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21 pages, 3936 KiB

Open AccessArticle

Metabolic Impact of Anticancer Drugs Pd₂Spermine and Cisplatin on the Brain of Healthy Mice

by Tatiana J. Carneiro, Martin Vojtek, Salomé Gonçalves-Monteiro, João R. Neves, Ana L. M. Batista de Carvalho, Maria Paula M. Marques, Carmen Diniz and Ana M. Gil

Pharmaceutics 2022, 14(2), 259; https://doi.org/10.3390/pharmaceutics14020259 - 22 Jan 2022

Cited by 5 | Viewed by 2641

Abstract

The new palladium agent Pd₂Spermine (Spm) has been reported to exhibit promising cytotoxic properties, while potentially circumventing the known disadvantages associated to cisplatin therapeutics, namely acquired resistance and high toxicity. This work presents a nuclear magnetic resonance (NMR) metabolomics study of [...] Read more.

The new palladium agent Pd₂Spermine (Spm) has been reported to exhibit promising cytotoxic properties, while potentially circumventing the known disadvantages associated to cisplatin therapeutics, namely acquired resistance and high toxicity. This work presents a nuclear magnetic resonance (NMR) metabolomics study of brain extracts obtained from healthy mice, to assess the metabolic impacts of the new Pd₂Spm complex in comparison to that of cisplatin. The proton NMR spectra of both polar and nonpolar brain extracts were analyzed by multivariate and univariate statistics, unveiling several metabolite variations during the time course of exposition to each drug (1–48 h). The distinct time-course dependence of such changes revealed useful information on the drug-induced dynamics of metabolic disturbances and recovery periods, namely regarding amino acids, nucleotides, fatty acids, and membrane precursors and phospholipids. Putative biochemical explanations were proposed, based on existing pharmacokinetics data and previously reported metabolic responses elicited by the same metal complexes in the liver of the same animals. Generally, results suggest a more effective response of brain metabolism towards the possible detrimental effects of Pd₂Spm, with more rapid recovery back to metabolites’ control levels and, thus, indicating that the palladium drug may exert a more beneficial role than cDDP in relation to brain toxicity. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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16 pages, 2131 KiB

Open AccessArticle

Anticancer Activity of Urease Mimetic Cobalt (III) Complexes on A549-Lung Cancer Cells: Targeting the Acidic Microenvironment

by Bhawna Uprety, Rahul Chandran, Charmaine Arderne and Heidi Abrahamse

Pharmaceutics 2022, 14(1), 211; https://doi.org/10.3390/pharmaceutics14010211 - 17 Jan 2022

Cited by 3 | Viewed by 2295

Abstract

Tumour cells maintain a local hypoxic and acidic microenvironment which plays a crucial role in cancer progression and drug resistance. Urease is a metallohydrolases that catalyses the hydrolysis of urea into ammonia and carbon dioxide, causing an abrupt increase of pH. This enzymatic [...] Read more.

Tumour cells maintain a local hypoxic and acidic microenvironment which plays a crucial role in cancer progression and drug resistance. Urease is a metallohydrolases that catalyses the hydrolysis of urea into ammonia and carbon dioxide, causing an abrupt increase of pH. This enzymatic activity can be employed to target the acidic tumour microenvironment. In this study, we present the anticancer activities of urease mimetic cobalt (III) complexes on A549 cells. The cells were treated with different doses of cobalt (III) complexes to observe the cytotoxicity. The change in cellular morphology was observed using an inverted microscope. The cell death induced by these complexes was analysed through ATP proliferation, LDH release and caspase 3/7 activity. The effect of extracellular alkalinization by the cobalt (III) complexes on the efficacy of the weakly basic drug, doxorubicin (dox) was also evaluated. This combination therapy of dox with cobalt (III) complexes resulted in enhanced apoptosis in A549 cells, as evidenced by elevated caspase 3/7 activity in treated groups. The study confirms the urease mimicking anticancer activity of cobalt (III) complexes by neutralizing the tumour microenvironment. This study will motivate the applications of transition metal-based enzyme mimics in targeting the tumour microenvironment for effective anticancer treatments. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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25 pages, 3003 KiB

Open AccessArticle

Anticancer Diiron Vinyliminium Complexes: A Structure–Activity Relationship Study

by Simona Braccini, Giorgia Rizzi, Lorenzo Biancalana, Alessandro Pratesi, Stefano Zacchini, Guido Pampaloni, Federica Chiellini and Fabio Marchetti

Pharmaceutics 2021, 13(8), 1158; https://doi.org/10.3390/pharmaceutics13081158 - 27 Jul 2021

Cited by 20 | Viewed by 2539

Abstract

A series of 16 novel diiron complexes of general formula [Fe₂Cp₂(CO)(μ-CO){μ-η¹:η³-C(R′)C(R″)CN(R)(Y)}]CF₃SO₃ (2–7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69–95% yields from the reactions of diiron [...] Read more.

