Palladium-Catalyzed Late-Stage Functionalization of Natural Antitumor Drug: Synthesis and Bioactivity of 5‑Aryl Camptothecins

Camptothecin (CPT) and its derivatives have garnered significant interest due to their potent anticancer activity. In this study, 62 novel CPT derivatives (1a–31a and 1b–31b) were designed and synthesized through Pd-catalyzed late-stage modification at the C-5 position. The anticancer efficacy of these compounds against three human cancer cell lines was evaluated. Compounds 5R-12a (IC50 = 0.05 ± 0.01 μM against HCT-116) and 5R-6a (IC50 = 0.04 ± 0.03 μM against MCF-7) exhibited enhanced antitumor activity when compared to CPT. The preliminary mechanism of apoptosis was investigated through cell viability assays, protein expression, and docking analysis. The results indicated that compounds 12a and 6a exhibited a greater ability to induce apoptosis and G2/M phase arrest than did CPT. Docking results provided a possible explanation for the superior activity of the 5R configuration. This work would offer new insights for CPT lead compound development.