title: Synthesis and biological evaluation of pentacyclic strychnos alkaloids as selective modulators of the ABCC10 (MRP7) efflux pump.
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 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.
authors.affiliation: Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
authors.forename: Christiana N
authors.initials: CN
authors.lastname: Teijaro
authors.forename: Surendrachary
authors.initials: S
authors.lastname: Munagala
authors.forename: Senzhi
authors.initials: S
authors.lastname: Zhao
authors.forename: Gopal
authors.initials: G
authors.lastname: Sirasani
authors.forename: Praveen
authors.initials: P
authors.lastname: Kokkonda
authors.forename: Ekaterina V
authors.initials: EV
authors.lastname: Malofeeva
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Hopper-Borge
authors.forename: Rodrigo B
authors.initials: RB
authors.lastname: Andrade
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors; D000470:Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects*; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D026121:Indole Alkaloids / Q000138:chemical synthesis* / Q000494:pharmacology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors*; D017239:Paclitaxel / Q000494:pharmacology; D031451:Strychnos / Q000737:chemistry*
chemical_list: D000251:Adenosine Triphosphatases; D000470:Alkaloids; D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D026121:Indole Alkaloids; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D017239:Paclitaxel; C421142:ABCC10 protein, human; C000595870:alstolucine B; C000595871:alstolucine F