Research

13 pages, 983 KiB

Open AccessArticle

Synthesis of Novel Arginine Building Blocks with Increased Lipophilicity Compatible with Solid-Phase Peptide Synthesis

by Mladena Glavaš, Agata Gitlin-Domagalska, Natalia Ptaszyńska, Dominika Starego, Sylwia Freza, Dawid Dębowski, Aleksandra Helbik-Maciejewska, Anna Łęgowska, Chaim Gilon and Krzysztof Rolka

Molecules 2023, 28(23), 7780; https://doi.org/10.3390/molecules28237780 - 25 Nov 2023

Viewed by 1006

Abstract

Arginine, due to the guanidine moiety, increases peptides’ hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide [...] Read more.

Arginine, due to the guanidine moiety, increases peptides’ hydrophilicity and enables interactions with charged molecules, but at the same time, its presence in a peptide chain might reduce its permeability through biological membranes. This might be resolved by temporary coverage of the peptide charge by lipophilic, enzyme-sensitive alkoxycarbonyl groups. Unfortunately, such a modification of a guanidine moiety has not been reported to date and turned out to be challenging. Here, we present a new, optimized strategy to obtain arginine building blocks with increased lipophilicity that were successfully utilized in the solid-phase peptide synthesis of novel arginine vasopressin prodrugs. Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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14 pages, 2865 KiB

Open AccessArticle

Synthesis, Characterization, and Anticancer Activity of New N,N′-Diarylthiourea Derivative against Breast Cancer Cells

by Mohamed A. El-Atawy, Mai S. Alsubaie, Mohammed L. Alazmi, Ezzat A. Hamed, Demiana H. Hanna, Hoda A. Ahmed and Alaa Z. Omar

Molecules 2023, 28(17), 6420; https://doi.org/10.3390/molecules28176420 - 03 Sep 2023

Cited by 3 | Viewed by 1221

Abstract

The goal of the current study was to prepare two new homologous series of N,N′-diarylurea and N,N′-diarylthiourea derivatives to investigate the therapeutic effects of these derivatives on the methodologies of inhibition directed on human MCF-7 cancer cells. The molecular structures of the prepared [...] Read more.

The goal of the current study was to prepare two new homologous series of N,N′-diarylurea and N,N′-diarylthiourea derivatives to investigate the therapeutic effects of these derivatives on the methodologies of inhibition directed on human MCF-7 cancer cells. The molecular structures of the prepared derivatives were successfully revealed through elemental analyses, ¹H-NMR, ¹³C-NMR and FT-IR spectroscopy. The cytotoxic results showed that Diarylthiourea (compound 4) was the most effective in suppressing MCF-7 cell growth when compared to all other prepared derivatives, with the most effective IC₅₀ value (338.33 ± 1.52 µM) after an incubation period of 24 h and no cytotoxic effects on normal human lung cells (wi38 cells). Using the annexin V/PI and comet tests, respectively, treated MCF-7 cells with this IC₅₀ value of the Diarylthiourea 4 compound displayed a considerable increase in early and late apoptotic cells, as well as an intense comet nucleus in comparison to control cells. An arrest of the cell cycle in the S phase was observed via flow cytometry in MCF-7 cells treated with the Diarylthiourea 4 compound, suggesting the onset of apoptosis. Additionally, ELISA research showed that caspase-3 was upregulated in MCF-7 cells treated with compound 4 compared to control cells, suggesting that DNA damage induced by compound 4 may initiate an intrinsic apoptotic pathway and activate caspase-3. These results contributed to recognizing that the successfully prepared Diarylthiourea 4 compound inhibited the proliferation of MCF-7 cancer cells by arresting the S cell cycle and caspase-3 activation via an intrinsic apoptotic route. These results, however, need to be verified through in vivo studies utilizing an animal model. Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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13 pages, 7168 KiB

Open AccessArticle

Design and Synthesis of New Acyl Urea Analogs as Potential σ1R Ligands

by Rajesh Thapa, Rafael Flores, Kwan H. Cheng, Bereket Mochona and Donald Sikazwe

Molecules 2023, 28(5), 2319; https://doi.org/10.3390/molecules28052319 - 02 Mar 2023

Cited by 1 | Viewed by 1801

Abstract

In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R [...] Read more.

