Chemical synthesis and biological properties of pyridine epothilones

Background: Numerous analogs of the antitumor agents epothilones A and B ha ve been synthesized in search of better pharmacological profiles. Insights into the structure-activity relationships within the epothilone family are still needed and more potent and selective analogs of these compounds are i n demand, both as biological tools and as chemotherapeutic agents, especial ly against drug-resistant tumors, Results: A series of pyridine epothilone B analogs were designed, synthesiz ed and screened. The synthesized compounds exhibited varying degrees of tub ulin polymerization and cytotoxicity properties against a number of human c ancer cell lines depending on the location of the nitrogen atom and the met hyl substituent within the pyridine nucleus. Conclusions: The biological screening results in this study established the importance of the nitrogen atom at the ortho position as well as the benef icial effect of a methyl substituent at the 4- or 5-position of the pyridin e ring. Two pyridine epothilone B analogs (i.e. compounds 3 and 4) possessi ng higher potencies against drug-resistant tumor cells than epothilone B, t he most powerful of the naturally occurring epothilones, were identified.