Development of 2-(alkoxycarbonyl)-allyl esters as anticancer agents

Abstract

Cancer is the second leading cause of human mortality in the United States, with the standard treatment options being surgery, cytotoxic chemotherapy, and radiation therapy. Recently, there has been strong emphasis in developing targeted small molecule therapies which has led to the development of numerous anticancer drugs. However, many of the current cancer chemotherapeutic options are burdened with toxicity and treatment resistance and hence novel therapies with reduced side effects are urgently needed. In the current work, a structurally diverse library of Baylis-Hillman reaction derived 2-(alkoxycarbonyl)-allyl esters have been synthesized, evaluated for their in vitro cell proliferation inhibition properties, in vitro cellular and molecular mechanisms of action, in vivo systemic toxicity study in CD-1 mice, and in vivo anticancer efficacy study in a triple negative breast cancer MDA-MB-231 xenograft model in NOD SCID mice. Several of the synthesized compounds exhibit promising in vitro anticancer properties. Further, the lead candidate compound is well tolerated in healthy mice as indicated by normal body weight changes, and exhibits similar if not slightly better tumor growth inhibition properties than clinically available cancer drug doxorubicin.