Immunomodulatory quinazoline-based thalidomide analogs: Design, synthesis, apoptosis and anticancer evaluations
Abdallah E. Abdallah, Ibrahim H. Eissa, Ahmed B. M. Mehany, Helmy Sakr, Ahmed Atwa, Khaled El‐Adl, Mohamed Ayman El‐Zahabi
Abstract
In our effort to discover potential immunomodulatory anticancer candidates, a new series of quinazolinone derivatives carrying glutarimide moiety were designed and synthesized as thalidomide analogs. The antiproliferative properties of the new compounds relative to that of thalidomide (racemic) were evaluated against four human cancer cell lines; namely: breast cancer (MCF-7), colorectal carcinoma (HCT-116), hepatocellular carcinoma (HepG-2), and prostate cancer (PC3). Compound 6d emerged as the most significant candidate. It showed IC 50 of 6.93, 8.13, 7.96, and 24.03 μM, compared to 45.76, 32.12, 61.10, and 76.91 µM reported for thalidomide against the four mentioned cell lines, respectively. Similarly, 6e and 6l , revealed far better results than thalidomide. Further biological data revealed that 6d caused significant decreases in TNF-α and IL-6 levels by 78.53% and 80.29%, respectively, compared to 41.39% and 45.11% caused by thalidomide. Additionally, 6d was comparable to thalidomide in raising caspase-3 levels by approximately 6 folds. COX-I and COX-II inhibitions by 6d were approximately six and fifteen times stronger than those of thalidomide. Meanwhile, 6d showed IC 50 of 241 nM against VEGFR compared to 874 nM reported for thalidomide. Furthermore, 6d was similar to thalidomide in suppressing the cell cycle and accumulation of MCF-7 cells at Pre-G1, revealing a sharp increase in apoptosis rate from 65.64% in control cells to 99.88% in cells treated with 6d . This work suggests that 6d is of great significant to be considered in the development of new antitumor clinical molecules.