Action of atrop-abyssomicin C as an inhibitor of 4-amino-4-deoxychorismate synthase PabB
Action of atrop-abyssomicin C as an inhibitor of 4-amino-4-deoxychorismate synthase PabB
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DOI：
10.1002/anie.200701836
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发表时间：
2007-01-01
影响因子：
16.6
通讯作者：
Suessmuth, Roderich D.
中科院分区：
文献类型：
--
作者：
Keller, Simone;Schadt, Heiko S.;Suessmuth, Roderich D.
在生物合成途径中，分支酸是一种重要的和中心的生物合成代谢物，它可以分支到芳香氨基酸Trp、Tyr和Phe的生物合成，也可以分支到对氨基苯甲酸(PABA)的生物合成。PABA和四氢叶酸的相应生物合成酶存在于许多微生物和寄生虫中，但在人类中不存在，这使得PABA的生物合成成为抗感染药物的有趣靶点。四氢叶酸途径的主要合成抑制剂是磺胺类和曲美托普林。[2]最近在PABA生物合成途径方面的筛选工作导致从革兰氏阳性海洋放线菌Verrucosipora AB-18-032(方案1)中分离出深霉素B、C(1)和D(4)[3，4]。在这三种代谢物中，阿霉素C被认为是唯一对革兰氏阳性菌，包括致病性金黄色葡萄球菌的有效成分。由于这种吸引人的结构，几个合成化学小组已经将他们的兴趣转向了abysSomicin C的全合成。[5-8]到目前为止，已经发表了两个成功的全合成，第一个由Sorensen及其同事[5]，第二个由Nicolaou和Harison[6，8]。
Among biosynthetic pathways, chorismate is an important and central biosynthetic metabolite that branches off to the biosynthesis of aromatic amino acids Trp, Tyr, and Phe, but also to p-aminobenzoic acid (pABA).[1] p-Aminobenzoic acid is a component of the biosynthesis of tetrahydrofolate. Corresponding biosynthesis enzymes of pABA and tetrahydrofolate occur in many microorganisms and parasites, but not in humans, which makes pABA biosynthesis an interesting target for anti-infective agents. Prominent synthetic inhibitors of the tetrahydrofolate pathway are sulfonamides and trimetoprim.[2]Recent screening efforts in the pABA biosynthesis pathway led to the isolation of abyssomicins B, C (1), and D (4)[3, 4] from the gram-positive marine actinomycete Verrucosispora AB-18-032 (Scheme 1). Out of the three metabolites, abyssomicin C has been described as the only active component against gram-positive bacteria including pathogenic Staphylococcus aureus strains. Because of the attractive structure, several synthetic chemistry groups have directed their interests towards the total synthesis of abyssomicinC.[5–8] Two successful total syntheses have been published so far, the first by Sorensen and co-workers [5] and the second by Nicolaou and Harrison.[6, 8]