Melanogenesis inhibitory, anti-inflammatory, and chemopreventive effects of limonoids from the seeds of Azadirachta indicia A. Juss. (neem).
Thirty-one nortriterpenoids, including 28 limonoids (1-28) and 3 degraded limonoids (29-31), and one diterpenoid (32), were isolated from the seed extract of Azadirachta indica (neem). Among these, six were new compounds and their structures were established to be 15-hydroxyazadiradione (3), 7-benzoyl-17-hydroxynimbocinol (5), 23-deoxyazadironolide (12), limocin E (13), 23-epilimocin E (14), and 7alpha-acetoxy-3-oxoisocopala-1,13-dien-15-oic acid (32). Upon evaluation of compounds 1-32 on the melanogenesis in the B16 melanoma cells, five compounds, 20, 26, 27, 29, and 31, exhibited marked inhibitory effect (74-91% reduction of melanin content at 25 microg/mL) with no or almost no toxicity to the cells. Seven compounds, 1, 6, 9, 10, 18, 20, and 26, on evaluation for their inhibitory effect against 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced inflammation (1 microg/ear) in mice, exhibited, except for compound 26, marked anti-inflammatory activity (ID(50) values 0.09-0.26 mg/ear). In addition, all of the 32 compounds exhibited moderate or potent inhibitory effects (IC(50) values of 230-501 mol ratio/32 pmol TPA) against the Epstein-Barr virus early antigen (EBV-EA) activation induced by TPA. Furthermore, on evaluation of azadirachtin B (21) for its anti-tumor-initiating activity on the two-stage carcinogenesis of mouse skin tumor induced by peroxynitrite (ONOO-; PN) as an initiator and TPA as a promoter, this exhibited marked inhibitory activity.
College of Science and Technology, Nihon University, Tokyo, Japan. akihisa@chem.cst.nihon-u.ac.jp
Toshihiro
T
Akihisa
Taisuke
T
Noto
Akitomo
A
Takahashi
Yukiko
Y
Fujita
Norihiro
N
Banno
Harukuni
H
Tokuda
Kazuo
K
Koike
Takashi
T
Suzuki
Ken
K
Yasukawa
Yumiko
Y
Kimura
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D000972:Antineoplastic Agents, Phytogenic / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D031601:Azadirachta / Q000737:chemistry* / Q000502:physiology; D004354:Drug Screening Assays, Antitumor / Q000379:methods; D036701:Limonins / Q000737:chemistry* / Q000302:isolation & purification / Q000627:therapeutic use; D009682:Magnetic Resonance Spectroscopy; D008543:Melanins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D008546:Melanoma, Experimental / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D010936:Plant Extracts / Q000737:chemistry / Q000302:isolation & purification / Q000627:therapeutic use; D012639:Seeds; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000972:Antineoplastic Agents, Phytogenic; D036701:Limonins; D008543:Melanins; D010936:Plant Extracts