J(¹H, ¹H) = 6.4 Hz, 3H, NH₂CH₃) ppm.

2.

(SP-4-1)-Amminedichloridodimethylamineplatinum(II) (1b)

General procedure 1. (SP-4-2)-diamminedichloridoplatinum(II) (2.887 g, 9.62 mmol, 1 eq) in H₂O (100 mL), dimethylamine (40%, 5.118 mL, 40.41 mmol, 4.2 eq), concentrated HCl (17.6 mL). Yield: 2.2517 g (71%). ¹H NMR (d₆-acetone): δ = 4.55 (b, 1H, NH), 3.38 (b, 3H, NH₃), 2.57 (d, ²J(¹H, ¹H) = 5.9 Hz, 6H, NHCH₃) ppm.

3.

(SP-4-1)-Amminedichloridocyclopentylamineplatinum(II) (1c)

General procedure 1. (SP-4-2)-diamminedichloridoplatinum(II) (1.007 g, 3.36 mmol, 1 eq) in H₂O (10 mL), cyclopentylamine (1.4 mL, 14.10 mmol, 4.2 eq), concentrated HCl (4.0 mL). Yield: 1.051 g (85%). ¹H NMR (d₆-acetone): δ = 3.98 (b, 2H, NH₂), 3.44–3.52 (m, 1H, CH) (in part overlapping with NH₃ signal), 3.39 (b, 3H, NH₃), 1.98–2,04 (m, 2H, cpa) (in part overlapping with acetone signal), 1.68–1.81 (m, 4H, cpa), 1.51–1.61 (m, 2H, cpa) ppm.

4.

(SP-4-1)-Dichloridocyclopentylaminemethylamineplatinum(II) (1d)

General procedure 1. (SP-4-2)-dichloridobis(methylamine)platinum(II) (1.573 g, 4.79 mmol, 1 eq) in H₂O (50 mL), cyclopentylamine (2.0 mL, 20.13 mmol, 4.2 eq), concentrated HCl (9.5 mL). Yield: 1.158 g (63%). ¹H NMR (d₆-acetone): δ = 3.93 (b, 4H, NH₂), 3.39–3.50 (m, 1H, CH), 2.41 (t, ³J(¹H, ¹H) = 6.4 Hz, 3H, NH₂CH₃), 1.97–2.03 (m, 2H, cpa) (in part overlapping with acetone signal), 1.68–1.80 (m, 4H, cpa), 1.51–1.61 (m, 2H, cpa) ppm.

5.

(SP-4-1)-Dichloridocyclopentylaminedimethylamineplatinum(II) (1e)

General procedure 1. (SP-4-2)-dichloridobis(dimethylamine)platinum(II) (3.088 g, 8.67 mmol, 1 eq) in H₂O (50 mL), cyclopentylamine (3.6 mL, 36.41 mmol, 4.2), concentrated HCl (18.5 mL). Yield: 2.576 g (75%). ¹H NMR (d₆-acetone): δ = 4.48 (b, 1H, NH), 3.93 (2, 2H, NH₂), 3.42 (m, 1H, CH), 2.55 (d, ²J(¹H, ¹H) = 5.9 Hz, 6H, NHCH₃), 1.98–2.04 (m, 2H, cpa), 1.68–1.80 (m, 4H, cpa), 1.52–1.62 (m, 2H, cpa) ppm.

3.10.2. General Procedure 2: Synthesis of Trans-Configured Diaminediiodidoplatinum(II) Complexes

The corresponding trans-dichloridoplatinum(II) complex dissolved in acetone was stirred for a few hours in the presence of potassium iodide at room temperature. Water was added and acetone was evaporated. The product precipitated, and was filtered off and dried in vacuum [16].

1.

(SP-4-1)-Amminediiodidomethylamineplatinum(II) (2a)

General procedure 2. 1a (657 mg, 2.09 mmol, 1 eq) in acetone (300 mL), potassium iodide (868 mg, 5.23 mmol, 2.5 eq). Yield: 972 mg (94%). ¹H NMR (d₆-acetone): δ = 3.97 (b, 2H, NH₂), 3.44 (b, 3H, NH₃), 2.51 (t, ³J(¹H, ¹H) = 6.3 Hz, 3H, NH₂CH₃) ppm. ¹³C NMR (d₆-acetone): δ = 35.0 (NH₂CH₃) ppm. ¹⁵N (d₆-acetone): δ = −83.0 (NH₃), −75.2 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-acetone): δ = −1737 ppm.

2.

(SP-4-1)-Amminedimethylaminediiodidoplatinum(II) (2b)

General procedure 2. 1b (624 mg, 1.90 mmol, 1eq) in acetone (300 mL), potassium iodide (789 mg, 4.75 mmol, 2.5 eq). Yield: 736 mg (76%). ¹H NMR (d₆-acetone): δ = 4.47 (b, 1H, NH), 3.45 (b, 2H, NH₂), 2.69 (d, ²J(¹H, ¹H) = 6.0 Hz, 6H, NHCH₃) ppm. ¹³C NMR (d₆-acetone): δ = 46.6 (NHCH₃) ppm. ¹⁵N (d₆-acetone): δ = −64.6 (NH), −85.6 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-acetone): δ = −1595 ppm.

3.

(SP-4-1)-Amminecyclopentylaminediiodidoplatinum(II) (2c)

General procedure 2. 1c (2.923 g, 7.94 mmol, 1 eq) in acetone (300 mL), potassium iodide (3.295 g, 19.85 mmol, 2.5 eq). Yield: 4.273 g (98%). ¹H NMR (d₆-acetone): δ = 3.98 (b, 2H, NH₂), 3.66 (m, 1H, CH), 3.46 (b, 3H, NH₃), 1.91–1.99 (m, 2H, cpa), 1.68–1.80 (m, 4H, cpa), 1.52–1.61 (m, 2H, cpa) ppm. ¹³C NMR (d₆-acetone): δ = 61.0 (CH), 34.6 (cpa), 24.1 (cpa) ppm. ¹⁵N (d₆-acetone): δ = −22.1 (NH₂), −59.6 (NH₃) ppm. ¹⁹⁵Pt NMR (d₆-acetone): δ = −1733 ppm.

4.

(SP-4-1)-Cyclopentylaminediiodidomethlamineplatinum(II) (2d)

General procedure 2. 1d (875 mg, 2.29 mmol, 1 eq) in acetone (200 mL), potassium iodide (950 mg, 5.72 mmol, 2.5 eq). Yield: 1.202 g (93%). ¹H NMR (d₆-acetone): δ = 3.93 (b, 4H, NH₂), 3.62 (m, 1H, CH), 2.49 (t, ³J(¹H, ¹H) = 6.3 Hz, 3H, NH₂CH₃), 1.90–1.99 (m, 2H, cpa), 1.67–1.79 (m, 4H, cpa), 1.52–1.62 (m, 2H, cpa) ppm. ¹³C NMR (d₆-acetone): δ = 60.9 (CH), 34.7 (cpa), 34.7 (NH₂CH₃), 24.1 (cpa) ppm. ¹⁵N (d₆-acetone): δ = −74.9 (NH₂), −44.5 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-acetone): δ = −1725 ppm.

5.

(SP-4-1)-Cyclopentylaminedimethylaminediiodidoplatinum(II) (2e)

General procedure 2. 1e (1.635 g, 4.13 mmol, 1 eq) in acetone (100 mL), potassium iodide (1.713 g, 10.32 mmol, 2.5 eq). Yield: 2.345 g (98%). ¹H NMR (d₆-acetone): δ = 4.43 (b, 1H, NH), 3.96 (b, 2H, NH₂), 3.61 (m, 1H, CH), 2.67 (d, ²J(¹H, ¹H) = 5.9 Hz, 6H, NHCH₃), 1.89–1.99 (m, 2H, cpa), 1.67–1.79 (m, 4H, cpa), 1.52–1.62 (m, 2H, cpa) ppm. ¹³C NMR (d₆-acetone): δ = 61.0 (CH), 46.4 (CH₃), 34.7 (cpa), 24.1 (cpa) ppm. ¹⁵N (d₆-acetone): δ = −93.6 (NH), −77.1 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-acetone): δ = −1575 ppm.

3.10.3. General Procedure 3: Synthesis of Trans-Configured Diamineplatinum(ii) Complexes Featuring Two Acetato, Propanoato, or 3,3,3-Trifluoropropanoato Ligands

The synthesis was adapted from a previously published procedure from our group [25]. The corresponding trans-diiodidoplatinum(II) complex was suspended in H₂O and stirred overnight with Ag₂SO₄ at room temperature. The formed AgI was filtered off by means of celite. The filtrate was added to a solution Ba(OH)₂∙8H₂O in H₂O and acetic acid, propionic anhydride, or CF₃CH₂COOH, and stirred overnight. BaSO₄ was removed and the slightly yellow powder was obtained via freeze drying. The crude product was used for further reactions without purification.

1.

(SP-4-1)-Amminemethylaminebis(3,3,3-trifluoropropanoato)platinum(II) (3a)

General procedure 3. 2a (1.479 g, 2.98 mmol, 1 eq) in H₂O (25 mL), Ag₂SO₄ (881 mg, 2.83 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (892 mg, 2.83 mmol, 0.95 eq), CF₃CH₂COOH (599 µL, 5.65 mmol, 1.9 eq). Yield: 1.274 g (impure).

2.