In search of synthetically accessible open-ring analogs of PD144418 or 5-(1-propyl-1,2,5,6-tetrahydropyridin-3-yl)-3-(p-tolyl)isoxazole, a highly potent sigma-1 receptor (σ1R) ligand, we herein report the design and synthesis of sixteen arylated acyl urea derivatives. Design aspects included modeling the target compounds for drug-likeness, docking at σ1R crystal structure 5HK1, and contrasting the lower energy molecular conformers with that of the receptor-embedded PD144418—a molecule we opined that our compounds could mimic pharmacologically. Synthesis of our acyl urea target compounds was achieved in two facile steps which involved first generating the N-(phenoxycarbonyl) benzamide intermediate and then coupling it with the appropriate amines weakly to strongly nucleophilic amines. Two potential leads (compounds 10 and 12, with respective in vitro σ1R binding affinities of 2.18 and 9.54 μM) emerged from this series. These leads will undergo further structure optimization with the ultimate goal of developing novel σ1R ligands for testing in neurodegeneration models of Alzheimer’s disease (AD). Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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18 pages, 1929 KiB

Open AccessArticle

Synthesis and the In Vitro Evaluation of Antitumor Activity of Novel Thiobenzanilides

by Maria João Álvaro-Martins, Violeta Railean, Filomena Martins, Miguel Machuqueiro, Rita Pacheco and Susana Santos

Molecules 2023, 28(4), 1877; https://doi.org/10.3390/molecules28041877 - 16 Feb 2023

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Abstract

Cancer is a generic term for a large group of diseases that are the second-leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Melanoma is a highly aggressive skin tumor with an increasing incidence and poor prognosis in the [...] Read more.

Cancer is a generic term for a large group of diseases that are the second-leading cause of death worldwide, accounting for nearly 10 million deaths in 2020. Melanoma is a highly aggressive skin tumor with an increasing incidence and poor prognosis in the metastatic stage. Breast cancer still stands as one of the major cancer-associated deaths among women, and diagnosed cases are increasing year after year worldwide. Despite the recent therapeutic advances for this type of cancer, novel drugs and treatment strategies are still urgently needed. In this paper, the synthesis of 18 thiobenzanilide derivatives (17 of them new) is described, and their cytotoxic potential against melanoma cells (A375) and hormone-dependent breast cancer (MCF-7) cells is evaluated using the MTT assay. In the A375 cell line, most of the tested thiobenzanilides derivatives showed EC₅₀ values in the order of μM. Compound 17 was the most promising, with an EC₅₀ (24 h) of 11.8 μM. Compounds 8 and 9 are also interesting compounds that deserve to be further improved. The MCF-7 cell line, on the other hand, was seen to be less susceptible to these thiobenzanilides indicating that these compounds show different selectivity towards skin and breast cancer cells. Compound 15 showed the highest cytotoxic potential for MCF-7 cells, with an EC₅₀ (24 h) of 43 μM, a value within the range of the EC₅₀ value determined for tamoxifen (30.0 μM). ADME predictions confirm the potential of the best compounds. Overall, this work discloses a new set of thiobenzanilides that are worth being considered as new scaffolds for the further development of anticancer agents. Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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24 pages, 2266 KiB

Open AccessArticle

Cannabidiol as Self-Assembly Inducer for Anticancer Drug-Based Nanoparticles

by Eleonora Colombo, Davide Andrea Coppini, Laura Polito, Umberto Ciriello, Giuseppe Paladino, Mariafrancesca Hyeraci, Maria Luisa Di Paolo, Giulia Nordio, Lisa Dalla Via and Daniele Passarella

Molecules 2023, 28(1), 112; https://doi.org/10.3390/molecules28010112 - 23 Dec 2022

Cited by 3 | Viewed by 1751

Abstract

Cannabidiol (CBD) is a biologically active compound present in the plants of the Cannabis family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The [...] Read more.

Cannabidiol (CBD) is a biologically active compound present in the plants of the Cannabis family, used as anticonvulsant, anti-inflammatory, anti-anxiety, and more recently, anticancer drug. In this work, its use as a new self-assembly inducer in the formation of nanoparticles is validated. The target conjugates are characterized by the presence of different anticancer drugs (namely N-desacetyl thiocolchicine, podophyllotoxin, and paclitaxel) connected to CBD through a linker able to improve drug release. These nanoparticles are formed via solvent displacement method, resulting in monodisperse and stable structures having hydrodynamic diameters ranging from 160 to 400 nm. Their biological activity is evaluated on three human tumor cell lines (MSTO-211H, HT-29, and HepG2), obtaining GI₅₀ values in the low micromolar range. Further biological assays were carried out on MSTO-211H cells for the most effective NP 8B, confirming the involvement of paclitaxel in cytotoxicity and cell death mechanism Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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14 pages, 2472 KiB

Open AccessArticle

Synthesis and Antiproliferative Effect of Halogenated Coumarin Derivatives

by Tinuccia Dettori, Giuseppina Sanna, Andrea Cocco, Gabriele Serreli, Monica Deiana, Vanessa Palmas, Valentina Onnis, Luca Pilia, Nicola Melis, Davide Moi, Paola Caria and Francesco Secci

Molecules 2022, 27(24), 8897; https://doi.org/10.3390/molecules27248897 - 14 Dec 2022

Cited by 4 | Viewed by 1875

Abstract

A series of 6- and 6,8-halocoumarin derivatives have been investigated as potential antiproliferative compounds against a panel of tumor and normal cell lines. Cytotoxic effects were determined by the MTT method. To investigate the potential molecular mechanism involved in the cytotoxic effect, apoptosis [...] Read more.

