From Lead to Drug Utilizing a Mannich Reaction: The Topotecan Story

Natural products are a rich source of bioactive compounds, and numerous natural compounds have found application in cancer chemotherapy. However, unfavorable physicochemical properties often prevent the use of the original natural product as a drug. A prominent example is camptothecin from the Chinese tree Camptotheca acuminata, which shows extraordinary cytotoxic activity based on a specific molecular mode of action (inhibition of human topoisomerase I). Due to its extremely poor solubility, the original natural product cannot be used as a drug. The marketed drug topotecan was developed from this lead structure by semi‐synthesis utilizing a Mannich aminomethylation as the crucial step. In this review, the long‐distance run leading to this drug and further perspectives are summarized. The marketed topoisomerase I inhibitor topotecan was developed by semi‐synthesis from the alkaloid camptothecin, with a Mannich aminomethylation as the central step. This review summarizes the long‐distance run leading to this drug as well as further perspectives.
Source: Archiv der Pharmazie - Category: Drugs & Pharmacology Authors: Tags: Review Article Source Type: research