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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
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Abstract
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 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.
Notes
Teijaro, 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.