Quinocidin, a Cytotoxic Antibiotic with an Unusual 3,4-Dihydroquinolizinium Ring and Michael Acceptor Reactivity toward Thiols

Abstract

Cytotoxicity-guided fractionation of the culture broth of Actinomadura sp. TP-A0019 led to the isolation of quinocidin (1), a cytotoxic antibiotic with an unusual 3,4-dihydroquinolizinium ring. The structural assignment was made on the basis of high-field NMR experiments and chemical synthesis. Comparison of the spectral properties of 1 with those of its synthetic counterparts revealed that 1 is a racemic mixture of two enantiomers, which showed similar cytotoxicity against HeLa-S3 cells. Nucleophile-trapping experiments demonstrated that 1 captured 2-mercaptoethanol and N-acetyl-l-cysteine by means of a Michael addition-type reaction, but was inert toward 2-aminoethanol and glycolic acid. Notably, the addition of 1 to thiols proceeded smoothly in neutral aqueous media at room temperature. In view of the thiol-trapping ability and the unusual structure, 1 provides a unique scaffold for designing drug leads and protein-labeling probes.

Keywords: Michael addition; drug discovery; natural products; nitrogen heterocycles; structure elucidation.