Synthesis of novel spirochromane incorporating Schiff's bases, potential antiproliferative activity, and dual EGFR/HER2 inhibition: Cell cycle analysis and in silico study.

Spirochromanes incorporating Schiff's bases and semicarbazones 4a-e and 5a-j were synthesizedand analyzed for their potential antiproliferative activity using four human cancer cell lines (MCF-7, HCT-116, PC3, and A549). Compounds 5a, 5b and 5g possessed the highest antiproliferative activity among the tested compounds,with an IC50 range of 1.154-9.09 µM. Compound 5j selectively inhibited the PC3 cell proliferation (IC50 = 5.47 µM). Spirochromanes 5a, 5b and 5g exhibited high inhibitory activity against EGFR (IC50 = 0.116, 0.132, and 0.077 µM, respectively) and HER2 (IC50 = 0.055, 0.210 and 0.085 µM, respectively) compared with the references, erlotinib (IC50 = 0.090 and 0.038 µM, respectively) and gefitinib (IC50 = 0.052 and 0.072 µM, respectively). Cell cycle analysis and apoptosis results showed that compounds 5a, 5b and 5g arrested growth inthe S phase, and the programmed cell death induced by these compounds was an apoptotic mechanism rather than a necrotic pathway. Molecular docking studies of spirochromanes 5a, 5b and 5g to EGFR and HER2 binding sites were performed to explore the orientation mode and interaction.

Synthesis, antitumor, and apoptosis-inducing activities of novel 5-arylidenethiazolidine-2,4-dione derivatives: Histone deacetylases inhibitory activity and molecular docking study.

The antitumor activity of the newly synthesized 5-arylidenethiazolidine-2,4-dione derivatives 18a-f and 19a-f was investigated, compared to doxorubicin (IC50 = 4.17-8.87 µM) and SAHA (IC50 = 2.70-7.11 µM). Among the tested molecules, compounds 18b, 18c, 18f, 19d, and 19e displayed the highest antitumor activity against cancer cell lines (IC50 = 3.16-28.94 µM). Further, compounds 18b, 18c, 18f, and 19d were tested as Histone deacetylases (HDACs) inhibitors compared with Entinostat (IC50 = 0.093-0.75 µM). Compounds 18b, 18c, 18f, and 19d inhibited HDAC1, HDAC2, HDAC8, and HDAC6 enzymes with IC50 values ranging from 0.144 to 1.741 µM. In addition, compound 18b caused apoptosis via a mitochondrial-mediated pathway and led to cell cycle arrest at the G1 phase. It also increased caspases-3 and caspases-7 by 5.2-3.9 and 9.1-3.7 folds, respectively. The molecular docking analysis of compounds 18b and 18c revealed that they could bind to the active sites of HDAC1, HDAC2, HDAC8, and HDAC6 like co-crystallized inhibitors.