(SP-4-1)-Amminedimethylaminebis(3,3,3-trifluoropropanoato)platinum(II) (3b)

General procedure 3. 2b (2.053 g, 4.02 mmol, 1 eq) in H₂O (25 mL), Ag₂SO₄ (1.190 g, 3.82 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (1.204 g, 3.82 mmol, 0.95 eq), CF₃CH₂COOH (674 µL, 7.63 mmol, 1.9 eq). Yield: 1.996 g (impure).

3.

(SP-4-1)-Amminecyclopentylaminebis(3,3,3-trifluoropropanoato)platinum(II) (3c)

General procedure 3. 2c (645 mg, 1.17 mmol, 1 eq) in H₂O (10 mL), Ag₂SO₄ (347 mg, 1.11 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (351 mg, 1.11 mmol, 0.95 eq), CF₃CH₂COOH (197 µL, 2.23 mmol, 1.9 eq). Yield: 594 mg (impure).

4.

(SP-4-1)-Cyclopentylaminemethylaminebis(3,3,3-trifluoropropanoato)platinum(II) (3d)

General procedure 3. 2d (946 mg, 1.68 mmol, 1 eq) in H₂O (10 mL), Ag₂SO₄ (496 mg, 1.59 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (502 mg, 1.59 mmol, 0.95 eq), CF₃CH₂COOH (281 µL, 3.18 mmol, 1.9 eq). Yield: 891 mg (impure).

5.

(SP-4-1)-Cyclopentylaminedimethylaminebis(3,3,3-trifluoropropanoato)platinum(II) (3e)

General procedure 3. 2e (1.233 g, 2.13 mmol, 1 eq) in H₂O (25 mL), Ag₂SO₄ (631 mg, 2.02 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (638 mg, 2.02 mmol, 0.95 eq), CF₃CH₂COOH (357 µL, 4.05 mmol, 1.9 eq). Yield: 1.181 g (impure).

6.

(SP-4-2)-Acetatoamminedimethylamine(3,3,3-trifluoropropanoato)platinum(II) (5b)

General procedure 3. 2b (261 mg, 0.51 mmol, 1 eq) in H₂O (25 mL), Ag₂SO₄ (151 mg, 0.49 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (153 mg, 0.49 mmol, 0.95 eq), CF₃CH₂COOH (43 µL, 0.49 mmol, 0.95 qu), CH₃COOH (28 µL, 0.49 mmol, 0.95 eq). Yield: 223 mg (impure).

7.

(SP-4-1)-Diacetatoamminemethylamineplatinum(II) (7a)

General procedure 3. 2a (374 mg, 0.75 mmol, 1 eq) in H₂O (25 mL), Ag₂SO₄ (223 mg, 0.71 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (225 mg, 0.71 mmol, 0.95), CH₃COOH (82 µL, 1.43 mmol, 1.9 eq). Yield: 281 mg (impure).

8.

(SP-4-1)-Diacetatoamminedimethylamineplatinum(II) (7b)

General procedure 3. 2b (280 mg, 0.55 mmol, 1 eq) in H₂O (25 mL), Ag₂SO₄ (162 mg, 0.52 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (164 mg, 0.52 mmol, 0.95 eq), CH₃COOH (69 µL, 1.21 mmol, 2.2 eq). Yield: 210 mg (impure).

9.

(SP-4-1)-Diacetatoamminecyclopentylamineplatinum(II) (7c)

General procedure 3. 2c (435 mg, 0.79 mmol) in H₂O (30 mL), Ag₂SO₄ (234 mg, 0.75 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (237 mg, 0.75 mmol, 0.95 eq), CH₃COOH (86 µL, 1.50 mmol, 1.9 eq). Yield: 346 mg (impure).

10.

(SP-4-1)-Diacetatocyclopentylaminemethylamineplatinum(II) (7d)

General procedure 3. 2d (263 mg, 0.47 mmol) in H₂O (25 mL), Ag₂SO₄ (138 mg, 0.44 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (140 mg, 0.44 mmol, 0.95 eq), CH₃COOH (51 µL, 1.05 mmol, 1.9 eq). Yield: 190 mg (impure).

11.

(SP-4-1)-Diacetatocyclopentylaminedimethylamineplatinum(II) (7e)

General procedure 3. 2e (318 mg, 0.55 mmol) in H₂O (50 mL), Ag₂SO₄ (163 mg, 0.52 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (165 mg, 0.52 mmol, 0.95 eq), CH₃COOH (60 µL, 1.04 mmol, 1.9 eq). Yield: 272 mg (impure).

12.

(SP-4-1)-Amminemethylaminedipropanoatoplatinum(II) (8a)

General procedure 3. 2a (597 mg, 1.20 mmol, 1 eq) in H₂O (25 mL), Ag₂SO₄ (356 mg, 1.14 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (360 mg, 1.14 mmol, 0.95), propionic anhydride (147 µL, 1.14 mmol, 0.95 eq). Yield: 481 mg (impure).

13.

(SP-4-1)-Amminedimethylaminedipropanoatoplatinum(II) (8b)

General procedure 3. 2b (322 mg, 0.63 mmol, 1 eq) in H₂O (30 mL), Ag₂SO₄ (187 mg, 0.60 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (190 mg, 0.60 mmol, 0.95), propionic anhydride (77 µL, 60 mmol, 0.95 eq). Yield: 212 mg (impure).

14.

(SP-4-1)-Amminecyclopentylaminepropanoatoplatinum(II) (8c)

General procedure 3. 2c (315 mg, 0.57 mmol, 1 eq) in H₂O (30 mL), Ag₂SO₄ (170 mg, 0.54 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (172 mg, 0.54 mmol, 0.95), propionic anhydride (70 µL, 1.47 mmol, 0.95 eq). Yield: 239 mg (impure).

15.

(SP-4-1)-Cyclopentylaminemethylaminedipropanoatoplatinum(II) (8d)

General procedure 3. 2d (325 mg, 0.58 mmol, 1 eq) in H₂O (30 mL), Ag₂SO₄ (170 mg, 0.55 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (172 mg, 0.55 mmol, 0.95), propionic anhydride (70 µL, 0.55 mmol, 0.95 eq). Yield: 268 mg (impure).

16.

(SP-4-1)-Cyclopentylaminedimethylaminedipropanoatoplatinum(II) (8e)

General procedure 3. 2e (291 mg, 0.50 mmol, 1 eq) in H₂O (50 mL), Ag₂SO₄ (149 mg, 0.48 mmol, 0.95 eq), Ba(OH)₂∙8H₂O (150 mg, 0.48 mmol, 0.95), propionic anhydride (61 µL, 0.48 mmol, 0.95 eq). Yield: 215 mg (impure).

3.10.4. General Procedure 4: Oxidation of Pt(II) Complexes

A suspension of the corresponding Pt(II) complex in water and hydrogen peroxide (30%) was stirred overnight at room temperature. The crude product was obtained via lyophilisation and used for further reactions. CAUTION: Although we have experienced no problems in handling aqueous H₂O₂ solutions, such solutions should be handled with care and in small quantities. Uncontrolled heating must be avoided. Under no conditions should (ambient pressure) distillation at elevated temperature be attempted because of the danger of violent explosions without warning. Mixtures of aqueous H₂O₂ solutions with organic solvents are critical (formation of peroxides) and should be avoided. Depending on pH, temperature, and other conditions, such mixtures tend to decompose with considerable force or may explode upon heating even in the absence of metals.

1.

(OC-6-12)-Amminedihydroxidomethylaminebis(3,3,3-trifluoropropanoato)platinum(IV) (4a)

General procedure 4. 3a (1.274 g, impure) in H₂O (100 mL), H₂O₂ (30%, 10 mL). Yield: 1.126 g (impure).

2.

(OC-6-12)-Amminedimethylaminedihydroxidobis(3,3,3-trifluoropropanoato)platinum(IV) (4b)

General procedure 4. 3b (1.996 g, impure) in H₂O (100 mL), H₂O₂ (30%, 10 mL). Yield: 1.981 g (impure).

3.

(OC-6-12)-Amminecyclopentylaminedihydroxidobis(3,3,3-trifluoropropanoato)platinum(IV) (4c)

General procedure 4. 3c (594 mg, impure) in H₂O (25 mL), H₂O₂ (30%, 1 mL). Yield: 552 mg (impure).

4.

(OC-6-12)-Cyclopentylaminedihydroxidomethylaminebis(3,3,3-trifluoropropanoato)platinum(IV) (4d)

General procedure 4. 3d (891 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 1 mL). Yield: 865 mg (impure).

5.

(OC-6-12)-Cyclopentylaminedimethylaminedihydroxidobis(3,3,3-trifluoropropanoato)platinum(IV) (4e)

General procedure 4. 3e (1.114 g, impure) in H₂O (100 mL), H₂O₂ (30%, 10 mL). Yield: 1.018 g (impure).

6.

(OC-6-23)-Acetatoamminedimethylaminedihydroxido(3,3,3-trifluoropropanoato)platinum(IV) (6b)

General procedure 4. 5b (223 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 0.5 mL). Yield: 204 mg (impure).

7.

(OC-6-12)-Diacetatoammindihydroxidomethylaminplatinum(IV) (9a)

General procedure 4. 7a (281 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 0.5 mL). Yield: 268 mg (impure).

8.

(OC-6-12)-Diacetatoammindimethylamindihydroxidoplatinum(IV) (9b)

General procedure 4. 7b (210 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 0.5 mL). Yield: 198 mg (impure).

9.

(OC-6-12)-Diacetatoamminecyclopentylaminedihydroxidoplatinum(IV) (9c)

General procedure 4. 7c (346 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 1 mL). Yield: 321 mg (impure).

