Akademik Veri Yönetim Sistemi
Bioorganic Chemistry, cilt.175, 2026 (SCI-Expanded, Scopus)
Cancer remains a formidable disease with significantly high mortality rates worldwide. Herein, we attempted to design and evaluate a new class of VEGFR-2 and HDAC dual acting anticancer agents. The rationale was based on the defined pharmacophores of VEGFR-2 inhibitors and HDAC inhibitors, as we synthesized new quinazolinone based-benzamides that bring together both features. The new candidates showed considerable in vitro activity against MDA-MB-231 and HCT-116 cancer cell lines, in particular 4-hydroxyphenylbenzamide derivative of 3-ethylquinazolinone 7d, which revealed IC50 of 5.39 ± 0.08 μM and 4.11 ± 0.13 μM, in comparison with IC50 of 29.13 ± 2.28 μM and 33.50 ± 2.43 μM, obtained for the reference drug, sorafenib, respectively. So, 7d was approximately 5.4-fold and 8.2-fold more potent than sorafenib against the aforementioned cell lines, respectively. Additionally, 7d had far better selectivity to cancer cells, showing selectivity indices of 5.11 and 6.68, compared to 1.73 and 1.51 recorded for sorafenib against the two cancer cell lines, respectively. Furthermore, it also showed a significant dual inhibition of VEGFR-2 and HDAC-2. It showed IC50 of 0.407 ± 0.015 μM against VEGFR-2, revealing approximately half the potency of sorafenib. Whereas, It was approximately 1.26 times more potent than vorinostat against HDAC-2, demonstrating an IC50 of 0.363 ± 0.013 μM. Furthermore, 7a was proven to be an apoptotic inducer to HCT-116 cells, increasing the apoptosis rate by 10-folds and causing cell cycle arrest at the G1 phase. Meanwhile, the expression level of caspase-3 and the BAX/BCL-2 ratio were markedly elevated in HCT-116 cells treated with 7d . Finally, the presented data are reliable for developing dual VEGFR-2 and HDAC inhibitors as anticancer drugs and reveal lead molecules for such purpose.