Structure–Activity Relationship and in Vitro and in Vivo Evaluation of the Potent Cytotoxic Anti-microtubule Agent <i>N</i>‑(4-Methoxyphenyl)‑<i>N</i>,2,6-trimethyl-6,7-dihydro‑5<i>H</i>‑cyclopenta[<i>d</i>]pyrimidin-4-aminium Chloride and Its Analogues As Antitumor Agents

Abstract

A series of 21 substituted cyclopenta­[<i>d</i>]­pyrimidines were synthesized as an extension of our discovery of the parent compound (±)-<b>1</b>·HCl as an anti-microtubule agent. The structure–activity relationship indicates that the <i>N</i>-methyl and a 4<i>N</i>-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 <b>30</b>·HCl was a one to two digit nanomolar inhibitor of most tumor cell proliferations and was up to 7-fold more potent than the parent compound (±)-<b>1</b>·HCl. In addition, <b>30</b>·HCl inhibited cancer cell proliferation regardless of Pgp or βIII-tubulin status, both of which are known to cause clinical resistance to several anti-tubulin agents. In vivo efficacy of <b>30</b>·HCl was demonstrated against a triple negative breast cancer xenograft mouse model. Compound <b>30</b>·HCl is water-soluble and easily synthesized and serves as a lead compound for further preclinical evaluation as an antitumor agent