10.

(OC-6-12)-Diacetatocyclopentylaminemethylaminedihydroxidoplatinum(IV) (9d)

General procedure 4. 7d (190 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 0.5 mL). Yield: 167 mg (impure).

11.

(OC-6-12)-Diacetatocyclopentylaminedimethylaminedihydroxidoplatinum(IV) (9e)

General procedure 4. 7e (272 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 1 mL). Yield: 252 mg (impure).

12.

(OC-6-12)-Amminedihydroxidomethylaminedipropanoatoplatinum(IV) (10a)

General procedure 4. 8a (481 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 1 mL). Yield: 421 mg (impure).

13.

(OC-6-12)-Amminedimethylaminedihydroxidodipropanoatoplatinum(IV) (10b)

General procedure 4. 8b (212 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 1 mL). Yield: 208 mg (impure).

14.

(OC-6-12)-Amminecyclopentylaminedihydroxidodipropanoatoplatinum(IV) (10c)

General procedure 4. 8c (239 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 1 mL). Yield: 224 mg (impure).

15.

(OC-6-12)-Cyclopentylaminedihydroxidomethylaminedipropanoatoplatinum(IV) (10d)

General procedure 4. 8d (268 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 1 mL). Yield: 226 mg (impure).

16.

(OC-6-12)-Cyclopentylaminedimethylaminedihydroxidodipropanoatoplatinum(IV) (10e)

General procedure 4. 8e (215 mg, impure) in H₂O (20 mL), H₂O₂ (30%, 1 mL). Yield: 153 mg (impure).

3.10.5. General Procedure 5: Carboxylation of Dihydroxidoplatinum(IV) Complexes

The corresponding dihydroxidoplatinum(IV) complex was stirred overnight under argon atmosphere in acetic anhydride or propionic anhydride at room temperature. The solvent was removed under reduced pressure and the crude product was purified via preparative RP-HPLC. The final product was obtained via lyophilisation.

1.

(OC-6-12)-Diacetatoamminemethylaminebis(3,3,3-trifluoropropanoato)platinum(IV) (11a)

General procedure 5. 4a (740 mg, impure) in acetic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 25:75 + 0.1% formic acid). Yield: 151 mg. Elemental analysis: C₁₁H₁₈F₆N₂O₈Pt; calcd. C 21.47, H 2.95, N 4.55, found C 21.19, H 2.87, N 4.60. ¹H NMR (d₇-DMF): δ = 7.28 (b, 2H, NH₂), 6.86 (t, ¹J(¹⁴N, ¹H) = 54.0 Hz, 3H, NH₃), 3.44 (q, ³J(¹⁹F, ¹H) = 11.1 Hz, 4H, CH₂CF₃), 2.25 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 1.94 (s, 6H, CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 178.1 ((C=O)CH₃), 170.8 (q, ³J(¹⁹F, ¹³C) = 4.2 Hz, (C=O)CH₂CF₃), 124.9 (q, ¹J(¹⁹F,¹³C) = 275.5 Hz, CF₃), 39.3 (q, ²J(¹⁹F,¹³C) = 29.0 Hz, CH₂CF₃), 28.0 (NH₂CH₃), 21.9 (CH₃) ppm. ¹⁵N (d₇-DMF): δ = −46.7 (NH₃), 32.5 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.7 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3931 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 638.05 [M + Na⁺]⁺.

2.

(OC-6-12)-Diacetatoamminedimethylaminebis(3,3,3-trifluoropropanoato)platinum(IV) (11b)

General procedure 5. 4b (1.037 g, impure) in acetic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 25:75 + 0.1% formic acid). Yield: 326 mg. Elemental analysis: C₁₂H₂₀F₆N₂O₈Pt∙H₂O; calcd. C 22.26, H 3.43, N 4.33, found C 22.34, H 3.08, N 4.47. ¹H NMR (d₇-DMF): δ = 7.81(b, 2H, NH), 7.13 (t, ¹J(¹⁴N, ¹H) = 54.4 Hz, 3H, NH₃), 3.47 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 4H, CH₂CF₃), 2.42 (d, ²J(¹H, ¹H) = 5.8 Hz, 6H, NHCH₃), 1.96 (s, 6H, CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 177.9 ((C=O)CH₃), 170.8 (q, ³J(¹⁹F,¹³C) = 4.2 Hz, (C=O)CH₂CF₃), 125.0 (q, ¹J(¹⁹F,¹³C) = 275.0 Hz, CF₃), 39.69 (q, ²J(¹⁹F,¹³C) = 29.1 Hz, CH₂CF₃), 39.65 (NHCH₃), 22.1 (CH₃) ppm. ¹⁵N (d₇-DMF): δ = −52.4 (NH₃), −20.4 (NH) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.6 (t, ³J(¹H, ¹⁹F) = 11.0 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3949 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 652.07 [M + Na⁺]⁺.

3.

(OC-6-12)-Diacetatoamminecyclopentylaminebis(3,3,3-trifluoropropanoato)platinum(IV) (11c)

General procedure 5. 4c (549 mg, impure) in acetic anhydride (15 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 45:55 + 0.1% formic acid). Yield: 48 mg. Elemental analysis: C₁₅H₂₄F₆N₂O₈Pt; calcd. C 26.91, H 3.61, N 4.19, found C 26.65, H 3.58, N 4.28. ¹H NMR (d₇-DMF): δ = 7.40 (b, 2H, NH₂), 6.90 (t, ¹J(¹⁴N, ¹H) = 53.6 Hz, 3H, NH₃), 3.46 (q, ³J(¹⁹F, ¹H) = 11.0 Hz, 4H, CH₂CF₃), superposition of CH and CH₂CF₃ signal, 1.97–2.07 (m, 2H, cpa), 1.94 (s, 6H, CH₃), 1.70–1.84 (m, 4H, cpa), 1.54–1.64 (m, 2H, cpa) ppm. ¹³C NMR (d₇-DMF): δ = 178.3 ((C=O)CH₃), 171.1 (q, ³J(¹⁹F,¹³C) = 4.3 Hz, (C=O)CH₂CF₃), 124.8 (q, ¹J(¹⁹F,¹³C) = 275.9 Hz, CF₃), 55.3 (CH), 39.4 (q, ²J(¹⁹F,¹³C) = 29.1 Hz, CH₂CF₃), 32.5 (CH₂, cpa), 24.0 (CH₂, cpa), 22.0 (CH₃) ppm. ¹⁵N (d₇-DMF): δ = −46.6 (NH₃), −6.8 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −64.7 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3961 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 692.10 [M + Na⁺]⁺.

4.

(OC-6-12)-Diacetatocyclopentylaminemethylaminebis(3,3,3-trifluoropropanoato)platinum(IV) (11d)

General procedure 5. 4d (865 mg, impure) in acetic anhydride (40 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 45:55 + 0.1% formic acid). Yield: 73 mg. Elemental analysis: C₁₆H₂₆F₆N₂O₈Pt∙H₂O; calcd. C 27.40, H 4.02, N 3.99, found C 27.68, H 3.88, N 4.31. ¹H NMR (d₇-DMF): δ = 7.66 (b, 2H, NH₂), 7.60 (b, 2H, NH₂), superposition of CH, CH₂CF₃ and water signal), 2.22 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 1.94–2.04 (m, 2H, cpa), 1.96 (s, 6H, CH₃), 1.69–1.80 (m, 4H, cpa), 1.54–1.64 (m, 2H, cpa) ppm. ¹³C NMR (d₇-DMF): δ = 178.1 ((C=O)CH₃), 170.9 (q, ³J(¹⁹F,¹³C) = 4.4 Hz, (C=O)CH₂CF₃), 124.6 (q, ¹J(¹⁹F,¹³C) = 275.8 Hz, CF₃), 55.1 (CH), 39.3 (q, ²J(¹⁹F,¹³C) = 29.1 Hz, CH₂CF₃), 32.3 (CH₂, cpa), 28.0 (NH₂CH₃), 23.6 (CH₂, cpa), 21.8 (CH₃) ppm. ¹⁵N (d₇-DMF): δ = −38.0 (NH₂), −10.9 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.6 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3958 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 706.11 [M + Na⁺]⁺.

5.

(OC-6-12)/(OC-6-22)-Diacetatocyclopentylaminemethylaminebis(3,3,3-trifluoropropanoato)platinum(IV) (11d/11d*)

General procedure 5. 4d (599 mg, impure) in acetic anhydride (15 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 45:55 + 0.1% formic acid). Yield: 58 mg. Elemental analysis: C₁₆H₂₆F₆N₂O₈Pt; calcd. C 28.12, H 3.83, N 4.10, found C 27.81, H 3.74, N 4.07. ¹H NMR (d₆-DMSO): δ = 7.39 (b, 2H, NH₂), 7.30 (b, 2H, NH₂), 3.40 (major isomer) + 3.44 (minor isomer) (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 4H, CH₂CF₃), superposition of CH and water signal, 2.04 (t, ³J(¹H, ¹H) = 6.3 Hz, 3H, NH₂CH₃), 1.92 (minor isomer) + 19.3 (major isomer) (s, 6H, CH₃), 1.84–1.90 (m, 2H, cpa), 1.59–1.69 (m, 4H, cpa), 1.49–1.56 (m, 2H, cpa) ppm. ¹⁹F NMR (d₇-DMF): δ = -62.19 + (−62.15)(t, ³J(¹H, ¹⁹F) = 11.0 Hz, 3F, CF₃) ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 706.11 [M + Na⁺]⁺. Isomer ratio 11d:11d* = 83:17 (based on ¹H NMR spectroscopy).

