Total synthesis of phenanthroindolizidine alkaloids (±)-antofine (±)-deoxypergularinine and their dehydro congeners and evaluation of their cytotoxic activity

摘要

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 EC50 values ranging from 0.16–16 ng/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).