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  2. Novel purine derivatives as selective CDK2 inhibitors with potential anticancer activities: Design, synthesis and biological evaluation

Novel purine derivatives as selective CDK2 inhibitors with potential anticancer activities: Design, synthesis and biological evaluation

  • Bioorg Chem. 2024 Sep 24:153:107841. doi: 10.1016/j.bioorg.2024.107841.
Alpesh Shah 1 Nishith Teraiya 2 Jignesh H Kamdar 3 Tanzil Juneja 3 Chetan B Sangani 4 Sarfaraz Ahmed 5 Khushal Kapadiya 6
Affiliations

Affiliations

  • 1 BRCC Laboratory, Department of Chemistry, School of Science, RK University, Rajkot 360 020, Gujarat, India.
  • 2 Department of Pharmaceutical Chemistry, K B Institute of Pharmaceutical Education and Research, Kadi Sarva Vishvavidhyalay, Gandhinagar 382023, Gujarat, India.
  • 3 Department of Microbiology, School of Science, RK University, Rajkot 360 020, Gujarat, India.
  • 4 Department of Chemistry, Government Science College Sector-15, Gandhinagar - 382016, Gujarat University, Gujarat, India.
  • 5 Department of Pharmacognosy, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
  • 6 BRCC Laboratory, Department of Chemistry, School of Science, RK University, Rajkot 360 020, Gujarat, India. Electronic address: khushal.kapadiya@rku.ac.in.
Abstract

Purine analogues were discovered to be inhibitors of CDK2, suggesting a potential therapeutic scaffold. This paper addresses the design, synthesis, and Anticancer evaluation of purine analogues as kinase inhibitors. In the early stages of the investigation, the designed compounds demonstrated a promising docking score and greater protein-ligand stability in MD simulation than the standard, indicating a higher affinity against CDK2. Thus, we synthesised new purine analogues under simple and optimised reaction conditions. Among the studies under NCI-60, 5g and 5i were the most effective, with a percentage GI of 98.09 and 90 against OVCAR-4 and SNB-75, respectively, at a dose of 10 µM. Additionally, 5g and 5i demonstrated 7.80-fold and 1.54-fold greater cytotoxicity against PA-1 and MCF-7, with IC50s of 1.08 µM and 3.54 µM, respectively, compared to seliciclib (8.43 µM and 5.46 µM). In addition, 5g and 5i showed selective cytotoxicity against PA-1 and MCF-7 than normal cells, with selectivity indexes of 26.40 and 15.45, respectively, as compared to the standard (SI=3.83 and 5.91). In the kinase selectivity assay, both compounds demonstrated greater affinity against CDK2 than other kinases, with IC50 of 0.21 µM and 0.59 µM, in contrast to the standard (IC50 = 0.63 µM). Furthermore, 5g confirmed kinase inhibition in the western blot by lowering CDK2, cyclin A2, and other downstream substrates. Moreover, it triggered cell death by Apoptosis and cell cycle arrest in G2/M. Taken together, 5g merits further investigation in PKPD research to discover a potential therapeutic candidate against Cancer.

Keywords

Apoptosis; CDKs inhibition; Docking study; Purine nucleoside.

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