Deuterium substitution at the intolerable site as a strategy to mitigate the toxicity of camptothecin derivatives.

Camptothecin (CPT) is characterized by a planar fused-ring system consisting of five-membered rings. Structure-activity relationship studies have demonstrated that introducing a substituent at the C-5 position of CPT can disrupt its planar structure, leading to a decrease in its biological activity. In this study, a straightforward hydrogen-deuterium exchange method was developed to achieve bis-deuterium substitution at the C-5 position of CPT. The method was successfully extended to a series of CPT analogues. In vitro biological activity studies demonstrated that deuterium substitution effectively preserves the pharmacological function of CPT analogues. Pharmacokinetic studies indicated that the deuterated analogue of topotecan (TOP), named as TOP-2D, exhibits a shorter half-life (T) and greater bioavailability (F%) compared to TOP when administered intraperitoneally (IP). Moreover, in vivo studies on antitumor activity showed that TOP-2D effectively inhibited tumor growth while having a minimal impact on the body weight of mice. In contrast, when administered via the same IP route and at the same dose, treatment with TOP caused a significant decrease in body weight. This reduced toxicity is likely attributable to deuteration, which promotes more rapid clearance of the drug and decreases metabolism-mediated toxicity, resulting in a safer profile.