6.

(OC-6-12)-Diacetatocyclopentylaminedimethylaminebis(3,3,3-trifluoropropanoato)platinum(IV) (11e)

General procedure 5. 4e (494 mg, impure) in acetic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 45:55 + 0.1% formic acid). Yield: 94 mg. Elemental analysis: C₁₇H₂₈F₆N₂O₈Pt; calcd. C 29.27, H 4.05, N 4.02, found C 28.97, H 3.96, N 3.98. ¹H NMR (d₇-DMF): δ = 8.42 (b, 2H, NH), 7.98 (b, 2H, NH₂), 3.52 (q, ³J(¹⁹F, ¹H) = 11.1 Hz, 4H, CH₂CF₃), superimposition of CH and CH₂CF₃ signal, 2.43 (d, ²J(¹H, ¹H) = 5.7 Hz, 6H, NHCH₃), 1.99 (s, 6H, CH₃), 1.94–2.02 (m, 2H, cpa), 1.67–1.76 (m, 4H, cpa), 1.55–1.63 (m, 2H, cpa) ppm. ¹³C NMR (d₇-DMF): δ = 178.3 (s, (C=O)CH₃), 171.1 (q, ³J(¹⁹F,¹³C) = 4.1 Hz, (C=O)CH₂CF₃), 125.0 (q, ¹J(¹⁹F,¹³C) = 275.5 Hz, CF₃), 56.1 (CH), 40.1 (NHCH₃), 39.7 (q, ²J(¹⁹F,¹³C) = 28.9 Hz, CH₂CF₃), 32.6 (CH₂, cpa), 23.8 (CH₂, cpa), 22.2 (CH₃) ppm. ¹⁵N (d₇-DMF): δ = −24.8 (NH), −16.3 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.5 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3987 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 720.13 [M + Na⁺]⁺.

7.

(OC-6-12)-Amminemethylaminedipropanoatobis(3,3,3-trifluoropropanoato)platinum(IV) (12a)

General procedure 5. 4a (272 mg, impure) in propionic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 40:60 + 0.1% formic acid). Yield: 37 mg. Elemental analysis: C₁₃H₂₂F₆N₂O₈Pt; calcd. C 24.27, H 3.45, N 4.35, found C 23.94, H 3.48, N 4.25. ¹H NMR (d₇-DMF): δ = 7.31 (b, 2H, NH₂), 6.89 (t, ¹J(¹⁴N, ¹H) = 53.8 Hz, 3H, NH₃), 3.43 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 4H, CH₂CF₃), 2.268 (q, ³J(¹H, ¹H) = 7.5 Hz, 4H, CH₂CH₃), 2.266 (t, ³J(¹H, ¹H) = 6.1 Hz, 3H, NH₂CH₃), 1.00 (t, ³J(¹H, ¹H) = 7.5 Hz, 6H, CH₂CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 181.4 (C=O)CH₂CH₃), 170.8 (q, ³J(¹⁹F,¹³C) = 4.2 Hz, (C=O)CH₂CF₃), 124.9 (q, ¹J(¹⁹F,¹³C) = 275.5 Hz, CF₃), 39.4 (q, ²J(¹⁹F,¹³C) = 29.0 Hz, CH₂CF₃), 29.0 (CH₂CH₃), 27.9 (NH₂CH₃), 10.1 (CH₂CH₃) ppm. ¹⁵N (d₇-DMF): δ = −46.9 (NH₃), −32.9 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.5 (t, ³J(¹H, ¹⁹F) = 11.2 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3925 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 666.08 [M + Na⁺]⁺.

8.

(OC-6-12)-Amminedimethylaminedipropanoatobis(3,3,3-trifluoropropanoato)platinum(IV) (12b)

General procedure 5. 4b (1.174 g, impure) in propionic anhydride (20 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 45:55 + 0.1% formic acid). Yield: 341 mg. Elemental analysis: C₁₄H₂₄F₆N₂O₈Pt∙H₂O; calcd. C 24.90, H 3.88, N 4.15, found C 25.15, H 3.96, N 4.35. ¹H NMR (d₇-DMF): δ = 7.84 (b, 1H, NH), 7.17 (t, ¹J(¹⁴N, ¹H) = 54.4 Hz, 3H, NH₃), 3.46 (q, ³J(¹⁹F, ¹H) = 11.1 Hz, 4H, CH₂CF₃), 2.42 (d, ³J(¹H, ¹H) = 5.8 Hz, 6H, NHCH₃), 2.28 (q, ³J(¹H, ¹H) = 7.5 Hz, 4H, CH₂CH₃), 1.01 (t, ³J(¹H, ¹H) = 7.6 Hz, 6H, CH₂CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 181.2 (C=O)CH₂CH₃), 170.7 (q, ³J(¹⁹F,¹³C) = 4.2 Hz, (C=O)CH₂CF₃), 125.0 (q, ¹J(¹⁹F,¹³C) = 276.0 Hz, CF₃), 39.68 (q, ²J(¹⁹F,¹³C) = 28.8 Hz, CH₂CF₃), 39.67 (NHCH₃), 29.2 (CH₂CH₃), 10.1 (CH₂CH₃) ppm. ¹⁵N (d₇-DMF): δ = −52.7 (NH₃), −20.6 (NH) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.6 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3942 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 680.10 [M + Na⁺]⁺.

9.

(OC-6-12)-Amminecyclopentylaminedipropanoatobis(3,3,3-trifluoropropanoato)platinum(IV) (12c)

General procedure 5. 4c (924 mg, impure) in propionic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 35:65 + 0.1% formic acid). Yield: 10 mg. ¹H NMR (d₇-DMF): δ = 7.43 (b, 2H, NH₂), 6.92 (b, 2H, NH₂), 3.44 (q, ³J(¹⁹F, ¹H) = 11.0 Hz, 2H, CH₂CF₃), superposition of CH and CH₂CF₃ signal, 2.26 (q, ³J(¹H, ¹H) = 7.4 Hz, 6H, CH₂CH₃), 1.98–2.08 (m, 2H, cpa), 171–1.86 (m, 4H, cpa), 1.54–1.64 (m, 2H, cpa), 1.00 (t, ³J(¹H, ¹H) = 7.5 Hz, 9H, CH₂CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 181.6 ((C=O)CH₂CH₃), 171.1 (q, ³J(¹⁹F,¹³C) = 4.1 Hz, (C=O)CH₂CF₃), 124.9 (q, ¹J(¹⁹F,¹³C) = 275.7 Hz, CF₃), 55.3 (CH), 39.5 (q, ²J(¹⁹F,¹³C) = 29.0 Hz, CH₂CF₃), 32.5 (CH₂, cpa), 29.1 (CH₂CH₃), 24.0 (CH₂, cpa), 10.0 (CH₂CH₃) ppm. ¹⁵N (d₇-DMF): δ = −47.3 (NH₂), −7.9 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.7 (t, ³J(¹H, ¹⁹F) = 11.2 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3964 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 720.13 [M + Na⁺]⁺.

10.

(OC-6-12)/(OC-6-22)-Amminecyclopentylaminedipropanoatobis(3,3,3-trifluoropropanoato)platinum(IV) (12c/12c*)

General procedure 5. 4c (1.801 g, impure) in propionic anhydride (15 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 35:65 + 0.1% formic acid). Yield: 117 mg. Elemental analysis: C₁₇H₂₈F₆N₂O₈Pt∙H₂O; calcd. C 28.57, H 4.23, N 3.92, found C 28.86, H 4.02, N 4.14. ¹H NMR (d₇-DMF): δ = 7.43 (b, 2H, NH₂), 6.92 (b, 2H, NH₂), 3.44 (major isomer) + 3.42 (minor isomer) (q, ³J(¹⁹F, ¹H) = 11.1 Hz, 2H, CH₂CF₃), superposition of CH and CH₂CF₃ signal, 2.28 (minor isomer) + 2.27 (major isomer) (q, ³J(¹H, ¹H) = 7.5 Hz, 6H, CH₂CH₃), 1.98–2.08 (m, 2H, cpa), 171–1.86 (m, 4H, cpa), 1.54–1.64 (m, 2H, cpa), 1.00 (major isomer) + 0.99 (minor isomer) (t, ³J(¹H, ¹H) = 7.6 Hz, 9H, CH₂CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 181.63 + 183.61 ((C=O)CH₂CH₃), 171.10 + 171.06 (q, ³J(¹⁹F,¹³C) = 4.1 Hz, (C=O)CH₂CF₃), 124.8 + 124.9 (q, ¹J(¹⁹F,¹³C) = 275.6 Hz, CF₃), 55.31 + 55.30 (CH), 39.6 + 39.5 (q, ²J(¹⁹F,¹³C) = 28.9 Hz, CH₂CF₃), 32.5 (CH₂, cpa), 29.1 + 29.0 (CH₂CH₃), 24.0 (CH₂, cpa), 10.1 (CH₂CH₃) ppm. ¹⁵N (d₇-DMF): δ = −47.3 (NH₂), −7.5 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.73 + (−63.71) (t, ³J(¹H, ¹⁹F) = 11.0 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3964 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 720.13 [M + Na⁺]⁺. Isomer ratio 12c:12c* = 64:36 (based on ¹H NMR spectroscopy).

11.

