title: Anti-HIV benzylisoquinoline alkaloids and flavonoids from the leaves of Nelumbo nucifera, and structure-activity correlations with related alkaloids.
abstract: (+)-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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Niigata University of Pharmacy and Applied Life Sciences, Niigata 950-2081, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Kashiwada
authors.forename: Akihiro
authors.initials: A
authors.lastname: Aoshima
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Ikeshiro
authors.forename: Yuh-Pan
authors.initials: YP
authors.lastname: Chen
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Furukawa
authors.forename: Masataka
authors.initials: M
authors.lastname: Itoigawa
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fujioka
authors.forename: Kunihide
authors.initials: K
authors.lastname: Mihashi
authors.forename: L Mark
authors.initials: LM
authors.lastname: Cosentino
authors.forename: Susan L
authors.initials: SL
authors.lastname: Morris-Natschke
authors.forename: Kuo-Hsiung
authors.initials: KH
authors.lastname: Lee
mesh_terms: 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
chemical_list: D000470:Alkaloids; D019380:Anti-HIV Agents; D007546:Isoquinolines; D044005:Tetrahydroisoquinolines; C443401:quercetin 3-O-glucuronide; D011794:Quercetin; C004690:coclaurine; C012348:higenamine