A xanthone scaffold
Xanthone shows the antagonism of endogenous nitric oxide synthase (NOS) inhibitors, it has antitumor, antihepatotoxic, anti-inflammatory and antimicrobial activities [1]. Two derivatives of xanthone potently inhibited nitric oxide synthesis with IC50 values of 4.3 and 4.4 μM, respectively [2].
In endothelial cells, NOS synthesizes nitric oxide (NO) from L-arginine. In the maintenance of vascular structure and tone, NO has been thought to play a key role [1].
Asymmetric dimethylarginine (ADMA) is synthesized by protein arginine methyltransferases (PRMTs), using S-adenosylmethionine as methyl group donor. Dimethylarginine dimethylaminohydrolase (DDAH) degrades ADMA to L-citrulline and dimethylamine. There are two different isoforms of DDAH, DDAH-1 and DDAH-2. Typically, DDAH-1 is found in tissues containing neuronal NOS, whereas DDAH-2 predominates in tissues expressing the endothelial isoform of NOS. In cultured endothelial cells, xanthones showed the inhibition of the upregulation of MCP-1 expression, the enhancement of monocytes adhesion and the increase in the release of LDH, concomitantly with the reduction of ADMA levels. These results suggest that xanthones protect against high-lipid-level-induced endothelial damage. This protective effect of xanthones is related to the reduction of ADMA concentration [1].
A single injection of native LDL caused a rapid accumulation and oxidation of LDL in the arterial wall. At 6 to 12 h after injection of LDL, ICAM-1 expression increased and led to endothelial dysfunction and an elevation of ADMA level. In vivo, pretreatment with xanthones attenuated the effect of the injection of LDL [1].
参考文献:
[1].? Jiang DJ, Dai Z and Li YJ. Pharmacological effects of xanthones as cardiovascular protective agents. Cardiovasc Drug Rev, 2004, 22(2):91-102.
[2].? Boonnak N, Khamthip A, Karalai C, et al. Nitric Oxide Inhibitory Activity of Xanthones from the Green Fruits of Cratoxylum formosum ssp. pruniflorum. Australian Journal of Chemistry, 2010, 63(11):1550-1556.
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