Melanogenesis‐Inhibitory Activities of Isomeric C‐seco Limonoids and Deesterified Limonoids

Abstract

Treatment of eight C-seco limonoids including six of salannin-type, 1 - 6, and two of nimbin-type, 7 and 8, with a combination of BF · Et O and iodide ion yielded the isomeric C-seco derivatives, i.e., six isosalannins, 1a - 6a, and two isonimbins, 7a and 8a, respectively. Ohchinin (1) was further subjected to LiAlH reduction which yielded a deesterified trihydroxy limonoid, nimbidinol (9). In addition, ten limonoids including seven of azadirone-type, 10 - 16, and three of gedunin-type, 17 - 19, all of which possess no ester functionality in the molecule, were obtained from the neutral fraction of Azadirachta indica seed extract after alkaline hydrolysis. Among the above, twelve compounds, i.e., 1a - 4a, 6a, 9, 13 - 16, 18, and 19, were new compounds, and their structures were elucidated on the basis of extensive spectroscopic analysis and comparison with literature data. Upon evaluation of all these limonoids for their inhibitory activities against melanogenesis in B16 melanoma cells induced with α-melanocyte-stimulating hormone (α-MSH), five structurally modified limonoids, 3-deacetyl-28-oxosalannin (6a), 9, 17-epi-17-hydroxynimbocinol (14), 17-epi-17-hydroxy-15-methoxynimbocinol (15), and 7-deacetyl-17-epinimolicinol (18), in addition to a natural limonoid, 1, exhibited potent inhibitory activities with 26 - 66% reduction of melanin content at 100 μm concentration with almost no or low toxicity to the B16 melanoma cells (70 - 99% cell viability at 100 μm).

Nitric Oxide Production‐Inhibitory Activity of Limonoids from Azadirachta indica and Melia azedarach

“…siamensis , and M . azedarach , while seven are semi‐synthetic compounds derived from the Meliaceae limonoids (see for details). Two, 2 and 32 , and five, 19 , 22 , 23 , 43 , and 67 , other limonoids were isolated from the non‐saponifiable lipid (NSL) fraction of A .…”

“…Twenty limonoids including 4 , 5 , 7 , 8 , 21 , 27 , 28 , 31 , 44 , 59 , 60 , and 73 from the seeds, 1 and 6 from the NSL fraction of the seed extract, and 3 , 12 , 45 , 61 , 63 , and 65 , from the leaves of A. indica , four limonoids including 26 and 30 from the roots, 62 from the leaves, and 64 from the bark of A. indica var. siamensis , and 32 limonoids including 9 , 11 , 13 – 18 , 20 , 24 , 25 , 29 , 33 , 35 , 37 – 40 , 42 , 58 , 66 , 69 , 70 , and 71 from the fruits, and 10 , 36 , 41 , and 47 – 51 from the leaves of M. azedarach , were isolated from Meliaceae plants.…”

“…siamensis , and 32 limonoids including 9 , 11 , 13 – 18 , 20 , 24 , 25 , 29 , 33 , 35 , 37 – 40 , 42 , 58 , 66 , 69 , 70 , and 71 from the fruits, and 10 , 36 , 41 , and 47 – 51 from the leaves of M. azedarach , were isolated from Meliaceae plants. Eight limonoids, 34 , 52 – 57 , and 72 , were semi‐synthesized from the Meliaceae limonoids . On the other hand, two limonoids, 2 and 32 , were isolated from the NSL fraction of A. indica seed extract, and five limonoids, 19 , 22 , 23 , 43 , and 67 , were semi‐synthesized from naturally occurring limonoids as described below.…”

“…The hexane extract (100 g) of A. indica seed was dissolved in 5% KOH/MeOH (1000 ml) and the mixture stirred vigorously for 24 h at r.t. The mixture was poured into water and extracted with diisopropyl ether (IPE).…”

“…var. siamensis Valeton (Siamese neem tree), and Melia azedarach L. (chinaberry tree), as well as on the semi‐synthetic limonoids derived from the Meliaceae limonoids, was undertaken, and this showed that some limonoids exhibit potent inhibitory activities against melanogenesis in B16 melanoma cells, against 12‐ O ‐tetradecanoylphorbol‐13‐acetate (TPA)‐induced inflammation in mice, and against TPA‐induced Epstein–Barr virus early antigen activation, as well as cytotoxic and apoptosis‐inducing activities against human cancer cell lines . In addition, some limonoids from M .…”