Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli
Marine natural products from the Turkish sponge Agelas oroides that inhibit the enoyl reductases from Plasmodium falciparum, Mycobacterium tuberculosis and Escherichia coli
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DOI：
10.1016/j.bmc.2007.07.032
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发表时间：
2007-11-01
影响因子：
3.5
通讯作者：
Rueedi, Peter
中科院分区：
文献类型：
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作者：
Tasdemir, Deniz;Topaloglu, Buelent;Rueedi, Peter
II型脂肪酸途径(Fas-II)是抗菌药物发现的有效靶点。基于恶性疟原虫Enoyl-ACP还原酶(PfFabI)的活性导向分离方法对土耳其海绵Agelas oroides的正己烷、CHCl3-和AQ MeOH提取物进行了酶抑制分析，得到了6种纯代谢物[24-乙基-胆甾醇-5-α-7-烯-3-β-醇(1)，4，5-二溴吡咯-2-羧酸甲酯(2)，4，5-二溴吡咯-2-羧酸(3)，(E)-冬凌草素(4)3-氨基-1-(2-氨基咪唑基)-1-丙烯(5)，(4)-氨基-1-(2-氨基咪唑基)-丙烯(5)，牛磺酸(6)]和一些次要的复杂脂肪酸混合物(FAMA-FAMG)。FAMA由(5Z，9Z)-5，9-二十三碳二烯(7)和(5Z，9Z)-5，9-四碳二烯(8)酸按1：2混合而成，FAMB由8，(5Z，9Z)-5，9-十五碳二烯(9)和(5Z，9Z)-5，9-十六碳二烯(10)按3：3：2比例组成，是正己烷提取物最有效的PfFabI抑制成分(IC50值为0.35mU/ml)。(E)-Oroidin为游离碱(4a)，鉴定为CHCl3提取物的活性成分。化合物4a是一种比(E)-oroidin TFA盐(4b)更有效的PfFabI抑制剂(IC50为0.30 mU/ml=0.77 mU M)，(E)-oroidin TFA盐是AQ甲醇提取物的活性和主要成分(IC50为5.0 mU g/ml)。酶动力学研究表明，4a是一种非竞争性的PfFabI抑制剂(相对于底物和辅因子，K-I分别为0.4+/-0.2和0.8+/-0.2µM)。对结核分枝杆菌(MtFabI，IC(50)S 9.4和8.2mU/ml)和大肠埃希氏菌(ECFabI，IC(50)S分别为0.5mU/m l和0.07mU/m l)的FABI均有抑制作用。大多数化合物在体外表现出抗疟原虫、杀锥虫和杀利什曼等活性，对哺乳动物细胞没有细胞毒性。这项研究代表了第一批抑制Fabi的海洋代谢物，Fabi是几种病原微生物Fas-II途径的临床相关酶靶标。(C)2007爱思唯尔有限公司。保留所有权利。
The type II fatty acid pathway (FAS-II) is a validated target for antimicrobial drug discovery. An activity-guided isolation procedure based on Plasmodium falciparum enoyl-ACP reductase (PfFabI) enzyme inhibition assay on the n-hexane-, the CHCl3- and the aq MeOH extracts of the Turkish marine sponge Agelas oroides yielded six pure metabolites [24-ethyl-cholest-5 alpha 7-en-3-beta-ol (1), 4,5-dibromopyrrole-2-carboxylic acid methyl ester (2), 4,5-dibromopyrrole-2-carboxylic acid (3), (E)-oroidin (4) 3-amino-1-(2-aminoimidazoyl)-prop-1-ene (5), taurine (6)] and some minor, complex fatty acid mixtures (FAMA-FAMG). FAMA, consisting of a 1:2 mixture of (5Z,9Z)-5,9-tricosadienoic (7) and (5Z,9Z)-5,9-tetracosadienoic (8) acids, and FAMB composed of 8, (5Z,9Z)-5,9-pentacosadienoic (9) and (5Z,9Z)-5,9-hexacosadienoic (10) acids in 3:3:2 ratio were the most active PfFabI inhibitory principles of the hexane extract (IC50 values 0.35 mu g/ml). (E)-Oroidin isolated as free base (4a) was identified as the active component of the CHCl3 extract. Compound 4a was a more potent PfFabI inhibitor (IC50 0.30 mu g/ml = 0.77 mu M) than the (E)-oroidin TFA salt (4b), the active and major component of the aq MeOH extract (IC50 5.0 mu g/ml). Enzyme kinetic studies showed 4a to be an uncompetitive PfFabI inhibitor (K-i: 0.4 +/- 0.2 and 0.8 +/- 0.2 mu M with respect to substrate and cofactor). In addition, FAMA and FAMD (mainly consisting of methyl-branched fatty acids) inhibited FabI of Mycobacterium tuberculosis (MtFabI, IC(50)s 9.4 and 8.2 mu g/ml, respectively) and Escherichia coli (EcFabI, IC(50)s 0.5 and 0.07 mu g/ml, respectively). The majority of the compounds exhibited in vitro antiplasmodial, as well as trypanocidal and leishmanicidal activities without cytotoxicity towards mammalian cells. This study represents the first marine metabolites that inhibit FabI, a clinically relevant enzyme target from the FAS-II pathway of several pathogenic microorganisms. (C) 2007 Elsevier Ltd. All rights reserved.