Teijaro Christiana N, Munagala Surendrachary, Zhao Senzhi, Sirasani Gopal, Kokkonda Praveen, Malofeeva Ekaterina V, Hopper-Borge Elizabeth, Andrade Rodrigo B
Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
J Med Chem. 2014 Dec 26;57(24):10383-90. doi: 10.1021/jm501189p. Epub 2014 Dec 8.
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.
对多药耐药性癌症（MDR）中过表达的ATP结合盒（ABC）外排泵进行选择性调节以及随之而来的对化疗药物重新致敏，是一种很有前景的癌症治疗策略。我们合成了四种新型五环马钱子生物碱阿尔斯托鲁辛B（2）、F（3）和A（5）以及N-去甲基阿尔斯托古辛（4），此外还合成了已知的马钱子生物碱埃奇他米定（16），并在与ABCC10和P-糖蛋白（P-gp）的生化测定中评估了化合物1-5。阿尔斯托鲁辛B（2）和F（3）在12.5 μM时抑制ABCC10 ATP酶活性，而不影响P-gp功能；此外，它们在10 μM时使转染了ABCC10的细胞系对紫杉醇重新致敏。总之，阿尔斯托鲁辛是开发针对过表达该泵的MDR癌症的ABCC10调节剂的有前景的先导候选物。
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