A series of 16 novel diiron complexes of general formula [Fe₂Cp₂(CO)(μ-CO){μ-η¹:η³-C(R′)C(R″)CN(R)(Y)}]CF₃SO₃ (2–7), bearing different substituents on the bridging vinyliminium ligand, was synthesized in 69–95% yields from the reactions of diiron μ-aminocarbyne precursors with various alkynes. The products were characterized by elemental analysis, IR, ¹H and ¹³C NMR spectroscopy; moreover the X-ray structures of 2c (R = Y = CH₂Ph, R′ = R″ = Me) and 3a (R = CH₂CH=CH₂, Y = R′ = Me, R″ = H) were ascertained by single-crystal X-ray diffraction studies. NMR and UV–Vis methods were used to assess the D₂O solubility, the stability in aqueous solution at 37 °C and the octanol–water partition coefficients of the complexes. A screening study evidenced a potent cytotoxicity of 2–7 against the A2780 cancer cell line, with a remarkable selectivity compared to the nontumoral Balb/3T3 cell line; complex 4c (R = Cy, Y = R′ = R″ = Me) revealed as the most performant of the series. The antiproliferative activity of a selection of complexes was also assessed on the cisplatin-resistant A2780cisR cancer cell line, and these complexes were capable of inducing a significant ROS production. Moreover, ESI-MS experiments indicated the absence of interaction of selected complexes with cytochrome c and the potentiality to inhibit the thioredoxin reductase enzyme (TrxR). Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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14 pages, 3122 KiB

Open AccessArticle

DNA-Binding and Cytotoxicity of Copper(I) Complexes Containing Functionalized Dipyridylphenazine Ligands

by Sammar Alsaedi, Bandar A. Babgi, Magda H. Abdellattif, Muhammad N. Arshad, Abdul-Hamid M. Emwas, Mariusz Jaremko, Mark G. Humphrey, Abdullah M. Asiri and Mostafa A. Hussien

Pharmaceutics 2021, 13(5), 764; https://doi.org/10.3390/pharmaceutics13050764 - 20 May 2021

Cited by 16 | Viewed by 3185

Abstract

A set of copper(I) coordination compounds with general formula [CuBr(PPh₃)(dppz-R)] (dppz-R = dipyrido[3,2-a:2’,3’-c]phenazine (Cu-1), 11-nitrodipyrido[3,2-a:2’,3’-c]phenazine (Cu-2), 11-cyanodipyrido[3,2-a:2’,3’-c]phenazine (Cu-3), dipyrido[3,2-a:2’,3’-c]phenazine-11-phenone (Cu-4), 11,12-dimethyldipyrido[3,2-a:2’,3’-c]phenazine (Cu-5)) have been prepared and characterized by elemental analysis, ¹ [...] Read more.

A set of copper(I) coordination compounds with general formula [CuBr(PPh₃)(dppz-R)] (dppz-R = dipyrido[3,2-a:2’,3’-c]phenazine (Cu-1), 11-nitrodipyrido[3,2-a:2’,3’-c]phenazine (Cu-2), 11-cyanodipyrido[3,2-a:2’,3’-c]phenazine (Cu-3), dipyrido[3,2-a:2’,3’-c]phenazine-11-phenone (Cu-4), 11,12-dimethyldipyrido[3,2-a:2’,3’-c]phenazine (Cu-5)) have been prepared and characterized by elemental analysis, ¹H-NMR and ³¹P-NMR spectroscopies as well as mass spectrometry. The structure of Cu-1 was confirmed by X-ray crystallography. The effect of incorporating different functional groups on the dppz ligand on the binding into CT-DNA was evaluated by absorption spectroscopy, fluorescence quenching of EtBr-DNA adducts, and viscosity measurements. The functional groups affected the binding modes and hence the strength of binding affinities, as suggested by the changes in the relative viscosity. The differences in the quenching constants (K_sv) obtained from the fluorescence quenching assay highlight the importance of the functional groups in altering the binding sites on the DNA. The molecular docking data support the DNA-binding studies, with the sites and mode of interactions against B-DNA changing with the different functional groups. Evaluation of the anticancer activities of the five copper compounds against two different cancer cell lines (M-14 and MCF-7) indicated the importance of the functional groups on the dppz ligand on the anticancer activities. Among the five copper complexes, the cyano-containing complex (Cu-3) has the best anticancer activities. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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10 pages, 1991 KiB

