In Silico Studies and In Vitro Microsomal Metabolism of Potent MetAP2 Inhibitor and In Vivo Tumor Suppressor for Prostate Cancer: A Thioether-Triazole Hybrid

Göknil Coşkun; Kaan Birgül; Asaf Evrim Evren; Ş. Güniz Küçükgüzel; Mert Ülgen

doi:10.31067/acusaglik.1210129

EN

In Silico Studies and In Vitro Microsomal Metabolism of Potent MetAP2 Inhibitor and In Vivo Tumor Suppressor for Prostate Cancer: A Thioether-Triazole Hybrid

Abstract

Background/aim: The in-vitro microsomal metabolism of (S)-3-((2,4,6-trimethylphenyl)thio)-4-(4-fluorophenyl)-5-(1-(6-methoxynaphtalene-2-yl)ethyl)-4H-1,2,4-triazole (SGK636), an anticancer drug candidate was studied using pig microsomal preparations fortified with NADPH to identify the potential S-oxidation and S-dealkylation metabolites. Materials and methods: In the present study, the sulfoxide metabolite was synthesized, purified and characterized by chromatographic and spectroscopic methods. SGK636, the S-oxidation and S-dealkylation metabolites were then separated by a reversed phase LC-MS, with UV detection and with an HP-TLC system. The results from the in-vitro microsomal metabolic experiments showed that SGK636 produced the corresponding S-oxidation metabolite (sulfoxide) which was observed by LC-MS, LC-MS/MS and HP-TLC with the identical Rt and Rfx100 values and UV/MS spectra in comparison with the authentic compounds, but no any S-dealkylation metabolite was detected. Results: The present results were proved with molecular docking and molecular dynamic studies. Since sulfoxidation process can be reversible and it may partly explain the low amount of sulfoxide metabolite in our experiment, we also incubated the sulphoxide. No conversion back to the substrate (SGK636) was observed, but it produced the corresponding sulphone metabolite. In order to establish if SGK636 is autooxidized, the substrate was also incubated in buffer under standard incubation conditions, but no any autooxidation was observed into the corresponding sulfoxide. We also did a stability work for SGK636-SO (sulfoxide) in buffer to see any possible autooxidation to sulphone or reduction back to SGK636. No conversion was observed in either way. The substrate seems to be stable to metabolic reactions and to autooxidation which could be an advantage in terms of its pharmacological activity. Conclusion: The present metabolic and study indicates that SGK 636 underwent S-oxidation. In order to identify the responsible oxydative enzyme, molecular docking and molecular dynamic studies were performed. CYP3A4 was found to be responsible enzyme for S-oxidation.

Keywords

Supporting Institution

TUBITAK

Project Number

215S009

Thanks

The synthesis and confirmation SGK636 and (S)-Naproxen triazole were supported by a grant of TUBITAK (Project number: 215S009). (+) (S)-Naproxen, was obtained from Deva Ilaç San. Tic. A. S. , Turkey. The pig livers were donated by Acibadem University, Animal Laboratory Centre from the Project by Dr. Mehmet Emin Aksoy; laparoscopic and robotic surgery course, with the 2021-01 ethical approval number. The liver tissue was obtained from the euthanized pig at the end of course. Authors are gratefull to Chemist Ummet Melikoğlu (Acıbadem LABMED employee) for performing LC-MS/MS analyses for the compounds.

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Details

Primary Language

English

Subjects

Endocrinology

Journal Section

Research Article

Authors

Göknil Coşkun ^*
0000-0001-5168-3866
Türkiye

Kaan Birgül
0000-0003-3963-4687
Türkiye

Asaf Evrim Evren
0000-0002-8651-826X
Türkiye

Ş. Güniz Küçükgüzel
0000-0001-9405-8905
Türkiye

Mert Ülgen
0000-0003-4913-4950
Türkiye

Publication Date

January 1, 2023

Submission Date

November 25, 2022

Acceptance Date

December 12, 2022

Published in Issue

Year 1970 Volume: 14 Number: 1

DOI

https://doi.org/10.31067/acusaglik.1210129

IZ

https://izlik.org/JA32ML83BS

Cite

RIS / Bibtex

EndNote

Coşkun G, Birgül K, Evren AE, Küçükgüzel ŞG, Ülgen M (January 1, 2023) In Silico Studies and In Vitro Microsomal Metabolism of Potent MetAP2 Inhibitor and In Vivo Tumor Suppressor for Prostate Cancer: A Thioether-Triazole Hybrid. Acıbadem Üniversitesi Sağlık Bilimleri Dergisi 14 1 10–23.