Total synthesis of phenanthroindolizidine alkaloids (+/-)-antofine, (+/-)-deoxypergularinine, and their dehydro congeners and evaluation of their cytotoxic activity.
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).
Su
Chung-Ren
CR
Department of Chemistry, National Cheng Kung University, Tainan 701, Taiwan, ROC.
Damu
Amooru G
AG
Chiang
Po-Cheng
PC
Bastow
Kenneth F
KF
Morris-Natschke
Susan L
SL
Lee
Kuo-Hsiung
KH
Wu
Tian-Shung
TS
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*
D000470:Alkaloids; D001965:Bromides; D002712:Chlorides; D007211:Indoles; D007212:Indolizines; D007546:Isoquinolines; D010618:Phenanthrolines; C473343:antofine; C521640:phenanthroindolizidine; C109635:pergularinine