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Teijaro CN , Munagala S , Zhao S , Sirasani G , Kokkonda P , Malofeeva EV , Hopper-Borge E , Andrade RB
Synthesis and biological evaluation of pentacyclic strychnos alkaloids as selective modulators of the ABCC10 (MRP7) efflux pump
J Med Chem. 2014 Dec 26;57(24) :10383-90
PMID: 25419978 PMCID: PMC4281106 URL: https://www.ncbi.nlm.nih.gov/pubmed/25419978
AbstractThe 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 muM without affecting P-gp function; moreover, they resensitized ABCC10-transfected cell lines to paclitaxel at 10 muM. Altogether, the alstolucines represent promising lead candidates in the development of modulators of ABCC10 for MDR cancers overexpressing this pump.
NotesTeijaro, Christiana N Munagala, Surendrachary Zhao, Senzhi Sirasani, Gopal Kokkonda, Praveen Malofeeva, Ekaterina V Hopper-Borge, Elizabeth Andrade, Rodrigo B eng K01 CA120091/CA/NCI NIH HHS/ P30 CA006927/CA/NCI NIH HHS/ K01CA120091/CA/NCI NIH HHS/ P30-CA06927/CA/NCI NIH HHS/ Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S. J Med Chem. 2014 Dec 26;57(24):10383-90. doi: 10.1021/jm501189p. Epub 2014 Dec 8.