CHEMISTRY AND STRUCTURE ELUCIDATION OF THE KEDARCIDIN CHROMOPHORE

Kedarcidin, a new chromoprotein antitumor antibiotic, was isolated from the fermentation broth of a novel actinomycete strain. Kedarcidin consists of a water-soluble apoprotein and a solvent-extractable, cytotoxic, and highly unstable chromophore. The chromophore is a new member of the enediyne class of antitumor agents. Details of the structure elucidation of kedarcidin chromophore (1, C53H60N3O16Cl), using a combination of NMR techniques, mass spectrometry, chemical degradation, derivatization, and sodium borohydride reduction experiments, are reported. Acidic methanolysis of 1 afforded three products: methyl alpha-L-mycaroside (2), the methyl alpha-glycoside of the novel amino sugar kedarosamine (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 sodium borohydride reduction experiments. The nine-membered enediyne core underwent rapid aromatization upon reduction with sodium borohydride to a cyclopentyl-indene ring system. This reduction was shown to be stereospecific using sodium borodeuteride. The absolute stereochemistry of the aglycone was inferred through a combination of NMR NOE and molecular modeling data. A mechanism of action is proposed, whereby the enediyne core is activated by chemical reduction followed by spontaneous cyclization to a diradical intermediate, the species believed to cause DNA damage.