Leveraging the Fragment Merging Approach for Synthetizing Novel Selanyl Phenyl Acetamide Thiazolidinedione Hybrids Endowed With Apoptotic Potential for Cancer Treatment.

Designing novel selenium-containing compounds (organoselenium compounds, OSe) has shown growing interest owing to their chemoprotective and antioxidant properties. Consequently, by harnessing a fragment merging approach, a series of novel OSe hybrid compounds bearing selanyl phenyl acetamide and thiazolidinedione scaffolds were designed and synthesized (8-10, 11a-c, 12a-c, 13a-c, and 14). The growth inhibition percentages (GI%) of the newly afforded OSe were evaluated using seven human cancer cells along with one normal cell line to ensure selectivity and safety. Interestingly, it was revealed that compound 9 exhibited the best mean GI% (75.54%), surpassing the doxorubicin (Dox) mean GI% of 72.28%. In addition, the inhibitory concentration 50 (IC50) values of the frontier compounds 9, 13a, 13c, 12b, and 12c were assessed against cancer cell lines PC3, MCF7, and HCT116. Compound 13c displayed the lowest IC50 value (5.195 µM) at the PC3 cancer cell line, surpassing doxorubicin (8.065 µM). Besides, compounds 9 and 12c revealed the lowest IC50 values (21.045 and 13.575 µM) against MCF7 and HCT116, respectively. Moreover, analogues 9 and 13c were chosen to examine their ability to induce apoptosis and showed the upregulation of proapoptotic proteins: Caspases (3, 7, and 9) and BAX, besides the downregulation of the antiapoptotic BCL2, MMP2, and MMP9 proteins. Furthermore, in silico molecular docking studies targeting BCL-2, along with ADMET analyses, were performed. The results indicated that the tested compounds demonstrated favourable binding affinity to the selected target and exhibited acceptable pharmacokinetic properties. Consequently, these compounds can be considered promising lead candidates for inducing apoptosis in cancer cells, warranting further optimization.