Yhthesis, Antineoplastic Activity And Molecular Docking Studies Of Novel Indole- Thiazolidinedione Derivatives

Introduction: Cyclin-dependent kinase 6 (CDK6) became a valid target for breast cancer therapy over the past decades. Binding of this enzyme to E2F transcription factors eventually controls cell division. Therefore, inhibition of this enzyme becomes vital in apoptosis of the breast cancer cells. Besides, indole-thiazolidinediones prove to be a valuable asset in breast cancer therapy. The wide range of findings in this study area has encouraged us to design and synthesize novel indole-thiazolidinedione derivatives (9-24) (1, 2). Materials and Methods: For the synthesis of the derivatives 9-24, mixture of appropriate indole-3-carboxaldehyde, phenacyl-methyl-thiazolidine-2,4-dione and diethanolamine in MeOH was refluxed until starting materials were consumed (determined by TLC, purified with cc). Aftersynthesizing these derivatives, their anticancer activity was probed on MCF-7 cell lines and their gene suppressing profiles were elucidated. For the thorough evaluation of their mechanism of action involving CDK6 pathway, docking of these compounds and standard Palbociclib was made with corresponding enzyme using AutoDock Vina (3). Moreover, druglikeness of indole-thiazolidinedione derivatives were calculated with SwissADME (4) and compared to the commercial anticancer drugs. Results: According to biological activity assays; compounds 10, 15, and 18 were found to possess favorable cytotoxicity on MCF-7 cells. Comparing to other genes, these compounds inhibited gene expression of CDK6 remarkably. Regarding docking analysis, 15 and 18 possessed higher affinity with better binding interactions relative to that of compound 10. Conclusions: With higher gene suppression characteristics, and low IC50 values, compounds 15 and 18 were highlighted as possible candidates for the upcoming design studies of CDK6 inhibitors. These compounds also have had better interaction profiles with the related enzyme. Acknowledgements The work was supported by Ankara University Research Grant under grant number: 19B0237003