Hybrid nucleobase–heterocycle–2-oxindole scaffolds as innovative cell cycle modulators with potential anticancer activity

Abstract

A series of hybrid molecules 6a–6d–13a–13d combining pyrazolo[3,4-d]pyrimidine or aminopurine frameworks with an oxindole moiety were designed as multitarget anticancer agents. Several compounds, especially 8b and 12a–12d, showed potent antiproliferative effects against three human cancer cell lines: A498 (kidney carcinoma), HepG-2 (hepatocellular carcinoma), and MDA-MB-231 (breast adenocarcinoma). Compounds 6b, 7b, 8b, and 12a–12c exhibited remarkable CDK6 inhibition (pIC₅₀ of up to 7.17), outperforming palbociclib, and VEGFR-2 inhibition comparable to sorafenib. These compounds also inhibited xanthine oxidase. Notably, 12a and 12c induced sub-G1 cell cycle arrest in HepG2 cells. Molecular modeling confirmed stable binding to CDK6 and VEGFR-2, while in silico ADMET profiling suggested favorable pharmacokinetics. These results support 8b and 12a–12c as strong leads for further multitarget cancer therapy development.