Separation, Structural Determination and Biological Evaluation of the Thymidylate Synthase Inhibitor 3,3-Di-(4'-hydroxyphenyl)-6(7)-chloro-1-oxo-1H,3H-naphtho[1,8-cd]pyran

摘要

The chloro substituted 3,3-di-(4'-hydroxyphenyl)-1-oxo-1H,3H-naphtho[1,8-cd]pyran was synthesized in a 40/60 mixture of C_6 or C_7 substituted isomere, respectively. The two isomere were separated by hplc. The X-ray crystal structure of the mixture was obtained. Both the mixture and the single isomere were tested against Lactobacillus Casei thymidylate synthase. The X-ray analysis clearly revealed co-crystallization of the two isomeric species. The apparent Ki of the mixture was 0.8 muM, while those of the C_6 and C_7 substituted isomere were 0.42 and 0.52 muM, respectively, thus showing that the position of the chlorine in the naphthalene ring was not critical for enzymatic activity.