CHEMISTRY AND STRUCTURE ELUCIDATION OF THE KEDARCIDIN CHROMOPHORE

Kedarcidin, a new chromoprotein antitumor antibiotic, was isolated fro m the fermentation broth of a novel actinomycete strain. Kedarcidin co nsists of a water-soluble apoprotein and a solvent-extractable, cytoto xic, and highly unstable chromophore. The chromophore is a new member of the enediyne class of antitumor agents. Details of the structure el ucidation of kedarcidin chromophore (1, C53H60N3O16Cl), using a combin ation of NMR techniques, mass spectrometry, chemical degradation, deri vatization, and sodium borohydride reduction experiments, are reported . Acidic methanolysis of 1 afforded three products: methyl alpha-L-myc aroside (2), the methyl alpha-glycoside of the novel amino sugar kedar osamine (3, C9H19NO3), and a 2'-chloroazatyrosyl naphthoamide fragment (4, C25H27N2O8Cl). The presence of a reactive 8,9-epoxybicyclo[7.3.0] dodecadienediyne core was established from heteronuclear NMR and sodiu m borohydride reduction experiments. The nine-membered enediyne core u nderwent rapid aromatization upon reduction with sodium borohydride to a cyclopentyl-indene ring system. This reduction was shown to be ster eospecific using sodium borodeuteride. The absolute stereochemistry of the aglycone was inferred through a combination of NMR NOE and molecu lar modeling data. A mechanism of action is proposed, whereby the ened iyne core is activated by chemical reduction followed by spontaneous c yclization to a diradical intermediate, the species believed to cause DNA damage.