New [1,2,4]triazolo[4,3-c]quinazolines As Intercalative Topo II Inhibitors: Design, Synthesis, Biological Evaluation, and in Silico Studies

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2023 Jan 30

PMID 36716311

Authors

Ahmed A Gaber

Mohamed Sobhy

Abdallah Turky

Wagdy M Eldehna

Samiha A El-Sebaey

Souad A El-Metwally

Abeer M El-Naggar

Ibrahim M Ibrahim

Eslam B Elkaeed

Ahmed M Metwaly

Ibrahim H Eissa

Affiliations

Soon will be listed here.

Abstract

Fifteen quinazoline derivatives were designed and synthesized as DNA intercalators. The cytotoxicity of the designed members was assessed against HCT-116 and HepG2 cancer cell lines. In addition, the topoisomerase II (Topo II) inhibitory effect was assessed. Compound 16 was the most cytotoxic and Topo II inhibitor with low cytotoxicity against Vero cells. Compounds 16, 17, and 18 showed significant DNA binding affinities. Compound 16 showed Topo II catalytic inhibitory effect at a concentration of 10 μM. Further mechanistic investigations revealed the capability of compound 16 to induce apoptosis in HCT-116 cells and arrest the growth at the S and G2/M phases. Also, compound 16 showed a significant increase in the level of BAX (2.18-fold) and a marked decrease in the level of Bcl-2 (1.9-fold) compared to the control cells. In silico studies revealed the ability of the synthesized members to bind to the DNA-Topo II complex.

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