ABSTRACT
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.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Biological Products/pharmacology , Camptotheca/chemistry , Neoplasms/drug therapy , Topoisomerase I Inhibitors/pharmacology , Topotecan/pharmacology , Animals , Antineoplastic Agents, Phytogenic/chemistry , Antineoplastic Agents, Phytogenic/isolation & purification , Biological Products/chemistry , Biological Products/isolation & purification , Cell Proliferation/drug effects , DNA Topoisomerases, Type I/metabolism , Humans , Molecular Structure , Neoplasms/pathology , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/isolation & purification , Topotecan/chemistry , Topotecan/isolation & purificationABSTRACT
Based on the chemotype of canthin-4-one alkaloids with moderate antimicrobial activity, a collection of variously substituted canthin-4-ones and desaza analogs were synthesized. Key steps in the syntheses were regioselective halogenations of (desaza) canthin-4-one, followed by Pd-catalyzed cross-coupling reactions. The in vitro screening for antimicrobial activity revealed that two 5-substituted canthin-4-ones (3-pyridyl, 2-bromophenyl) exhibit significant activity against Streptococcus entericus, coupled with high selectivity and the lack of cytotoxicity against mammalian cells. The intact canthin-4-one ring system was demonstrated to be essential for antibacterial activity.
