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Quinocidin, a Cytotoxic Antibiotic with an Unusual 3,4‐Dihydroquinolizinium Ring and Michael Acceptor Reactivity toward Thiols
Author(s) -
Nakagawa Yu,
Sawaki Yuki,
Kimura Takahiro,
Tomura Tomohiko,
Igarashi Yasuhiro,
Ojika Makoto
Publication year - 2017
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201704729
Subject(s) - chemistry , hela , cytotoxicity , glycolic acid , reactivity (psychology) , ring (chemistry) , cysteine , michael reaction , thiol , stereochemistry , combinatorial chemistry , organic chemistry , in vitro , biochemistry , enzyme , bacteria , medicine , lactic acid , alternative medicine , pathology , biology , genetics , catalysis
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.