Open AccessCommunication

Cyclodextrin Inclusion Complexes of Auranofin and Its Iodido Analog: A Chemical and Biological Study

by Damiano Cirri, Ida Landini, Lara Massai, Enrico Mini, Francesca Maestrelli and Luigi Messori

Pharmaceutics 2021, 13(5), 727; https://doi.org/10.3390/pharmaceutics13050727 - 15 May 2021

Cited by 4 | Viewed by 2019

Abstract

Auranofin (AF) and its iodido analog, i.e., Au(PEt₃) I (AFI), were reported to exhibit very promising anticancer properties both in vitro and in vivo. However, both these gold compounds have a scarce aqueous solubility that hampers their pharmaceutical use. Here, we [...] Read more.

Auranofin (AF) and its iodido analog, i.e., Au(PEt₃) I (AFI), were reported to exhibit very promising anticancer properties both in vitro and in vivo. However, both these gold compounds have a scarce aqueous solubility that hampers their pharmaceutical use. Here, we explore whether encapsulation of these metallodrugs inside hydroxypropyl-beta–cyclodextrin (HPβ–CD) may lead to an improved biopharmaceutical profile for the resulting adducts. Phase solubility studies, performed at 25 °C in an aqueous buffer, revealed, in both cases, the formation of a 1:1 drug to cyclodextrin complex; a far greater apparent stability constant (K_1:1) was measured for AFI compared to AF (331 M⁻¹ versus ca. 30 M⁻¹). NMR studies conducted on the AFI/HPβ–CD system confirmed the formation of a stable 1:1 adduct. Then, binary systems of AF and AFI with HPβ–CD were prepared by colyophilization and characterized by DSC and PXRD. The results revealed the occurrence of drug complexation and/or amorphization for the AFI/HPβ–CD binary system. Afterwards, the antiproliferative properties of the two cyclodextrin adducts and of the corresponding free drugs were comparatively evaluated in vitro in three representative ovarian cancer cell lines, i.e., A2780, SKOV3, and IGROV-1. The results, in all cases, point out that CD complexation of the two gold drugs does not substantially affect their biological activity. The implications of these findings are discussed in the frame of the current knowledge of AF and its analogs. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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16 pages, 9375 KiB

Open AccessArticle

Synthesis and Evaluation of the Cytotoxic Activity of Water-Soluble Cationic Organometallic Complexes of the Type [Pt(η¹-C₂H₄OMe)(L)(Phen)]⁺ (L = NH₃, DMSO; Phen = 1,10-Phenanthroline)

by Federica De Castro, Erika Stefàno, Danilo Migoni, Giorgia N. Iaconisi, Antonella Muscella, Santo Marsigliante, Michele Benedetti and Francesco P. Fanizzi

Pharmaceutics 2021, 13(5), 642; https://doi.org/10.3390/pharmaceutics13050642 - 30 Apr 2021

Cited by 12 | Viewed by 2020

Abstract

Starting from the [PtCl(η¹-C₂H₄OMe)(phen)] (phen = 1,10-phenanthroline, 1) platinum(II) precursor, we synthesized and characterized by multinuclear NMR new [Pt(η¹-C₂H₄OMe)(L)(phen)]⁺ (L = NH₃, 2; DMSO, 3) [...] Read more.

Starting from the [PtCl(η¹-C₂H₄OMe)(phen)] (phen = 1,10-phenanthroline, 1) platinum(II) precursor, we synthesized and characterized by multinuclear NMR new [Pt(η¹-C₂H₄OMe)(L)(phen)]⁺ (L = NH₃, 2; DMSO, 3) complexes. These organometallic species, potentially able to interact with cell membrane organic cation transporters (OCT), violating some of the classical rules for antitumor activity of cisplatin analogues, were evaluated for their cytotoxicity. Interestingly, despite both complexes 2 and 3 resulting in greater cell uptake than cisplatin in selected tumor cell lines, only 3 showed comparable or higher antitumor activity. General low cytotoxicity of complex 2 in the tested cell lines (SH-SY5Y, SK-OV-3, Hep-G2, Caco-2, HeLa, MCF-7, MG-63, ZL-65) appeared to depend on its stability towards solvolysis in neutral water, as assessed by NMR monitoring. Differently, the [Pt(η¹-C₂H₄OMe)(DMSO)(phen)]⁺ (3) complex was easily hydrolyzed in neutral water, resulting in a comparable or higher cytotoxicity in cancer cells with respect to cisplatin. Further, both IC₅₀ values and the uptake profiles of the active complex appeared quite different in the used cell lines, suggesting the occurrence of diversified biological effects. Nevertheless, further studies on the metabolism of complex 3 should be performed before planning its possible use in tissue- and tumor-specific drug design. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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Review

