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Benign Synthesis of Thiazolo-androstenone Derivatives as Potent Anticancer Agents.

ABSTRACT: An unprecedented reaction of thiourea derivatives with 6?-bromoandrostenedione has been discovered for the formation of aminothiazolo-androstenones via a simple, safer, cascade protocol that enables the syntheses of novel molecules by using readily available reagents. The reaction mechanism of product formation has been rationalized by density functional theory calculations. This benign methodology accentuates a domino protocol deploying a renewable solvent, ethanol, while generating novel compounds that display potent growth inhibitory effects in in vitro studies for several cancer cell lines at submicromolar concentrations.

SUBMITTER: Ali MA

PROVIDER: S-EPMC6441354 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Benign Synthesis of Thiazolo-androstenone Derivatives as Potent Anticancer Agents.

Ali Mohamad Akbar MA Okolo ChrisTina C Alsharif Zakeyah A ZA Whitt Jedidiah J Chambers Steven A SA Varma Rajender S RS Alam Mohammad A MA

Organic letters 20180911 18

An unprecedented reaction of thiourea derivatives with 6β-bromoandrostenedione has been discovered for the formation of aminothiazolo-androstenones via a simple, safer, cascade protocol that enables the syntheses of novel molecules by using readily available reagents. The reaction mechanism of product formation has been rationalized by density functional theory calculations. This benign methodology accentuates a domino protocol deploying a renewable solvent, ethanol, while generating novel compo ...[more]

PMID: 30204455

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Project description:This study reports the formation of 5-FU co-crystals with four different pharmacologically safe co-formers; Urea, Thiourea, Acetanilide and Aspirin using methanol as a solvent. Two fabrication schemes were followed i.e., solid-state grinding protocol, in which API and co-formers were mixed through vigorous grinding while in the other method separate solutions of both the components were made and mixed together. The adopted approaches offer easy fabrication protocols, no temperature maintenance requirements, no need of expensive solvents, hardly available apparatus, isolation and purification of the desired products. In addition, there is no byproducts formation, In fact, a phenomenon embracing the requirements of green synthesis. Through FTIR analysis; for API the N-H absorption frequency was recorded at 3409.02 cm-1 and that of -C[bond, double bond]O was observed at 1647.77 cm-1. These characteristics peaks of 5-FU were significantly shifted and recorded at 3499.40 cm-1 and 1649.62 cm-1 for 5-FU-Ac (3B) and 3496.39 cm-1 and 1659.30 cm-1 for 5-FU-As (4B) co-crystals for N-H and -C[bond, double bond]O groups respectively. The structural differences between API and co-crystals were further confirmed through PXRD analysis. The characteristic peak of 5-FU at 2? = 28.79918o was significantly shifted in the graphs of co-crystals not only in position but also with respect to intensity and FWHM values. In addition, new peaks were also recorded in all the spectra of co-formers confirming the structural differences between API and co-formers. In addition, percent growth inhibition was also observed by all the co-crystals through MTT assay against HCT 116 colorectal cell lines in vitro. At four different concentrations; 25, 50, 100 and 200 µg/mL, slightly different trends of the effectiveness of API and co-crystals were observed. However; among all the co-crystal forms, 5-FU-thiourea co-crystals obtained through solution method (2B) proved to be the most effective growth inhibitor at all the four above mentioned concentrations.

Project description:Objective:There is an urgent need drugs against particularly difficult to treat solid tumors such as pancreatic, triple negative breast, lung, colon, metastatic prostate cancers and melanoma. Thus, the objective of this study was to synthesize compounds based computational modeling that indicated the pyrido[3,4-b]indole class bind to MDM2, a new cancer target for which there are still no drug on the market. Methods:Compounds were synthesized by established methods and tested for antiproliferative activity against a broad range of human cancer cell lines, comprising HCT116 colon, HPAC, MIA PaCa-2 and Panc-1 pancreatic, MCF-7 and MDA-MB-468 breast, A375 and WM164 melanoma, A549 lung, and LNCaP, DU145 and PC3 prostate cancer lines. Computational docking was also undertaken. Results:The novel pyrido[3,4-b]indoles synthesized exhibited a clear SAR with regards to antiproliferative activity, with potent broad-spectrum anticancer activity with IC50s down to 80, 130, 130 and 200 nM for breast, colon, melanoma and pancreatic cancer cells, respectively. 1-Naphthyl at C1 combined with methoxy at C6 provided the best antiproliferative activity. Thus, compound 11 (1-naphthyl-6-methoxy-9H-pyrido[3,4-b]indole) showed the highest potency. A mechanistic feature of the compounds as a group is a strongly selective G2/M cell cycle phase arrest. Docking at on MDM2 suggested a hydrogen bond interaction between the 6-methoxy Tyr106, hydrophobic interaction with Val93, pi-pi stacking interactions with Tyr100 and His96 and hydrophobic interactions with Leu54 and Ile99. An N9-methyl group disrupted binding interactions, such as H-bond interactions involving the N9 hydrogen. Conclusion:We have identified a novel series of pyrido[3,4-b]indoles with potent broad spectrum anticancer activity towards the most aggressive and difficult to treat cancers including metastatic pancreatic cancer, non-small cell lung cancer, triple negative breast cancers, and BRAFV600E mutant melanoma, as well as metastatic colon and prostate cancers. There was also evidence of selectivity towards cancer cells relative to normal cells. These compounds will serve as new leads from which novel therapeutics and molecular tools can be developed for a wide variety of cancers.

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Benign Synthesis of Thiazolo-androstenone Derivatives as Potent Anticancer Agents.

Publications

Benign Synthesis of Thiazolo-androstenone Derivatives as Potent Anticancer Agents.

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