Title : Novel nucleobase–2-oxindole–heterocyclic hybrids as selective cell cycle regulators with potential anticancer activities
Abstract:
Cancer remains a global health threat despite advances in research and technology. According to International Agency for Research on Cancer, the cancer burden will increase by about 77% by 2050, further straining health systems, people and communities. Although cancer chemotherapy has progressed in major strides in recent years, there is still an unmet need for new anti-cancer agents with good potency, diminished toxicity and able to treat tumors that are resistant to currently known drugs. In recent years, cell cycle and checkpoint pathways regulation are offering new therapeutic approaches against cancer. Targeting the cell cycle holds promise but further optimization is necessary to fully exploit it as an anti-cancer strategy across diverse malignancies. Accordingly, a novel series of small molecules integrating pyrazolo[3,4-d]pyrimidine or aminopurine cores with an oxindole moiety (6a–d–13a–d) was synthesized as potential multitarget anticancer agents. Compounds 8b and 12a–d displayed notable antiproliferative activity against A498, HepG2, and MDA-MB-231 cell lines, with IC?? values in the low micromolar range. Select compounds (6b, 7b, 8b, 12a–c) exhibited potent CDK6 inhibition (pIC?? up to 7.17), surpassing palbociclib, and VEGFR-2 inhibition comparable to sorafenib. Additionally, they demonstrated significant xanthine oxidase inhibition. Compounds 12a and 12c induced sub-G1 phase arrest and caspase-3-mediated apoptosis in HepG2 cells, supporting selective CDK6 inhibition. Docking and molecular dynamics studies confirmed stable binding to CDK6 and VEGFR-2. In silico ADMET analysis predicted favorable pharmacokinetic properties. These findings highlight 8b and 12a–c as promising multitarget anticancer leads.
