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.
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Munich, Germany.
Franz
F
Bracher
Department of Pharmacy, Center for Drug Research, Ludwig-Maximilians University, Munich, Germany.
Tim
T
Tremmel
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D029769:Camptotheca / Q000737:chemistry*; D049109:Cell Proliferation / Q000187:drug effects; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D019772:Topotecan / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*
D000972:Antineoplastic Agents, Phytogenic; D001688:Biological Products; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D004264:DNA Topoisomerases, Type I
Camptothecin; Mannich reaction; Semi-synthesis; Topoisomerase inhibitor; Topotecan