Synthetic derivatives of vinpocetine as antiproliferative agents

Vincamine is an indole alkaloid initially isolated from plants of the Vinca genus and has previously been demonstrated to have antioxidant, hypoglycemic, and hypolipidemic activities. Vinpocetine, a synthetic derivative of vincamine with an enhanced pharmacological profile, has demonstrated promising antiproliferative properties. While previously reported vinpocetine derivatives have undergone extensive investigation for their pharmacological properties, the role of the E-ring ethyl ester in the anticancer properties of compounds with this scaffold has not yet been fully described. Here, we report the antiproliferative activity of two vinpocetine analogs with modifications at the E-ring. MTT assays revealed that reduction of the ethyl ester to an alcohol exhibited strong dose-dependent antiproliferative activity across five mammalian cell lines, but did not induce significant markers of apoptosis or necrotic death as determined by FITC/Annexin V and cell cycle flow cytometry, respectively. We further observe that vinpocetine and both analogs exhibit dose-dependent modulation of a TCF/LEF reporter cell, which appears to be decoupled from trends in antiproliferative activity Altogether, this work demonstrates the potential for E-ring modifications of vinpocetine as anticancer agents.