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Total Synthesis Of Phenanthroindolizidine Alkaloids (+/-)-antofine, (+/-)-deoxypergularinine, And Their Dehydro Congeners And Evaluation Of Their Cytotoxic Activity.
Chung-Ren Su, A. G. Damu, Po-Cheng Chiang, K. Bastow, S. Morris-Natschke, Kuo-Hsiung Lee, Tian-Shung Wu
Published 2008 · Chemistry, Medicine
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Due to their limited natural abundance and significant biochemical effects, we synthesized the alkaloids (+/-)-antofine (1a), (+/-)-deoxypergularinine (1b), and their dehydro congeners (2 and 3) starting from the corresponding phenanthrene-9-carboxaldehydes. We also evaluated their in vitro cytotoxic activity. Compounds 1a and 1b showed significant potency against various human tumor cell lines, including a drug-resistant variant, with EC(50) values ranging from 0.16 to 16ng/mL. Structure-activity correlations of these alkaloids and some of their synthetic intermediates were also ascertained. The non-planar structure between the two major moieties, phenanthrene and indolizidine, plays a crucial role in the cytotoxic activity of phenanthroindolizidines. Increasing the planarity and rigidity of the indolizidine moiety significantly reduced potency. A methoxy group at the 2-position (1a) was more favorable for cytotoxic activity than a hydrogen atom (1b).
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