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

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.