Synthesis and Biological Evaluationof Pentacyclic Strychnos Alkaloidsas Selective Modulators of theABCC10 (MRP7) Efflux Pump

摘要

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 (>2), F (>3), and A (>5) and N-demethylalstogucine (>4), in addition to known Strychnos alkaloid echitamidine (>16), and we evaluated compounds >1–>5 in biochemical assays with ABCC10 and P-glycoprotein (P-gp). Alstolucines B (>2) and F (>3) 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.