Enantioselective synthesis of (R)-(+)- and (S)-(-)-higenamine and their analogues with effects on platelet aggregation and experimental animal model of disseminated intravascular coagulation.
Optically active tetrahydroisoquinoline alkaloids, (R)-(+)-higenamine (1R) and (S)-(-)-higenamine (1 S), and their optically active 1-naphthylmethyl analogues (2 and 3), were synthesized by enantioselective hydrogenation of the corresponding dihydroisoquinoline intermediates 7 as a key step. The evaluation of the platelet anti-aggregation effect demonstrated clearly that the (S)-(-)-enantiomers, 1S, 2S, and 3S, had higher inhibitory potency than the corresponding (R)-(+)-antipodes, 1R, 2R, and 3R, respectively, to platelet aggregation induced by epinephrine. 1S enantiomer was superior to the corresponding 1R enantiomer in attenuating all of the disseminated intravascular coagulation (DIC) and multiple organ failure (MOF) parameters tested, while the S enantiomers 2S and 3S ameliorated some of the DIC and MOF parameters more effectively than the corresponding antipodes 2R and 3R.
Pyo
Mi Kyung
MK
Natural Product Research Institute, College of Pharmacy, Seoul National University, Yeongeon-dong 28, Jongro-gu, Seoul 110-460, Republic of Korea.
Lee
Duck-Hyung
DH
Kim
Doo-Hyun
DH
Lee
Ji-Hye
JH
Moon
Jong-Cheon
JC
Chang
Ki Churl
KC
Yun-Choi
Hye Sook
HS
D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000577:Amides / Q000737:chemistry; D000818:Animals; D002384:Catalysis; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy*; D015195:Drug Design; D004837:Epinephrine / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D010974:Platelet Aggregation / Q000187:drug effects*; D051381:Rats; D013237:Stereoisomerism; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry
D000470:Alkaloids; D000577:Amides; D044005:Tetrahydroisoquinolines; C012348:higenamine; D004837:Epinephrine