(OC-6-12)-Cyclopentylaminemethylaminedipropanoatobis(3,3,3-trifluoropropanoato)platinum(IV) (12d)

General procedure 5. 4d (980 mg, impure) in propionic anhydride (20 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 60:40 + 0.1% formic acid). Yield: 7 mg. ¹H NMR (d₇-DMF): δ = 7.71 (b, 2H, NH₂), 7.62 (b, 2H, NH₂), superposition of CH and water signal, 3.48 (q, ³J(¹⁹F, ¹H) = 11.3 Hz, 4H, CH₂CF₃), 2.29 (q, ³J(¹H, ¹H) = 7.6 Hz, 4H, CH₂CH₃), 2.23 (t, ³J(¹H, ¹H) = 6.3 Hz, 3H, NH₂CH₃), 1.95–2.05 (m, 2H, cpa), 1.69–1.80 (m, 4H, cpa), 1.55–1.65 (m, 2H, cpa), 1.01 (t, ³J(¹H, ¹H) = 7.6 Hz, 6H, CH₂CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 181.7 ((C=O)CH₂CH₃), 171.1 (q, ³J(¹⁹F,¹³C) = 4.2 Hz, (C=O)CH₂CF₃), 124.9 (q, ¹J(¹⁹F,¹³C) = 275.8 Hz, CF₃), 55.3 (CH), 39.6 (q, ²J(¹⁹F,¹³C) = 29.0 Hz, CH₂CF₃), 32.6 (CH₂, cpa), 29.3 (CH₂CH₃), 28.2 (NH₂CH₃), 23.9 (CH₂, cpa), 10.1 (CH₂CH₃) ppm. ¹⁵N (d₇-DMF): δ = −37.8 (NH₂), −11.5 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = -63.6 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3950 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 734.14 [M + Na⁺]⁺.

12.

(OC-6-12)/(OC-6-22)-Cyclopentylaminemethylaminedipropanoatobis(3,3,3-trifluoropropanoato)platinum(IV) (12d/12d*)

General procedure 5. 4d (549 mg, impure) in propionic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 60:40 + 0.1% formic acid). Yield: 46 mg. Elemental analysis: C₁₈H₃₀F₆N₂O₈Pt; calcd. C 30.39, H 4.25, N 3.94, found C 30.07, H 4.22, N 4.14. ¹H NMR (d₇-DMF): δ = 7.71 (b, 2H, NH₂), 7.63 (b, 2H, NH₂), superposition of CH and water signal, 3.48 (major isomer) +3.45 (minor isomer)(q, ³J(¹⁹F, ¹H) = 11.2 Hz, 4H, CH₂CF₃), 2.30 (minor isomer) + 2.29 (major isomer) (q, ³J(¹H, ¹H) = 7.5 Hz, 4H, CH₂CH₃), 2.234 (minor isomer) + 2.232 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 1.95–2.05 (m, 2H, cpa), 1.69–1.80 (m, 4H, cpa), 1.55–1.65 (m, 2H, cpa), 1.012 (major isomer) + 1.007 (t, ³J(¹H, ¹H) = 7.6 Hz, 6H, CH₂CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 181.7 + 181.6 ((C=O)CH₂CH₃), 171.1 (q, ³J(¹⁹F,¹³C) = 4.2 Hz, (C=O)CH₂CF₃), 125.0 + 124.9 (q, ¹J(¹⁹F,¹³C) = 275.9 Hz, CF₃), 55.34 + 55.32 (CH), 39.8 + 39.6 (q, ²J(¹⁹F,¹³C) = 29.0 Hz, CH₂CF₃), 32.6 (CH₂, cpa), 29.29 + 29.28 (CH₂CH₃), 28.2 (NH₂CH₃), 23.9 (CH₂, cpa), 10.07 + 10.06 (CH₂CH₃) ppm. ¹⁵N (d₇-DMF): δ = −37.8 (NH₂), −11.4 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = -63.63 + (−63.62) (t, ³J(¹H, ¹⁹F) = 11.0 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3951 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 734.15 [M + Na⁺]⁺. Isomer ratio 12d:12d* = 68:32 (based on ¹H NMR spectroscopy).

13.

(OC-6-12)-Cyclopentylaminedimethylaminedipropanoatobis(3,3,3-trifluoropropanoato)platinum(IV) (12e)

General procedure 5. 4e (649 mg, impure) in propionic anhydride (20 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 65:35 + 0.1% formic acid). Yield: 5 mg. ¹H NMR (d₇-DMF): δ = 8.46 (b, 1H, NH), 8.02 (b, 2H, NH₂), superposition of CH and water signal, 3.51 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 4H, CH₂CF₃), 2.43 (d, ³J(¹H, ¹H) = 5.7 Hz, 6H, NHCH₃), 2.32 (q, ³J(¹H, ¹H) = 7.5 Hz, 4H, CH₂CH₃), 1.92- 2.02 (m, 2H, cpa), 1.66–1.76 (m, 4H, cpa), 1.55–1.63 (m, 2H, cpa), 1.02 (t, ³J(¹H, ¹H) = 7.5 Hz, 6H, CH₂CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 181.6 (C=O)CH₂CH₃), 171.0 (q, ³J(¹⁹F,¹³C) = 4.4 Hz, (C=O)CH₂CF₃), 125.0 (q, ¹J(¹⁹F,¹³C) = 275.9 Hz, CF₃), 56.0 (CH), 40.0 (NHCH₃), 39.8 (q, ²J(¹⁹F,¹³C) = 29.0 Hz, CH₂CF₃), 32.5 (CH₂, cpa), 29.4 (CH₂CH₃), 23.7 (CH₂, cpa), 10.0 (CH₂CH₃) ppm. ¹⁵N (d₇-DMF): δ = −24.7 (NH), −16.6 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.5 (t, ³J(¹H, ¹⁹F) = 11.0 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3978 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 748.16 [M + Na⁺]⁺.

14.

(OC-6-12)/(OC-6-22)-Cyclopentylaminedimethylaminedipropanoatobis(3,3,3-trifluoropropanoato)platinum(IV) (12e/12e*)

General procedure 5. 4e (505 mg, impure) in propionic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 65:35 + 0.1% formic acid). Yield: 125 mg. Elemental analysis: C₁₉H₃₂F₆N₂O₈Pt; calcd. C 31.45, H 4.45, N 3.86, found C 31.13, H 4.40, N 3.90. ¹H NMR (d₇-DMF): δ = 8.47 (b, 1H, NH), 8.02 (b, 2H, NH₂), superposition of CH, CH₂CF₃ (minor isomer) and water signal, 3.51 (major isomer) (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 4H, CH₂CF₃), 2.43 (d, ³J(¹H, ¹H) = 5.8 Hz, 6H, NHCH₃), 2.33 (minor isomer) + 2.32 (major isomer) (q, ³J(¹H, ¹H) = 7.5 Hz, 4H, CH₂CH₃), 1.92–2.02 (m, 2H, cpa), 1.66–1.76 (m, 4H, cpa), 1.55–1.63 (m, 2H, cpa), 1.03 (major isomer) + 1.02 (minor isomer) (t, ³J(¹H, ¹H) = 7.5 Hz, 6H, CH₂CH₃) ppm. ¹³C NMR (d₇-DMF): δ = 181.6 + 181.5 (C=O)CH₂CH₃), 171.0 (q, ³J(¹⁹F,¹³C) = 4.4 Hz, (C=O)CH₂CF₃), 125.0 + 124.9 (q, ¹J(¹⁹F,¹³C) = 276.0 Hz, CF₃), 55.95 + 55.93 (CH), 40.0 (NHCH₃), 39.9 + 39.7 (q, ²J(¹⁹F,¹³C) = 29.1 Hz, CH₂CF₃), 32.5 (CH₂, cpa), 29.41 + 29.36 (CH₂CH₃), 23.7 (CH₂, cpa), 10.00 + 9.99 (CH₂CH₃) ppm. ¹⁵N (d₇-DMF): δ = −24.7 (NH), −16.6 (NH₂) ppm. ¹⁹F NMR (d₇-DMF): δ = −63.51 + (−63.50) (t, ³J(¹H, ¹⁹F) = 11.0 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₇-DMF): δ = 3979 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 748.16 [M + Na⁺]⁺. Isomer ratio 12e:12e* = 64:36 (based on ¹H NMR spectroscopy).

15.

(OC-6-22)-Triacetatoamminemethylamine(3,3,3-trifluoropropanoato)platinum(IV) (13a)

13a was obtained as a side product of 11a. Yield: 85 mg. Elemental analysis: C₁₀H₁₉F₃N₂O₈Pt; calcd. C 21.94, H 3.50, N 5.12, found C 21.77, H 3.47, N 5.33. ¹H NMR (d₆-DMSO): δ = 6.98 (b, 2H, NH₂), 6.56 (t, ¹J(¹⁴N, ¹H) = 53.6 Hz, 3H, NH₃), 3.38 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 2H, CH₂CF₃), 2.04 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 1.92 (s, 3H, CH₃), 1.91 (s, 6H, CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 177.2 + 177.1 ((C=O)CH₃), 170.0 (q, ³J(¹⁹F,¹³C) = 4.4 Hz, (C=O)CH₂CF₃), 124.3 (q, ¹J(¹⁹F,¹³C) = 275.5 Hz, CF₃), superimposition of the CH₂CF₃ and DMSO signal, 27.6 (NH₂CH₃), 22.3 + 22.2 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −45.4 (NH³), −32.3 (NH²) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.2 (t, ³J(¹H, ¹⁹F) = 11.0 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3937 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 570.06 [M + Na⁺]⁺.

16.