A series of 6- and 6,8-halocoumarin derivatives have been investigated as potential antiproliferative compounds against a panel of tumor and normal cell lines. Cytotoxic effects were determined by the MTT method. To investigate the potential molecular mechanism involved in the cytotoxic effect, apoptosis assay, cell cycle analysis, reactive oxygen species (ROS), and reduced glutathione analysis were performed. Among the screened compounds, coumarins 6,8-dibromo-2-oxo-2H-chromene-3-carbonitrile 2h and 6,8-diiodo-2-oxo-2H-chromene-3-carbonitrile 2k exhibited the most antiproliferative effect in thyroid cancer-derived cells TPC-1. The apoptosis assay showed that both 2h and 2k induced apoptosis in TPC-1 thyroid cancer cells. According to these experiments, both coumarins induced a slight increase in TPC-1 cells in the G2/M phase and a decrease in the S phase. A significant increase in ROS levels was observed in TPC-1 treated with diiodocoumarin 2k, while the dibromocoumarin 2h induced a decrease in ROS in a dose and time-dependent manner. Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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15 pages, 693 KiB

Open AccessArticle

Synthesis of Sulfonamides Incorporating Piperidinyl-Hydrazidoureido and Piperidinyl-Hydrazidothioureido Moieties and Their Carbonic Anhydrase I, II, IX and XII Inhibitory Activity

by Davide Moi, Alessandro Deplano, Andrea Angeli, Gianfranco Balboni, Claudiu T. Supuran and Valentina Onnis

Molecules 2022, 27(17), 5370; https://doi.org/10.3390/molecules27175370 - 23 Aug 2022

Cited by 3 | Viewed by 1443

Abstract

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. [...] Read more.

Here we report a small library of hydrazinocarbonyl-ureido and thioureido benzenesulfonamide derivatives, designed and synthesized as potent and selective human carbonic anhydrase inhibitors (hCAIs). The synthesized compounds were evaluated against isoforms hCA I, II, IX and XII using acetazolamide (AAZ) as standard inhibitor. Several urea and thiourea derivatives showed inhibitory activity at low nanomolar levels with selectivity against the cytosolic hCA II isoform, as well as the transmembrane, tumor-associated enzymes hCA IX and XII. The thiourea derivatives showed enhanced potency as compared to urea analogues. Additionally, eight compounds 5g, 5m, 5o, 5q, 6l, 6j, 6o and 6u were selected for docking analysis on isoform I, II, IX, XII to illustrate the potential interaction with the enzyme to better understand the activity against the different isoforms. Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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9 pages, 2296 KiB

Open AccessArticle

One-Step, Low-Cost, Operator-Friendly, and Scalable Procedure to Synthetize Highly Pure N-(4-ethoxyphenyl)-retinamide in Quantitative Yield without Purification Work-Up

by Silvana Alfei and Guendalina Zuccari

Molecules 2022, 27(11), 3632; https://doi.org/10.3390/molecules27113632 - 06 Jun 2022

Viewed by 1569

Abstract

It is widely reported that N-(4-hydroxyphenyl)-retinamide or fenretinide (4-HPR), which is a synthetic amide of all-trans-retinoic acid (ATRA), inhibits in vitro several types of tumors, including cancer cell lines resistant to ATRA, at 1–10 µM concentrations. Additionally, studies in rats and mice [...] Read more.

It is widely reported that N-(4-hydroxyphenyl)-retinamide or fenretinide (4-HPR), which is a synthetic amide of all-trans-retinoic acid (ATRA), inhibits in vitro several types of tumors, including cancer cell lines resistant to ATRA, at 1–10 µM concentrations. Additionally, studies in rats and mice have confirmed the potent anticancer effects of 4-HPR, without evidencing hemolytic toxicity, thus demonstrating its suitability for the development of a new chemo-preventive agent. To this end, the accurate determination of 4-HPR levels in tissues is essential for its pre-clinical training, and for the correct determination of 4-HPR and its metabolites by chromatography, N-(4-ethoxyphenyl)-retinamide (4-EPR) has been suggested as an indispensable internal standard. Unfortunately, only a consultable old patent reports the synthesis of 4-EPR, starting from dangerous and high-cost reagents and using long and tedious purification procedures. To the best of our knowledge, no article existed so far describing the specific synthesis of 4-EPR. Only two vendors worldwide supply 4-ERP, and its characterization was incomplete. Here, a scalable, operator-friendly, and one-step procedure to synthetize highly pure 4-EPR without purification work-up and in quantitative yield is reported. Additionally, a complete characterization of 4-EPR using all possible analytical techniques has been provided. Full article

(This article belongs to the Special Issue Research of Organic Chemicals for Biological Applications)

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