The University of Sydney, School of Medical Sciences (Pharmacology), and Bosch Institute, New South Wales 2006, Australia.
The University of Sydney, School of Medical Sciences (Pharmacology), and Bosch Institute, New South Wales 2006, Australia.
J Inorg Biochem. 2017 Dec;177:344-351. doi: 10.1016/j.jinorgbio.2017.07.033. Epub 2017 Aug 1.
Macrocyclic hydroxamic acids coordinate Fe(III) with high affinity as part of siderophore-mediated bacterial iron acquisition. Trimeric hydroxamic acid macrocycles, such as desferrioxamine E (DFOE), are prevalent in nature, with fewer dimeric macrocycles identified, including putrebactin (pbH), avaroferrin (avH), bisucaberin (bsH) and alcaligin (alH). This work used metal-templated synthesis (MTS) to pre-assemble complexes between one equivalent of Fe(III) and two equivalents of 4-((4-aminobutyl)(hydroxy)amino)-4-oxobutanoic acid (BBH) or 4-((5-aminopentyl)(hydroxy)amino)-4-oxobutanoic acid (PBH). Following peptide coupling, the respective Fe(III) complexes of pbH or bsH were formed, which analysed by LC-MS under acidic pH as [Fe(pb)] ([M], m/z 426.1) or [Fe(bs)] ([M], m/z 454.2). The mixed-ligand 1:1:1 Fe(III):BBH:PBH system furnished [Fe(pb)] and [Fe(bs)], together with chimeric [Fe(av)] ([M], m/z 440.2). The deviation from the expected 1:2:1 distribution of [Fe(pb)]:[Fe(av)]:[Fe(bs)] to 1:3.2:1.6 suggested the MTS-mediated formation of dimeric macrocycles could be influenced by steric effects in the pre-complex and/or cavity size, as governed by the monomer. 21-Membered avH defined the lower boundary of the optimal architecture. Mixed-ligand MTS between Fe(III):PBH-d:ret-PBH at 1:1.5:1.5, where ret-PBH=3-(6-amino-N-hydroxyhexanamido)propanoic acid, gave four Fe(III)-loaded trimeric hydroxamic acid macrocycles in a distribution of 1.0:3.0:2.9:1.1 that closely matched the expected distribution 1:3:3:1 for a system without any kinetic and/or thermodynamic bias. Apo-macrocycles pbH, avH and bsH were produced upon incubation with diethylenetriaminepentaacetic acid (DTPA) and co-eluted with a biosynthetic mixture of the native macrocycles. The work has demonstrated the utility of single- and mixed-ligand MTS for producing a variety of homo- and heteroleptic dimeric hydroxamic acid macrocycles as Fe(III) complexes and free ligands.
大环羟肟酸作为铁载体介导的细菌铁获取的一部分，以高亲和力与 Fe(III)配位。三聚体羟肟酸大环，如去铁胺 E (DFOE)，在自然界中很普遍，而鉴定出的二聚体大环较少，包括腐黑菌素 (pbH)、阿瓦罗芬 (avH)、双苏卡宾 (bsH) 和阿利加林 (alH)。本工作使用金属模板合成 (MTS) 预先组装 Fe(III)与二当量的 4-((4-氨基丁基)(羟基)氨基)-4-氧代丁酸 (BBH) 或 4-((5-氨基戊基)(羟基)氨基)-4-氧代丁酸 (PBH) 之间的配合物。肽偶联后，形成相应的 pbH 或 bsH 的 Fe(III)配合物，在酸性 pH 下通过 LC-MS 分析为 [Fe(pb)]([M]，m/z 426.1) 或 [Fe(bs)]([M]，m/z 454.2)。混合配体 1:1:1 Fe(III):BBH:PBH 体系提供了 [Fe(pb)] 和 [Fe(bs)]，以及嵌合的 [Fe(av)]([M]，m/z 440.2)。预期的 [Fe(pb)]:[Fe(av)]:[Fe(bs)] 1:2:1 分布与 1:3.2:1.6 的偏差表明，MTS 介导的二聚体大环的形成可能受到预配合物和/或腔大小的空间位阻的影响，这由单体决定。21 元的 avH 定义了最佳结构的下限。Fe(III):PBH-d:ret-PBH 之间的混合配体 MTS 为 1:1.5:1.5，其中 ret-PBH=3-(6-氨基-N-羟基己酰胺基)丙酸，以 1.0:3.0:2.9:1.1 的分布得到四个负载 Fe(III)的三羟肟酸大环，与无任何动力学和/或热力学偏差的系统的预期分布 1:3:3:1 非常匹配。apo-大环 pbH、avH 和 bsH 在与二乙三胺五乙酸 (DTPA) 孵育后产生，并与天然大环的生物合成混合物共洗脱。这项工作证明了单配体和混合配体 MTS 用于生产各种同系物和异系物二聚体羟肟酸大环作为 Fe(III)配合物和游离配体的用途。