(OC-6-22)-Triacetatoamminedimethylamine(3,3,3-trifluoropropanoato)platinum(IV) (13b)

General procedure 5. 6b (204 mg, impure) in acetic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 15:85 + 0.1% formic acid). Yield: 114 mg. Elemental analysis: C₁₁H₂₁F₃N₂O₈Pt∙H₂O; calcd. C 22.80, H 4.00, N 4.84, found C 22.96, H 3.63, N 5.05. ¹H NMR (d₆-DMSO): δ = 7.61(b, 2H, NH), 6.86 (t, ¹J(¹⁴N, ¹H) = 54.1 Hz, 3H, NH₃), 3.40 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 2H, CH₂CF₃), 2.23 (d, ²J(¹H, ¹H) = 5.8 Hz, 6H, NHCH₃), 1.93 (s, 3H, CH₃), 1.92 (s, 6H, CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 177.1 + 177.0 ((C=O)CH₃), 169.9 (q, ³J(¹⁹F,¹³C) = 4.0 Hz, (C=O)CH₂CF₃), 124.4 (q, ¹J(¹⁹F,¹³C) = 276.3 Hz, CF₃), superimposition of the CH₂CF₃ signal and DMSO signal, 39.2 (NHCH₃), 22.4 + 22.3 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −50.9 (NH₃), −20.8 (NH) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.1 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3948 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 584.08 [M + Na⁺]⁺.

17.

(OC-6-22)-Triacetatoamminecyclopentylamine(3,3,3-trifluoropropanoato)platinum(IV) (13c)

13c was obtained as a side product of 11c. Yield: 40 mg. Elemental analysis: C₁₄H₂₅F₃N₂O₈Pt; calcd. C 27.96, H 4.19, N 4.66, found C 27.69, H 4.11, N 4.98. ¹H NMR (d₆-DMSO): δ = 7.18 (b, 2H, NH₂), 6.60 (t, ¹J(¹⁴N, ¹H) = 53.2 Hz, 3H, NH₃), 3.38 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 2H, CH₂CF₃), 3.29 (m, 1H, CH) (in part overlapping with the water signal), 1.92 (s, 3H, CH₃), 1.91 (s, 6H, CH₃), 1.83–1.90 (m, 2H, cpa), 1.62–1.71 (m, 4H, cpa), 1.46–1.54 (m, 2H, cpa) ppm. ¹³C NMR (d₆-DMSO): δ = 177.41 + 177.40 ((C=O)CH₃), 170.2 (q, ³J(¹⁹F,¹³C) = 4.3 Hz, (C=O)CH₂CF₃), 124.2 (q, ¹J(¹⁹F,¹³C) = 276.0 Hz, CF₃), 54.3 (CH), superposition of CH₂CF₃ and DMSO signal, 31.7 (CH₂, cpa), 23.5 (CH₂, cpa), 22.3 + 22.2 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −45.6 (NH₃), −7.7 (NH₂) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.2 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3976 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 624.11 [M + Na⁺]⁺.

18.

(OC-6-22)-Triacetatocyclopentylaminemethylamine(3,3,3-trifluoropropanoato)platinum(IV) (13d)

13d was obtained as a side product of 11d. Yield: 115 mg. Elemental analysis: C₁₅H₂₇F₃N₂O₈Pt; calcd. C 29.27, H 4.42, N 4.55, found C 29.15, H 4.41, N 4.75. ¹H NMR (d₆-DMSO): δ = 7.47 (b, 2H, NH₂), 7.34 (b, 2H, NH₂), 3.42 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 2H, CH₂CF₃), 3.36 (m, 1H, CH), 2.05 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 1.94 (s, 3H, CH₃), 1.93 (s, 6H, CH₃), 1.83–1.90 (m, 2H, cpa), 1.59–1.70 (m, 4H, cpa), 1.48–1.56 (m, 2H, cpa) ppm. ¹³C NMR (d₆-DMSO): δ = 177.4 ((C=O)CH₃), 170.2 (q, ³J(¹⁹F,¹³C) = 4.3 Hz, (C=O)CH₂CF₃), 124.3 (q, ¹J(¹⁹F,¹³C) = 276.6 Hz, CF₃), 54.4 (CH), superposition of the CH₂CF₃ and DMSO signal, 31.8 (CH₂, cpa), 27.9 (NH₂CH₃), 23.4 (CH₂, cpa), 22.4 + 22.3 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −37.9 (NH₂), −11.4 (NH₂) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.1 (t, ³J(¹H, ¹⁹F) = 11.1 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3954 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 638.13 [M + Na⁺]⁺.

19.

(OC-6-22)-Triacetatocyclopentylaminedimethylamine(3,3,3-trifluoropropanoato)platinum(IV) (13e)

13e was obtained as a side product of 11e. Yield: 104 mg. Elemental analysis: C₁₆H₂₉F₃N₂O₈Pt∙H₂O; calcd. C 29.68, H 4.83, N 4.33, found C 29.97, H 4.61, N 4.45. ¹H NMR (d₆-DMSO): δ = 8.23 (b, 2H, NH), 7.81 (b, 2H, NH₂), 3.42 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 4H, CH₂CF₃), superimposition of CH and CH₂CF₃ signal, 2.27 (d, ²J(¹H, ¹H) = 5.8 Hz, 6H, NHCH₃), 1.95 (s, 3H, CH₃), 1.93 (s, 6H, CH₃), 1.82–1.91 (m, 2H, cpa), 1.57–1.68 (m, 4H, cpa), 1.49–1.56 (m, 2H, cpa) ppm. ¹³C NMR (d₆-DMSO): δ = 177.5 + 177.4 ((C=O)CH₃), 170.1 (q, ³J(¹⁹F,¹³C) = 4.4 Hz, (C=O)CH₂CF₃), 124.4 (q, ¹J(¹⁹F,¹³C) = 275.9 Hz, CF₃), 55.1 (CH), superimposition of NHCH₃, CH₂CF₃ and DMSO signal, 31.9 (CH₂, cpa), 23.3 (CH₂, cpa), 22.5 + 22.4 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −24.5 (NH), −16.5 (NH₂) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.1 (t, ³J(¹H, ¹⁹F) = 11.3 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3980 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 652.14 [M + Na⁺]⁺.

20.

(OC-6-22)-Amminemethylaminetripropanoato(3,3,3-trifluoropropanoato)platinum(IV) (14a)

14a was obtained as a side product of 12a. Yield: 72 mg. Elemental analysis: C₁₃H₂₅F₃N₂O₈Pt∙H₂O; calcd. C 25.70, H 4.48, N 4.61, found C 25.97, H 4.48, N 4.83. ¹H NMR (d₆-DMSO): δ = 7.03 (b, 2H, NH₂), 6.61 (t, ¹J(¹⁴N, ¹H) = 52.8 Hz, 3H, NH₃), 3.38 (q, ³J(¹⁹F, ¹H) = 11.2 Hz, 2H, CH₂CF₃), 2.24 + 2.23 (q, ³J(¹H, ¹H) = 7.6 Hz, 6H, CH₂CH₃), 2.05 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 0.95 + 0.94 (t, ³J(¹H, ¹H) = 7.6 Hz, 9H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.5 + 180.4 ((C=O)CH₂CH₃), 170.0 ((C=O)CH₂CF₃), 124.4 (CF₃, taken from HMBC NMR spectra), superposition of CH₂CF₃ and DMSO signal, 28.6 + 28.4 (CH₂CH₃), 27.5 (NH₂CH₃), 10.15 + 10.14 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −45.7 (NH₃), −32.4 (NH₂) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.2 (t, ³J(¹H, ¹⁹F) = 11.0 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3932 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 612.11 [M + Na⁺]⁺.

21.

(OC-6-22)-Amminedimethylaminetripropanoato(3,3,3-trifluoropropanoato)platinum(IV) (14b)

14b was obtained as a side product of 12b. Yield: 297 mg. Elemental analysis: C₁₄H₂₇F₃N₂O₈Pt∙H₂O; calcd. C 27.06, H 4.70, N 4.51, found C 27.16, H 4.49, N 4.67. ¹H NMR (d₆-DMSO): δ = 7.66 (b, 1H, NH), 6.92 (t, ¹J(¹⁴N, ¹H) = 54.2 Hz, 3H, NH₃), 3.40 (q, ³J(¹⁹F, ¹H,) = 11.4 Hz, 2H, CH₂CF₃), 2.25 + 2.23 (q, ³J(¹H, ¹H) = 7.6 Hz, 6H, CH₂CH₃), 2.24 (d, ³J(¹H, ¹H) = 5.7 Hz, 6H, NHCH₃), 0.952 + 0.951 (t, ³J(¹H, ¹H) = 7.6 Hz, 9H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.33 + 180.27 ((C=O)CH₂CH₃), 169.8 (q, ³J(¹⁹F,¹³C) = 3.8 Hz, ((C=O)CH₂CF₃), 124.4 (q, ¹J(¹⁹F,¹³C) = 275.9 Hz, CF₃), superposition of CH₂CF₃, NHCH₃ and DMSO signal, 28.7 + 28.6 (CH₂CH₃), 10.14 + 10.13 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −51.5 (NH₃), −21.0 (NH) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.1 (t, ³J(¹H, ¹⁹F) = 11.5 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3941 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 626.13 [M + Na⁺]⁺.

22.

