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 (<b>1a</b>-<b>31a</b> and <b>1b</b>-<b>31b</b>) 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 5<i>R</i>-<b>12a</b> (IC₅₀ = 0.05 ± 0.01 μM against HCT-116) and 5<i>R</i>-<b>6a</b> (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 <b>12a</b> and <b>6a</b> 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 5<i>R</i> configuration. This work would offer new insights for CPT lead compound development.