Structure activity-relationship and in vitro and in vivo evaluation of the potent cytotoxic anti-microtubule agent N-(4-methoxyphenyl)-N26-trimethyl-67-dihydro-5H-cyclopentadpyrimidin-4-aminium chloride and its analogues as antitumor agents

摘要

A series of 21 substituted cyclopenta[d]pyrimidines were synthesized as an extension of our discovery of the parent compound >1·HCl as an antimicrotubule agent. The structure-activity relationship indicates that the N-methyl and a 4′-methoxy groups appear important for potent activity. In addition, the 6-substituent in the parent analogue is not necessary for activity. The most potent compound >30·HCl was a 1–2 digit nanomolar inhibitor of most tumor cell proliferations and was up to 7-fold more potent than the parent compound >1·HCl. In addition, >30·HCl inhibited cancer cell proliferation regardless of Pgp or βIII-tubulin status, both of which are known to cause clinical resistance to several antitubulin agents. In vivo efficacy of >30·HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound >30·HCl is water soluble, easily synthesized and serves as a lead compound for further preclinical evaluation as an antitumor agent.