title: Total synthesis of phenanthroindolizidine alkaloids (+/-)-antofine, (+/-)-deoxypergularinine, and their dehydro congeners and evaluation of their cytotoxic activity.
abstract: 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).
authors.affiliation: Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC.
authors.forename: Chung-Ren
authors.initials: CR
authors.lastname: Su
authors.forename: Amooru G
authors.initials: AG
authors.lastname: Damu
authors.forename: Po-Cheng
authors.initials: PC
authors.lastname: Chiang
authors.forename: Kenneth F
authors.initials: KF
authors.lastname: Bastow
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
authors.forename: Tian-Shung
authors.initials: TS
authors.lastname: Wu
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000633:toxicity; D001965:Bromides / Q000138:chemical synthesis / Q000633:toxicity; D045744:Cell Line, Tumor; D002712:Chlorides / Q000138:chemical synthesis / Q000633:toxicity; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000633:toxicity*; D007212:Indolizines / Q000138:chemical synthesis* / Q000633:toxicity*; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000633:toxicity*; D007624:KB Cells; D010618:Phenanthrolines / Q000138:chemical synthesis* / Q000633:toxicity*
chemical_list: D000470:Alkaloids; D001965:Bromides; D002712:Chlorides; D007211:Indoles; D007212:Indolizines; D007546:Isoquinolines; D010618:Phenanthrolines; C473343:antofine; C521640:phenanthroindolizidine; C109635:pergularinine