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33 pages, 1769 KiB

Open AccessReview

Bioactivity and Development of Small Non-Platinum Metal-Based Chemotherapeutics

by Maria Grazia Ferraro, Marialuisa Piccolo, Gabriella Misso, Rita Santamaria and Carlo Irace

Pharmaceutics 2022, 14(5), 954; https://doi.org/10.3390/pharmaceutics14050954 - 28 Apr 2022

Cited by 36 | Viewed by 2392

Abstract

Countless expectations converge in the multidisciplinary endeavour for the search and development of effective and safe drugs in fighting cancer. Although they still embody a minority of the pharmacological agents currently in clinical use, metal-based complexes have great yet unexplored potential, which probably [...] Read more.

Countless expectations converge in the multidisciplinary endeavour for the search and development of effective and safe drugs in fighting cancer. Although they still embody a minority of the pharmacological agents currently in clinical use, metal-based complexes have great yet unexplored potential, which probably hides forthcoming anticancer drugs. Following the historical success of cisplatin and congeners, but also taking advantage of conventional chemotherapy limitations that emerged with applications in the clinic, the design and development of non-platinum metal-based chemotherapeutics, either as drugs or prodrugs, represents a rapidly evolving field wherein candidate compounds can be fine-tuned to access interactions with druggable biological targets. Moving in this direction, over the last few decades platinum family metals, e.g., ruthenium and palladium, have been largely proposed. Indeed, transition metals and molecular platforms where they originate are endowed with unique chemical and biological features based on, but not limited to, redox activity and coordination geometries, as well as ligand selection (including their inherent reactivity and bioactivity). Herein, current applications and progress in metal-based chemoth are reviewed. Converging on the recent literature, new attractive chemotherapeutics based on transition metals other than platinum—and their bioactivity and mechanisms of action—are examined and discussed. A special focus is committed to anticancer agents based on ruthenium, palladium, rhodium, and iridium, but also to gold derivatives, for which more experimental data are nowadays available. Next to platinum-based agents, ruthenium-based candidate drugs were the first to reach the stage of clinical evaluation in humans, opening new scenarios for the development of alternative chemotherapeutic options to treat cancer. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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31 pages, 6452 KiB

Open AccessReview

Ruthenium Complexes: An Alternative to Platinum Drugs in Colorectal Cancer Treatment

by Kazi Mustafa Mahmud, Mahruba Sultana Niloy, Md Salman Shakil and Md Asiful Islam

Pharmaceutics 2021, 13(8), 1295; https://doi.org/10.3390/pharmaceutics13081295 - 19 Aug 2021

Cited by 32 | Viewed by 4522

Abstract

Colorectal cancer (CRC) is one of the intimidating causes of death around the world. CRC originated from mutations of tumor suppressor genes, proto-oncogenes and DNA repair genes. Though platinum (Pt)-based anticancer drugs have been widely used in the treatment of cancer, their toxicity [...] Read more.

Colorectal cancer (CRC) is one of the intimidating causes of death around the world. CRC originated from mutations of tumor suppressor genes, proto-oncogenes and DNA repair genes. Though platinum (Pt)-based anticancer drugs have been widely used in the treatment of cancer, their toxicity and CRC cells’ resistance to Pt drugs has piqued interest in the search for alternative metal-based drugs. Ruthenium (Ru)-based compounds displayed promising anticancer activity due to their unique chemical properties. Ru-complexes are reported to exert their anticancer activities in CRC cells by regulating different cell signaling pathways that are either directly or indirectly associated with cell growth, division, proliferation, and migration. Additionally, some Ru-based drug candidates showed higher potency compared to commercially available Pt-based anticancer drugs in CRC cell line models. Meanwhile Ru nanoparticles coupled with photosensitizers or anticancer agents have also shown theranostic potential towards CRC. Ru-nanoformulations improve drug efficacy, targeted drug delivery, immune activation, and biocompatibility, and therefore may be capable of overcoming some of the existing chemotherapeutic limitations. Among the potential Ru-based compounds, only Ru (III)-based drug NKP-1339 has undergone phase-Ib clinical trials in CRC treatment. Full article

(This article belongs to the Special Issue Beyond the Platinum in Metal-Based Cancer Therapy)

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