Design, synthesis, and biological evaluation of a hydrophilic 20-O-glycyl ester prodrug of 10-methoxycamptothecin against lung cancer.

10-Methoxycamptothecin (MCPT), a naturally occurring derivative of camptothecin (CPT), exhibits potent antitumor activity but is hampered by poor aqueous solubility and limited oral bioavailability. To overcome these limitations, we rationally designed and synthesized MG16, a hydrophilic 20-O-glycyl ester prodrug of MCPT. MG16 showed markedly improved solubility in a 5% glucose solution, supporting its suitability for intravenous administration. In vitro, MG16 exhibited strong cytotoxic activity against Lewis lung carcinoma (LLC) cells and the human lung cancer cell lines A549 and H446. Although its potency was modestly reduced compared with that of MCPT, MG16 was substantially more active than SN-38, the active metabolite of CPT-11. Consistent with these findings, MG16 achieved superior tumor growth inhibition relative to CPT-11 in both syngeneic LLC and A549 xenograft mouse models. Mechanistically, MG16 and MCPT more effectively downregulated cyclin-dependent kinase 6 (CDK6) and upregulated apoptosis signal-regulating kinase 1 (ASK1) than SN-38 did, accompanied by pronounced G0/G1 cell cycle arrest and increased induction of apoptosis. This coordinated modulation of cell cycle progression and apoptotic signaling likely underpins the enhanced antitumor efficacy of MG16. Collectively, these results highlight MG16 as a promising hydrophilic prodrug candidate for the treatment of lung cancer.