黄河三角洲盐碱土壤来源真菌Penicillium terrigenum RD 4-3次级代谢产物及其抗炎抗肿瘤活性

Secondary metabolites and their activities of Penicillium terrigenum RD 4-3 isolated from saline-alkali soil in the Yellow River Delta

目的研究黄河三角洲盐碱土壤中真菌Penicillium terrigenum RD 4-3的次级代谢产物及其生物活性。方法采用多种色谱分离技术对真菌液态发酵次级代谢产物进行分离纯化,并根据化合物的理化性质及波谱数据进行结构鉴定,同时进行细胞毒活性和NO检测,探究其抗肿瘤与抗炎活性。结果最终从Penicillium terrigenum RD 4-3发酵产物中分离鉴定14个单体化合物,分别为倍半萜类14-hydroxypetasol(1)、6-dehydropetasol(2)、isopetasol(3)、acremeremophilane G(4)、phomenone(6)、7-hydroxypetasol(7)、sporogen-AO1(9)、petasol(10)、JBIR-28(11)、JBIR-27(12)、3-acetyl-13-deoxyphome(13)、penicilleremophilane A(14),以及苯的衍生物3-chloro-4-hydroxypheylacetamide(5)、phenols(8),其中化合物1(14-hydroxypetasol)为新化合物。活性结果显示,化合物6(phomenone)和9(sporogen-AO1)对非小细胞肺癌细胞A549和H1299均具有显著的抗肿瘤活性,IC_(50)值均在10μmol/L以下。在浓度为50μmol/L时,化合物6(phomenone)、10(petasol)、11(JBIR-28)在LPS诱导的炎症模型中表现出一定的抗炎活性。初步的构效关系研究发现,6,7位的氧环结构可以显著提高化合物的抗肿瘤及抗炎活性。结论真菌Penicillium terrigenum RD 4-3的次级代谢产物中的倍半萜类在抗肿瘤抗炎先导化合物发现方面具有巨大研发潜力。

Objective To study the secondary metabolites and biological activities of fungus Penicillium terrigenum RD 4-3 isolated from saline-alkali soil in the Yellow River Delta.Methods The secondary metabolites were isolated and purified using various chromatographic methods from culture broth,and the structures of the pure compounds were identified based on their physicochemical properties and spectral data.Cytotoxic activity and NO detection were performed to explore antineoplastic activity and anti-inflammatory activity.Results Fourteen pure compounds were isolated and identified from the extracts of Penicillium terrigenum RD 4-3,including sesquiterpenes 14-hydroxypetasol(1),6-dehydropetasol(2),isopetasol(3),acremeremophilane G(4),phomenone(6),7-hydroxypetasol(7),sporogen-AO1(9),petasol(10),JBIR-28(11),JBIR-27(12),3-acetyl-13-deoxyphome(13)and penicilleremophilane A(14),and benzene derivatives 3-chloro-4-hydroxypheylacetamide(5)and phenols(8),among which 14-hydroxypetasol was a new compound.The activity results showed that phomenone(6)and sporogen-AO1(9)exhibited significant antitumor activities against non-small cell lung cancer cells A549 and H1299,with IC_(50) values below 10μmol/L.At a concentration of 50μmol/L,phomenone,petasol and JBIR-28 exhibited anti-inflammatory activity in the LPS-induced inflammation model.Preliminary structure-activity relationship revealed that the 6,7-epoxyl structure could significantly increase the antitumor and anti-inflammatory activities of the compounds.Conclusion The sesquiterpenes of the secondary metabolitesfrom fungus Penicillium terrigenum RD 4-3 from the Yellow River Delta exhibit great potential in the discovery of antitumor and anti-inflammatory lead compounds.