Design and novel synthetic approach supported with molecular docking and biological evidence for naphthoquinone-hydrazinotriazolothiadiazine analogs as potential anticancer inhibiting topoisomerase-IIB.

Autor: Mohamady S; Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Center of Drug Research and Development (CDRD), The British University in Egypt, Cairo, Egypt. Electronic address: samy.mohamady@bue.edu.eg., Gibriel AA; Center of Drug Research and Development (CDRD), The British University in Egypt, Cairo, Egypt; Biochemistry & Molecular Biology Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt., Ahmed MS; Department of Internal Medicine, Division of Cardiology, University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: mahmoud.ahmed@utsouthwestern.edu., Hendy MS; Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Center of Drug Research and Development (CDRD), The British University in Egypt, Cairo, Egypt., Naguib BH; Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt, Cairo, Egypt; Center of Drug Research and Development (CDRD), The British University in Egypt, Cairo, Egypt; Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Jazyk: angličtina
Zdroj: Bioorganic chemistry [Bioorg Chem] 2020 Mar; Vol. 96, pp. 103641. Date of Electronic Publication: 2020 Jan 30.
DOI: 10.1016/j.bioorg.2020.103641
Abstrakt: A novel synthetic approach was developed for the synthesis of 3-hydrazinotriazolothiadiazines in just one step from Purpald and phenacyl bromides. They were then selectively tethered to naphthoquinone fragments through hydrazine moiety generating novel Naphthoquinone-hydrazinotriazolothiadiazine analogues. In vitro cytotoxicity for the synthesized chemical entities was validated against HepG2 and MCF-7 cell lines and recorded IC 50 inhibitory profile range of 0.07-19.68 µM and 1.19-67.32 µM respectively. Among the synthesized series, compound 4c had maximal cytotoxicity against HepG2 and was therefore selected for further downstream biological investigations. Caspase 3 apoptotic marker was significantly upregulated in cells treated with compound 4c with induction of apoptosis at Pre-G1 phase and cell death at G2/M phase. Compounds 4a, 4c and 4d exhibited the most powerful inhibitory range (0.55-0.64 µM) against Topo IIB. Molecular docking study revealed potential interactions of those compounds within the ATP catalytic binding domain of Topo-IIB with high scores. In conclusion, the novel Naphthoquinone-hydrazinotriazolothiadiazine analogues could serve as promising anticancer agents through inhibition of Topoisomerase-IIB.
Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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