Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids.
(+)-1(R)-Coclaurine (1) and (-)-1(S)-norcoclaurine (3), together with quercetin 3-O-beta-D-glucuronide (4), were isolated from the leaves of Nelumbo nucifera (Nymphaceae), and identified as anti-HIV principles. Compounds 1 and 3 demonstrated potent anti-HIV activity with EC50 values of 0.8 and <0.8 microg/mL, respectively, and therapeutic index (TI) values of >125 and >25, respectively. Compound 4 was less potent (EC50 2 microg/mL). In a structure-activity relationship study, other benzylisoquinoline, aporphine, and bisbenzylisoquinoline alkaloids, including liensinine (14), negferine (15), and isoliensinine (16), which were previously isolated from the leaves and embryo of Nelumbo nucifera, were evaluated for anti-HIV activity. Compounds 14-16 showed potent anti-HIV activities with EC50 values of <0.8 microg/mL and TI values of >9.9, >8.6, and >6.5, respectively. Nuciferine (12), an aporphine alkaloid, had an EC50 value of 0.8 microg/mL and TI of 36. In addition, synthetic coclaurine analogs were also evaluated. Compounds 1, 3, 12, and 14-16 can serve as new leads for further development of anti-AIDS agents.
Kashiwada
Yoshiki
Y
Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 950-2081, Japan.
Aoshima
Akihiro
A
Ikeshiro
Yasumasa
Y
Chen
Yuh-Pan
YP
Furukawa
Hiroshi
H
Itoigawa
Masataka
M
Fujioka
Toshihiro
T
Mihashi
Kunihide
K
Cosentino
L Mark
LM
Morris-Natschke
Susan L
SL
Lee
Kuo-Hsiung
KH
D000470:Alkaloids / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D002460:Cell Line; D015497:HIV-1 / Q000187:drug effects; D007546:Isoquinolines / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D031653:Nelumbo / Q000737:chemistry*; D018515:Plant Leaves / Q000737:chemistry; D011794:Quercetin / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology
D000470:Alkaloids; D019380:Anti-HIV Agents; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C443401:quercetin 3-O-glucuronide; D011794:Quercetin; C004690:coclaurine; C012348:higenamine