Development of New Chemopreventive Agents from Monascus pilosus-Fermented Rice (Red-Mold Rice)

对从红曲霉发酵大米(红霉米)提取物中分离得到的6种氮杂环酮类化合物红曲菌素(1)、红曲霉毒素(2)、红曲霉毒素(3)、红曲霉毒素(4)、红曲霉酚丁胺(5)和单抗坏血酸(6)，两种呋喃异苯二甲酸酯(黄单胞菌素A(7)和黄单胞菌素B(8))以及两种氨基酸(+)-单胞酸(9)和(-)-单胞酸(10)对小鼠12-O-tetradecanoylphorbol-13-acetate(TPA)-induced炎症的抑制作用进行了研究。关于TPA在Raji细胞中诱导EB病毒早期抗原(EBV-EA)，以及对一氧化氮(NO)供体(±)-(E)-methyl-2[(E)-hydroxy-imino]-5-nitro-6-methoxy-3-hexemide(NOR 1)激活的影响。在所测试的化合物中，有7个化合物(1-6和10)对TPA诱导的炎症反应有抑制作用，6个化合物(1，3-5，9和10)对EBV-EA活性有较强的抑制作用。所有受试化合物对NOR-1活性均有中等程度的抑制作用。以过氧亚硝酸根(ONOO)和紫外线B(UVB)为引发剂，12-O-十四酰佛波醇-13-乙酸酯(TPA)为促进剂，对过氧亚硝酸根(ONOO)和紫外线B(UVB)诱导的小鼠皮肤肿瘤的两步致癌作用进行了研究，进一步评价了化合物1的抗癌活性。化合物1对Pn和UVB诱导的小鼠皮肤癌变均有明显的抑制作用。这些发现表明，化合物1可能在化学致癌和环境致癌方面作为潜在的癌症化学预防药物。

Six azaphilones, monascin (1), ankaflavin (2), rubropunctatin (3), monascorburin (4), rubropunctamine (5), and monascorburamine (6), two furanoisophthalides, xanthomonasin A (7) and xanthomonasin B (8), and two amino acids, (+)-monascumic acid (9) and (-)-monascumic acid (10), isolated from the extracts of Monascus pilosus-fermented rice (red-mold rice) were evaluated for their inhibitory effects on 12-O-tetradecanoylphorbol-13-acetate(TPA)-induced inflammation in mice, on the induction of Epstein-Barr virus early antigen(EBV-EA) by TPA in Raji cells, and on the activation of (±)-(E)-methyl-2[(E)-hydroxy-imino]-5-nitro-6-methoxy-3-hexemide (NOR 1), a nitric oxide(NO) donor. Among the compounds tested, seven compounds (1-6,and 10) on TPA-induced inflammation, and six compounds (1,3-5,9,and 10) on EBV-EA activation, exhibited potent inhibitory effects. All of the compounds tested showed moderate inhibitory effects on NOR 1 activation. Compound 1 was further evaluated for its anti-tumor-initiating activity via oral administration on the two-stage carcinogenesis of mouse skin tumor induced by peroxynitrite (ONOO^-;PN) or by ultraviolet light B(UVB) as an initiator and 12-O-tetradecanoylphorbol-13-acetate(TPA) as a promoter. Compound 1 exhibited marked inhibitory activity on both PN and UVB induced mouse skin carcinogenesis tests. These findings suggest that compound 1 may be valuable as potential cancer chemopreventive agents in chemical and environmental carcinogenesis.