Design, synthesis, molecular docking and ADME studies of novel indole-thiazolidinedione derivatives and their antineoplastic activity as CDK6 inhibitors


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Kışla M. M., Zengin Karadayı F., Baran S., Doğan T., Mutlu P., Ateş-Alagöz Z.

NEW JOURNAL OF CHEMISTRY, cilt.45, ss.111-133, 2021 (SCI-Expanded)

  • Yayın Türü: Makale / Tam Makale
  • Cilt numarası: 45
  • Basım Tarihi: 2021
  • Doi Numarası: 10.1039/dinj02808a
  • Dergi Adı: NEW JOURNAL OF CHEMISTRY
  • Derginin Tarandığı İndeksler: Science Citation Index Expanded (SCI-EXPANDED), Scopus, Academic Search Premier, Biotechnology Research Abstracts, Chemical Abstracts Core, Chimica, Compendex, EMBASE, DIALNET
  • Sayfa Sayıları: ss.111-133
  • Orta Doğu Teknik Üniversitesi Adresli: Evet

Özet

Several 5-((5-substituted-1H-indole-3-yl)methylene)-3-(2-oxo-2-(3/4-substituted-phenylethyl)-thiazolidine-2,4-dione derivatives (9–24) were designed and synthesized as CDK6 inhibitors, and their anticancer activity was probed on the MCF-7 breast cancer cell line and their effects on gene expression profiles were elucidated. According to biological activity assays, compounds 10, 15, and 18 were found to possess favorable cytotoxicity on this cell line. For a better understanding of their activity rationale, genomic studies were conducted. Changes in gene expression levels occurring in MCF-7 cells were studied on 48 genes selected among genes associated with the estrogen receptor, tumor suppressor and oncogenes, microtubule formation, apoptosis, the cell cycle, drug resistance and inflammation. It was determined that there are significant differences in gene expression levels in 21 of these genes. Comparing to other genes, these compounds inhibited gene expression of CDK6 much more. For a more thorough evaluation of their mechanism of action involving this pathway, docking analysis was performed with a corresponding enzyme that is synthesized by the CDK6 gene. By doing so, the binding profiles of these derivatives were compared to the reference study. In the end, the impact of the indole-thiazolidinediones on CDK6 and their mechanisms of action were elucidated. Compounds 15 and 18 possess higher affinity with better binding interactions relative to that of compound 10. These two compounds were highlighted as possible candidates for upcoming design studies of CDK6 inhibitors. Moreover, the druglikeness of the indole-thiazolidinediones was calculated and compared to commercial anticancer drugs.