Synthesis and Biological Evaluation of Pentacyclic Strychnos Alkaloids as Selective Modulators of the ABCC10 (MRP7) Efflux Pump

The selective modulation of ATP-binding cassette (ABC) efflux pumps overexpressed in multidrug resistant cancers (MDR) and attendant resensitization to chemotherapeutic agents represent a promising strategy for treating cancer. We have synthesized four novel pentacyclic Strychnos alkaloids alstolucines B (<b>2</b>), F (<b>3</b>), and A (<b>5</b>) and <i>N</i>-demethylalstogucine (<b>4</b>), in addition to known Strychnos alkaloid echitamidine (<b>16</b>), and we evaluated compounds <b>1</b>–<b>5</b> in biochemical assays with ABCC10 and P-glycoprotein (P-gp). Alstolucines B (<b>2</b>) and F (<b>3</b>) inhibited ABCC10 ATPase activity at 12.5 μM without affecting P-gp function; moreover, they resensitized ABCC10-transfected cell lines to paclitaxel at 10 μM. Altogether, the alstolucines represent promising lead candidates in the development of modulators of ABCC10 for MDR cancers overexpressing this pump