Cytotoxic and Nitric Oxide Production‐Inhibitory Activities of Limonoids and Other Compounds from the Leaves and Bark of Melia azedarach

Abstract

Nine limonoids, 1-9, one apocarotenoid, 11, one alkaloid, 12, and one steroid, 13, from the leaf extract; and one triterpenoid, 10, five steroids, 14-18, and two flavonoids, 19 and 20, from the bark extract of Melia azedarach L. (Chinaberry tree; Meliaceae) were isolated. Among these compounds, three compounds, 4-6, were new, and their structures were established as 3-deacetyl-28-oxosalannolactone, 3-deacetyl-28-oxosalanninolide, and 3-deacetyl-17-defurano-17,28-dioxosalannin, respectively, on the basis of extensive spectroscopic analyses and comparison with literature data. All of the isolated compounds were evaluated for their cytotoxic activities against leukemia (HL60), lung (A549), stomach (AZ521), and breast (SK-BR-3) cancer cell lines. 3-Deacetyl-4'-demethyl-28-oxosalannin (3) against HL60 and AZ521 cells, and methyl kulonate (10) against HL60 cells exhibited potent cytotoxicities with IC50 values in the range of 2.8-5.8 μM. In addition, upon evaluation of compounds 1-13 against production of nitric oxide (NO) in mouse macrophage RAW 264.7 cells induced by lipopolysaccharide (LPS), seven, i.e., trichilinin B (1), 4, ohchinin (7), 23-hydroxyohchininolide (8), 21-hydroxyisoohchininolide (9), 10, and methyl indole 3-carboxylate (12), inhibited production of NO with IC50 values in the range of 4.6-87.3 μM with no, or almost no, toxicity to the cells (IC50 93.2-100 μM). Western blot analysis revealed that compound 7 reduced the expression levels of the inducible NO synthase (iNOS) and COX-2 proteins in a concentration-dependent manner. Furthermore, compounds 5, 6, 13, and 18-20 exhibited potent inhibitory effects (IC50 299-381 molar ratio/32 pmol TPA) against Epstein-Barr virus early antigen (EBV-EA) activation induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) in Raji cell line.

Recent progress in the chemistry and biology of limonoids

“…13, 8 new limonoids, including 3-deacetyl-28-oxosalannolactone 300, 3-deacetyl-28-oxosalanninolide 301, 3-deacetyl-17-defurano-17,28-dioxosalannin 302, 3-deacetyl-4 0 -demethylsalannin 303, 3-deacetyl-28-oxosalannin 304, 1-detigloylohchinolal 305, 3a-acetoxy-1a,7a-dihydroxy-12a-methoxynimbolinin 306, and 3a-acetoxy-1a,12a-dihydroxy-7a-(2-methylprop-2-enoyl)nimbolinin 307, were isolated from the leaves, fruits and stem barks of Melia azedarach. [102][103][104] Recently, an investigation on the fruits of M. toosendan resulted in four new limonoids, such as 1a,7a-dihydroxyl-3a-acetoxyl-12a-ethoxylnimbolinin 308, 105 1a-tigloyloxy-3a-acetoxyl-7a-hydroxyl-12b-ethoxylnimbolinin 309, 105 (Fig. 14), was isolated from the bark of Chisocheton cuminganus.…”

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 .…”

“…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 .…”

“…In addition, some limonoids from M . azedarach have been demonstrated to inhibit lipopolysaccharide (LPS)‐induced production of nitric oxide (NO) in mouse macrophage RAW 264.7 cells . NO is a signaling molecule that is implicated in a variety of inflammatory conditions including rheumatoid arthritis, atherosclerosis, sepsis, Crohn 's disease, asthma, and hepatitis .…”

Cytotoxic and Antiproliferative Activities of Melia azedarach Leaves Ethanolic Extract on A549 Human Lung Cancer Cells

“…Exploration of anticancer herbal with high effectiveness and minimum side effects need to be developed. One of the plants that potentially contains anticancer compounds is Melia azedarach (Pan et al 2014). This plant is versatile because it can be used for various purposes including health remedy .…”