A Concise and Scalable Synthesis of a Camptothecin Analogue with Enhanced Topoisomerase i Inhibition

Abstract

Camptothecin (CPT) and its derivatives remain among the most potent inhibitors of DNA topoisomerase I, yet their clinical utility is often limited by chemical instability of the E-ring lactone and dose-limiting toxicities. Continuous exploration of structurally modified CPT analogues is therefore essential to improve stability, activity, and structure–activity relationship (SAR) understanding. Herein, we report a short, scalable, and efficient synthetic strategy for a novel CPT analogue based on a new approach to the construction of rings C, D, and E. The methodology employs 2-chloroquinoline as an inexpensive and readily available starting material to access a tricyclic ABC core, which is subsequently coupled with a newly designed ring E. A key feature of this work is the isosteric replacement of the unique six-membered bifunctional (4 1-hydroxy) lactone E-ring of camptothecin with a five-membered heterocyclic motif, aimed at improving chemical robustness while retaining topoisomerase I inhibitory activity. The synthetic route proceeds in fewer steps than conventional CPT syntheses, tolerates scale-up, and enables rapid analogue diversification. Preliminary biological evaluation suggests enhanced topoisomerase I inhibition relative to parent CPT, highlighting the promise of this scaffold for further medicinal chemistry development.