SYHTHESIS, ANTINEOPLASTIC ACTIVITY AND MOLECULAR DOCKING STUDIES OF NOVEL INDOLE- THIAZOLIDINEDIONE DERIVATIVES


Kışla M. M. , Zengin Karadayı F., Doğan T., Mutlu P., Alagöz Z.

13 th International Symposium on Pharmaceutical Sciences, Ankara, Turkey, 22 - 25 June 2021, pp.63

  • Publication Type: Conference Paper / Summary Text
  • City: Ankara
  • Country: Turkey
  • Page Numbers: pp.63
  • Middle East Technical University Affiliated: Yes

Abstract

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). After
synthesizing 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.