(OC-6-22)-Amminecyclopentylaminetripropanoato(3,3,3-trifluoropropanoato)platinum(IV) (14c)

14c was obtained as a side product of 12c. Yield: 53 mg. Elemental analysis: C₁₇H₃₁F₃N₂O₈Pt∙H₂O; calcd. C 30.87, H 5.03, N 4.24, found C 31.01, H 4.85, N 4.50. ¹H NMR (d₆-DMSO): δ = 7.23 (b, 2H, NH₂), 6.64 (t, ¹J(¹⁴N, ¹H) = 53.7 Hz, 3H, NH₃), 3.38 (q, ³J(¹⁹F, ¹H,) = 11.3 Hz, 2H, CH₂CF₃), 3.29 (m, 1H, CH), 2.24 + 2.23 (q, ³J(¹H, ¹H) = 7.5 Hz, 6H, CH₂CH₃), 1.84–1.93 (m, 2H, cpa), 1.62–1.71 (m, 4H, cpa), 1.45–1.55 (m, 2H, cpa), 0.95 + 0.94 (t, ³J(¹H, ¹H) = 7.6 Hz, 9H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.8 + 180.7 ((C=O)CH₂CH₃), 170.2 ((C=O)CH₂CF₃), 124.2 (q, ¹J(¹⁹F,¹³C) = 276.6 Hz, CF₃), 54.3 (CH), superposition of CH₂CF₃ and DMSO signal, 31.8 (CH₂, cpa), 28.6 + 28.5 (CH₂CH₃), 23.4 (CH₂, cpa), 10.13 + 10.11 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −45.7 (NH₃), −7.8 (NH₂) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.2 (t, ³J(¹H, ¹⁹F) = 11.3 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3970 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 666.16 [M + Na⁺]⁺.

23.

(OC-6-22)-Cyclopentylaminemethylaminetripropanoato(3,3,3-trifluoropropanoato)platinum(IV) (14d)

14d was obtained as a side product of 12d. Yield: 69 mg. Elemental analysis: C₁₈H₃₃F₃N₂O₈Pt∙H₂O; calcd. C 32.00, H 5.22, N 4.15, found C 32.35, H 5.09, N 4.44. ¹H NMR (d₆-DMSO): δ = 7.54 (b, 2H, NH₂), 7.39 (b, 2H, NH₂), 3.40 (q, ³J(¹⁹F, ¹H) = 11.0 Hz, 2H, CH₂CF₃), 3.36 (m, 1H, CH, in part overlapping with CH₂CF₃ and water signal), 2.25 + 2.24 (q, ³J(¹H, ¹H) = 7.6 Hz, 6H, CH₂CH₃), 2.05 (t, ³J(¹H, ¹H) = 6.3 Hz, 3H, NH₂CH₃), 1.83–1.91 (m, 2H, cpa), 1.59–1.70 (m, 4H, cpa), 1.46–1.56 (m, 2H, cpa), 0.951 + 0.948 (t, ³J(¹H, ¹H) = 7.6 Hz, 9H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.74 + 180.73 ((C=O)CH₂CH₃), 170.2 (q, ³J(¹⁹F,¹³C) = 4.0 Hz, (C=O)CH₂CF₃), 124.3 (q, ¹J(¹⁹F,¹³C) = 276.0 Hz, CF₃), 54.3 (CH), superposition of CH₂CF₃ and DMSO signal, 31.9 (CH₂, cpa), 28.8 + 28.6 (CH₂CH₃), 27.8 (NH₂CH₃), 23.3 (CH₂, cpa), 10.10 + 10.09 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −37.8 (NH₂), −11.8 (NH₂) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.2 (t, ³J(¹H, ¹⁹F) = 11.2 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3948 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 680.17 [M + Na⁺]⁺.

24.

(OC-6-22)-Cyclopentylaminedimethylaminetripropanoato(3,3,3-trifluoropropanoato)platinum(IV) (14e)

14e was obtained as a side product of 12e. Yield: 125 mg. Elemental analysis: C₁₉H₃₅F₃N₂O₈Pt∙H₂O; calcd. C 33.09, H 5.41, N 4.06, found C 33.33, H 5.07, N 4.38. ¹H NMR (d₆-DMSO): δ = 8.34 (b, 1H, NH), 7.88 (b, 2H, NH₂), 3.43 (q, ³J(¹H, ¹⁹F) = 11.2 Hz, 2H, CH₂CF₃), superposition of CH and CH₂CF₃ signal, 2.28 (d, ³J(¹H, ¹H) = 5.7 Hz, 6H, NHCH₃), 2.26 + 2.25 (q, ³J(¹H, ¹H) = 7.5 Hz, 6H, CH₂CH₃), 1.83–1.91 (m, 2H, cpa), 1.57–1.68 (m, 4H, cpa), 1.49–1.68 (m, 2H, cpa), 0.957 + 0.955 (t, ³J(¹H, ¹H) = 7.6 Hz, 9H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.7 + 180.6 ((C=O)CH₂CH₃), 170.1 (q, ³J(¹⁹F,¹³C) = 4.1 Hz, (C=O)CH₂CF₃), 124.4 (q, ¹J(¹⁹F,¹³C) = 275.3 Hz, CF₃), 55.0 (CH), superposition of NHCH₃, CH₂CF₃ and DMSO signal, 31.8 (CH₂, cpa), 28.9 + 28.7 (CH₂CH₃), 23.2 (CH₂, cpa), 10.08 + 10.07 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −24.5 (NH), −17.2 (NH₂) ppm. ¹⁹F NMR (d₆-DMSO): δ = −62.1 (t, ³J(¹H, ¹⁹F) = 11.3 Hz, 3F, CF₃) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3973 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 694.19 [M + Na⁺]⁺.

25.

(OC-6-11)-Tetraacetatoamminemethylamineplatinum(IV) (15a)

General procedure 5. 9a (268 mg, impure) in acetic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 5:95 + 0.1% formic acid). Yield: 89 mg. Elemental analysis: C₉H₂₀N₂O₈Pt; calcd. C 22.55, H 4.21, N 5.84, found C 22.32, H 4.12, N 5.92. ¹H NMR (d₆-DMSO): δ = 6.98 (b, 2H, NH₂), 6.59 (t, ¹J(¹⁴N, ¹H) = 53.2 Hz, 3H, NH₃), 2.03 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 1.91 (s, 12H, CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 177.2 ((C=O)CH₃), 27.5 (NH₂CH₃), 22.4 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −46.5 (NH₃), −33.0 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3931 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 502.08 [M + Na⁺]⁺.

26.

(OC-6-11)-Tetraacetatoamminedimethylamineplatinum(IV) (15b)

General procedure 5. 9b (198 mg, impure) in acetic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 10:90 + 0.1% formic acid). Yield: 84 mg. Elemental analysis: C₁₀H₂₂N₂O₈Pt; calcd. C 24.34, H 4.49, N 5.68, found C 24.14, H 4.50, N 5.78. ¹H NMR (d₆-DMSO): δ = 7.63 (b, 2H, NH), 6.90 (t, ¹J(¹⁴N, ¹H) = 54.4 Hz, 3H, NH₃), 2.23 (d, ²J(¹H, ¹H) = 5.8 Hz, 6H, NHCH₃), 1.92 (s, 12H, CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 177.0 ((C=O)CH₃), 39.1 (NHCH₃), 22.5 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −52.1 (NH₃), −22.0 (NH) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3939 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 516.09 [M + Na⁺]⁺.

27.

(OC-6-11)-Tetraacetatoamminecyclopentylamineplatinum(IV) (15c)

General procedure 5. 9c (321 mg, impure) in acetic anhydride (15 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 20:80 + 0.1% formic acid). Yield: 114 mg. Elemental analysis: C₁₃H₂₆N₂O₈Pt; calcd. C 29.27, H 4.91, N 5.25, found C 28.95, H 4.81, N 5.31. ¹H NMR (d₆-DMSO): δ = 7.22 (b, 2H, NH₂), 6.62 (t, ¹J(¹⁴N, ¹H) = 52.9 Hz, 3H, NH₃), 3.28 (in part overlapping with water signal) (m, 1H, CH), 1.91 (s, 12H, CH₃), 1.84–1.94 (in part overlapping with acetate signal) (m, 2H, cpa), 1.61–1.71 (m, 4H, cpa), 1.45–1.55 (m, 2H, cpa) ppm. ¹³C NMR (d₆-DMSO): δ = 177.5 ((C=O)CH₃), 54.3 (CH), 31.8 (CH₂, cpa), 23.6 (CH₂, cpa), 22.4 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −46.8 (NH₃), −7.8 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3969 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 556.12 [M + Na⁺]⁺.

28.

(OC-6-11)-Tetraacetatocyclopentylaminemethylamineplatinum(IV) (15d)

General procedure 5. 9d (168 mg, impure) in acetic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 23:77 + 0.1% formic acid). Yield: 39 mg. Elemental analysis: C₁₄H₂₈N₂O₈Pt; calcd. C 30.71, H 5.16, N 5.12, found C 30.43, H 5.15, N 5.16. ¹H NMR (d₆-DMSO): δ = 7.54 (b, 2H, NH₂), 7.37 (b, 2H, NH₂), 3.34 (m, 1H, CH), 2.03 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 1.92 (s, 12H, CH₃), 1.82–1.90 (m, 2H, cpa), 1.59–1.70 (m, 4H, cpa), 1.46–1.57 (m, 2H, cpa) ppm. ¹³C NMR (d₆-DMSO): δ = 177.5 ((C=O)CH₃), 54.3 (CH), 31.9 (CH₂, cpa), 27.8 (NH₂CH₃), 23.4 (CH₂, cpa), 22.5 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −38.7 (NH₂), −12.0 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3946 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 570.14 [M + Na⁺]⁺.

