次黄嘌呤核苷酸脱氢酶抑制剂产生菌的筛选及aquayamycin的结构鉴定

Screening of inosine 5'-monophosphate dehydrogenase inhibitors and structural identification of aquayamycin

筛选次黄嘌呤核苷酸脱氢酶(IMPDH)抑制剂及其产生菌,为新的抗癌药物和免疫抑制药物的研发提供先导化合物。对菌株进行发酵培养,通过以IMPDH为靶点的高通量筛选模型获得微生物活性代谢产物及其阳性菌种,采用16s rDNA序列构建阳性菌株的系统发育进化树,综合波谱解析确定化合物结构,并利用相关细胞对化合物进行活性评价。结果鉴定N05WA-1324A产生菌菌株为链霉菌属菌株,m/z 486,分子式为C_(25)H_(26)O_(10),为aquayamycin。该化合物具有较强的IMPDH抑制活性,IC50为18.1μmol/L;对T淋巴细胞有很强的抑制活性,在2.5μmol/L浓度下能抑制99.8%的细胞增殖;同时对人结肠癌细胞株SW-620和人乳腺癌细胞株MDA-MB-231具有较强的增殖抑制活性,IC50分别为8.6和23.3μmol/L。N05WA-1324A具有很强的IMPDH和免疫抑制活性为国内外首次报道,在细胞水平上的活性评价显示其具有抗癌药物和免疫抑制药物的开发潜力。

Inosine 5'-monophosphate dehydrogenase (IMPDH)inhibitors were screened from the cultures collection for new anticancer and immunosuppressive drugs to provide lead compounds,and microbial strains. The strains from culture collection were fermented,microbial active metabolites and their positive strains were obtained by high-throughput screening model targeting IMPDH.The 16S rDNA sequence was used to construct the phylogenetic tree of the positive strain,the extract of the fermentation broth from the positive strain was purified to get active compounds,and the chemical structure was elucidated on the basis of comprehensive spectral data analysis. Furthermore,the antiproliferative effects of the compound on related cells were evaluated.The strain producing N05WA-1324A was identified as Streptomyces,m/z was 486,the molecular formula was C25H26O10,and it was aquayamycin.This compound has a stronger inhibiting activity of IMPDH,and IC50 is 18.1mol/L.It has a strong inhibitory activity on T lymphocytes,and can inhibit the proliferation of 99.8% cells at a concentration of 20.5μmol/L. At the same time,it showed the stronger proliferation inhibition activity on human colon cancer cell lines SW-620 and human breast cancer cell lines MDA-MB-231 with the IC50 of 8.6 and 23.3μmol/L.N05WA-1324A are reported as a specific IMPDH and immunosuppressive activities for the first time,and results indicated that the compound has a potential to be developed as anticancer agent and immunosuppressant.