Person:

Myers, Andrew

Structures of the protein-chromophore complex and the apoprotein form of neocarzinostatin were determined at 1.8 angstrom resolution. Neocarzinostatin is composed of a labile chromophore with DNA-cleaving activity and a stabilizing protein. The chromophore displays marked nonlinearity of the triple bonds and is bound noncovalently in a pocket formed by the two protein domains. The chromophore pi-face interacts with the phenyl ring edges of Phe^52 and Phe^78. The amino sugar and carbonate groups of the chromophore are solvent exposed, whereas the epoxide, acetylene groups, and carbon C-12, the site of nucleophilic thiol addition during chromophore activation, are unexposed. The position of the amino group of the chromophore carbohydrate relative to C-12 supports the idea that the amino group plays a role in thiol activation.

A 6-step synthesis of the naphthoic acid component of the natural antitumor agent neocarzinostatin chromophore is described. The synthetic route employs a 4-bromo-3-methylanisole as the starting material, proceeds in 31-37% yield for the 6 steps, and features as the key step a photocyclization reaction that is an interesting variant of known photocyclization reactions of stilbenes and phenylbutadienes.