29.

(OC-6-11)-Tetraacetatocyclopentylaminedimethylamineplatinum(IV) (15e)

General procedure 5. 9e (252 mg, impure) in acetic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 20:80 + 0.1% formic acid). Yield: 42 mg. Elemental analysis: C₁₅H₃₀N₂O₈Pt; calcd. C 32.09, H 5.39, N 4.99, found C 31.77, H 5.48, N 5.16. ¹H NMR (d₆-DMSO): δ = 8.31 (b, 2H, NH), 7.87 (b, 2H, NH₂), 3.41 (m, 1H, CH), 2.27 (d, ²J(¹H, ¹H) = 5.8 Hz, 6H, NHCH₃), 1.93 (s, 12H, CH₃), 1.82–1.89 (m, 2H, cpa), 1.57–1.68 (m, 4H, cpa), 1.49–1.56 (m, 2H, cpa) ppm. ¹³C NMR (d₆-DMSO): δ = 177.4 (C=O)CH₃), 55.0 (CH), superposition of NHCH₃ and DMSO signal, 31.9 (CH₂, cpa), 23.3 (CH₂, cpa), 22.6 (CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −25.2 (NH), −17.8 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3972 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 584.15 [M + Na⁺]⁺.

30.

(OC-6-11)-Amminemethylaminetetrapropanoatoplatinum(IV) (16a)

General procedure 5. 10a (421 mg, impure) in propionic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 20:80 + 0.1% formic acid). Yield: 224 mg. Elemental analysis: C₁₃H₂₈N₂O₈Pt∙H₂O; calcd. C 28.21, H 5.46, N 5.06, found C 28.60, H 5.18, N 5.38. ¹H NMR (d₆-DMSO): δ = 7.06 (b, 2H, NH₂), 6.66 (t, ¹J(¹⁴N, ¹H) = 53.4 Hz, 3H, NH₃), 2.22 (q, ³J(¹H, ¹H) = 7.6 Hz, 8H, CH₂CH₃), 2.04 (t, ³J(¹H, ¹H) = 6.4 Hz, 3H, NH₂CH₃), 0.94 (t, ³J(¹H, ¹H) = 7.6 Hz, 12H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.5 (C=O)CH₂CH₃), 28.6 (CH₂CH₃), 27.4 (NH₂CH₃), 10.2 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −46.4 (NH₃), −33.2 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3928 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 558.14 [M + Na⁺]⁺.

31.

(OC-6-11)-Amminedimethylaminetetrapropanoatoplatinum(IV) (16b)

General procedure 5. 10b (208 mg, impure) in propionic anhydride (20 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 20:80 + 0.1% formic acid). Yield: 87 mg. Elemental analysis: C₁₄H₃₀N₂O₈Pt∙H₂O; calcd. C 29.63, H 5.68, N 4.94, found C 29.91, H 5.37, N 5.28. ¹H NMR (d₆-DMSO): δ = 7.70 (b, 1H, NH), 6.98 (t, ¹J(¹⁴N, ¹H) = 54.0 Hz, 3H, NH₃), 2.24 (d, ³J(¹H, ¹H) = 5.7 Hz, 6H, NHCH₃), 2.23 (q, ³J(¹H, ¹H) = 7.6 Hz, 8H, CH₂CH₃), 0.95 (t, ³J(¹H, ¹H) = 7.5 Hz, 12H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.3 (C=O)CH₂CH₃), 39.0 (NHCH₃), 28.8 (CH₂CH₃), 10.2 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −52.5 (NH₃), −22.2 (NH) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3932 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 572.15 [M + Na⁺]⁺.

32.

(OC-6-11)-Amminecyclopentylaminetetrapropanoatoplatinum(IV) (16c)

General procedure 5. 10c (224 mg, impure) in propionic anhydride (15 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 40:60 + 0.1% formic acid). Yield: 59 mg. Elemental analysis: C₁₇H₃₄N₂O₈Pt∙H₂O; calcd. C 33.61, H 5.97, N 4.61, found C 33.68, H 5.74, N 4.84. ¹H NMR (d₆-DMSO): δ = 7.30 (b, 2H, NH₂), 6.68 (t, ¹J(¹⁴N, ¹H) = 53.6 Hz, 3H, NH₃), 3.29 (m, 1H, CH), 2.22 (q, ³J(¹H, ¹H) = 7.6 Hz, 8H, CH₂CH₃), 1.83–1.93 (m, 2H, cpa), 1.62–1.72 (m, 4H, cpa), 1.45–1.54 (m, 2H, cpa), 0.94 (t, ³J(¹H, ¹H) = 7.5 Hz, 12H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.7 (C=O)CH₂CH₃), 54.1 (CH), 31.8 (CH₂, cpa), 28.7 (CH₂CH₃), 23.4 (CH₂, cpa), 10.2 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −46.6 (NH₃), −8.6 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3963 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 612.19 [M + Na⁺]⁺.

33.

(OC-6-11)-Cyclopentylaminemethylaminetetrapropanoatoplatinum(IV) (16d)

16d was obtained as a side product of 12d. Yield: 62 mg. Elemental analysis: C₁₈H₃₆N₂O₈Pt∙H₂O; calcd. C 34.78, H 6.16, N 4.51, found C 34.92, H 5.85, N 4.70. ¹H NMR (d₆-DMSO): δ = 7.64 (b, 2H, NH₂), 7.46 (b, 2H, NH₂), 3.33 (m, 1H, CH, in part overlapping with water signal), 2.23 (q, ³J(¹H, ¹H) = 7.6 Hz, 8H, CH₂CH₃), 2.04 (t, ³J(¹H, ¹H) = 6.2 Hz, 3H, NH₂CH₃), 1.83–1.92 (m, 2H, cpa), 1.60–1.72 (m, 4H, cpa), 1.47–1.57 (m, 2H, cpa), 0.95 (t, ³J(¹H, ¹H) = 7.6 Hz, 12H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.7 (C=O)CH₂CH₃), 54.2 (CH), 31.9 (CH₂, cpa), 28.8 (CH₂CH₃), 27.6 (NH₂CH₃), 23.3 (CH₂, cpa), 10.2 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −38.6 (NH₂), −12.4 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3942 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 626.20 [M + Na⁺]⁺.

34.

(OC-6-11)-Cyclopentylaminedimethylaminetetrapropanoatoplatinum(IV) (16e)

General procedure 5. 10e (153 mg, impure) in propionic anhydride (10 mL). Preparative RP-HPLC (isocratic, acetonitrile/Milli-Q water = 45:55 + 0.1% formic acid). Yield: 48 mg. Elemental analysis: C₁₉H₃₈N₂O₈Pt∙H₂O; calcd. C 35.90, H 6.34, N 4.40, found C 36.22, H 6.04, N 4.79. ¹H NMR (d₆-DMSO): δ = 8.46 (b, 1H, NH), 7.98 (b, 2H, NH₂), 3.43 (m, 1H, CH), 2.28 (d, ³J(¹H, ¹H) = 5.8 Hz, 6H, NHCH₃), 2.24 (q, ³J(¹H, ¹H) = 7.6 Hz, 8H, CH₂CH₃), 1.82–1.90 (m, 2H, cpa), 1.56–1.68 (m, 4H, cpa), 1.49–1.67 (m, 2H, cpa), 0.95 (t, ³J(¹H, ¹H) = 7.6 Hz, 12H, CH₂CH₃) ppm. ¹³C NMR (d₆-DMSO): δ = 180.6 (C=O)CH₂CH₃), 54.8 (CH), superimposition of NHCH₃ and DMSO signal, 31.9 (CH₂, cpa), 28.9 (CH₂CH₃), 23.2 (CH₂, cpa), 10.1 (CH₂CH₃) ppm. ¹⁵N (d₆-DMSO): δ = −25.6 (NH), −18.2 (NH₂) ppm. ¹⁹⁵Pt NMR (d₆-DMSO): δ = 3964 ppm. ESI-MS (ACN/MeOH + 1% H₂O): (pos) m/z 640.22 [M + Na⁺]⁺.

4. Conclusions

In total, thirty trans-configured tetracarboxylatoplatinum(IV) complexes with mixed am(m)ine and varying numbers of trifluoropropanoato ligands were synthesised and characterised in detail. Due to the introduction of fluorine-containing ligands, highly sensitive ¹⁹F NMR spectroscopy could be used for characterisation. Additionally, ¹⁹F NMR spectroscopy is of special interest based on the absence of ¹⁹F in biological matrices, allowing prospective investigations of, e.g., aquation and stability behaviour in vitro or in vivo. Investigations of lipophilicity and cytotoxicity revealed a general connection between these two parameters. The most lipophilic platinum(IV) complexes displayed IC₅₀ values in the low micromolar range tested by the MTT assay in human cancer cell lines. Additionally, the rate of apoptosis was investigated by the flow-cytometric annexin V/PI assay, suggesting dependencies on the structural pattern regarding both the am(m)ine and the number of trifluoropropanoato moieties. Due to their geometrical structure, trans-configured platinum complexes form different DNA cross-links than their cis-coordinated counterparts, and their different mode of action (trans vs. cis, as well as platinum(IV) vs. platinum(II)) may open up the possibility to circumvent drug resistance. Consequently, testing trans-configured tetracarboxylatoplatinum(IV) complexes in animal models would be the next step to judge their potential in vivo. Out of the presented compounds, 12e/12e* would be of high interest for future activity studies based on the high cytotoxicity and highest rate of induction of late apoptosis followed by 12d/12d* and 12c/12c*.