Lifa Tulip, Tieu William, Hocking Rosalie K, Codd Rachel
†School of Medical Sciences (Pharmacology) and Bosch Institute, The University of Sydney, Sydney, New South Wales 2006, Australia.
Inorg Chem. 2015 Apr 6;54(7):3573-83. doi: 10.1021/acs.inorgchem.5b00141. Epub 2015 Mar 19.
A metal-templated synthesis (MTS) approach was used to preorganize the forward endo-hydroxamic acid monomer 4-[(5-aminopentyl)(hydroxy)amino]-4-oxobutanoic acid (for-PBH) about iron(III) in a 1:3 metal/ligand ratio to furnish the iron(III) siderophore for-[Fe(DFOE)] (ferrioxamine E) following peptide coupling. Substitution of for-PBH with the reverse (retro) hydroxamic acid analogue 3-(6-amino-N-hydroxyhexanamido)propanoic acid (ret-PBH) furnished ret-[Fe(DFOE)] (ret-ferrioxamine E). As isomers, for-[Fe(DFOE)] and ret-[Fe(DFOE)] gave identical mass spectrometry signals (M + H(+), m/zcalc 654.3, m/zobs 654.3), yet for-[Fe(DFOE)] eluted in a more polar window (tR = 23.44 min) than ret-[Fe(DFOE)] (tR = 28.13 min) on a C18 reverse-phase high-performance liquid chromatography (RP-HPLC) column. for-[Ga(DFOE)] (tR = 22.99 min) and ret-[Ga(DFOE)] (tR = 28.11 min) were prepared using gallium(III) as the metal-ion template and showed the same trend for the retention time. Ring-expanded analogues of for-[Fe(DFOE)] and ret-[Fe(DFOE)] were prepared from endo-hydroxamic acid monomers with one additional methylene unit in the amine-containing region, 4-[(6-aminohexyl)(hydroxy)amino]-4-oxobutanoic acid (for-HBH) or 3-(7-amino-N-hydroxyheptanamido)propanoic acid (ret-HBH), to give the corresponding tris(homoferrioxamine E) macrocycles, for-[Fe(HHDFOE)] or ret-[Fe(HHDFOE)] (M + H(+), m/zcalc 696.3, m/zobs 696.4). The MTS reaction using a constitutional isomer of for-HBH that transposed the methylene unit to the carboxylic acid containing region, 5-[(5-aminopentyl)(hydroxy)amino]-5-oxopentanoic acid (for-PPH), gave the macrocycle for-[Fe(HPDFOE)] in a yield significantly less than that for for-[Fe(HHDFOE)], with the gallium(III) analogue for-[Ga(HPDFOE)] unable to be detected. The work demonstrates the utility and limits of MTS for the assembly of macrocyclic siderophores from endo-hydroxamic acid monomers. Indirect measures (RP-HPLC order of elution, c log P values, molecular mechanics, and density functional theory calculations) of the relative water solubility of the ligands, the iron(III) macrocycles, and the apomacrocycles were consistent in identifying for-DFOE as the most water-soluble macrocycle from for-DFOE, ret-DFOE, for-HHDFOE, ret-HHDFOE, and for-HPDFOE. From this group, only for-DFOE is known in nature, which could suggest that water solubility is an important trait in its natural selection.
采用金属模板合成（MTS）方法，以1:3的金属/配体比例将正向内异羟肟酸单体4-[(5-氨基戊基)(羟基)氨基]-4-氧代丁酸（for-PBH）围绕铁（III）进行预组装，在肽偶联后得到铁（III）铁载体for-[Fe(DFOE)]（去铁胺E）。用反向（反转）异羟肟酸类似物3-(6-氨基-N-羟基己酰胺基)丙酸（ret-PBH）取代for-PBH，得到ret-[Fe(DFOE)]（ret-去铁胺E）。作为异构体，for-[Fe(DFOE)]和ret-[Fe(DFOE)]给出相同的质谱信号（M + H(+)，计算值m/z 654.3，实测值m/z 654.3），然而在C18反相高效液相色谱（RP-HPLC）柱上，for-[Fe(DFOE)]比ret-[Fe(DFOE)]在更具极性的窗口洗脱（保留时间tR = 23.44分钟对tR = 28.13分钟）。使用镓（III）作为金属离子模板制备了for-[Ga(DFOE)]（tR = 22.99分钟）和ret-[Ga(DFOE)]（tR = 28.11分钟），并显示出相同的保留时间趋势。for-[Fe(DFOE)]和ret-[Fe(DFOE)]的扩环类似物由在含胺区域带有一个额外亚甲基单元的内异羟肟酸单体4-[(6-氨基己基)(羟基)氨基]-4-氧代丁酸（for-HBH）或3-(7-氨基-N-羟基庚酰胺基)丙酸（ret-HBH）制备，得到相应的三（高去铁胺E）大环化合物for-[Fe(HHDFOE)]或ret-[Fe(HHDFOE)]（M + H(+)，计算值m/z 696.3，实测值m/z 696.4）。使用for-HBH的一种构造异构体将亚甲基单元转移到含羧酸区域，即5-[(5-氨基戊基)(羟基)氨基]-5-氧代戊酸（for-PPH）进行MTS反应，得到大环化合物for-[Fe(HPDFOE)]，产率明显低于for-[Fe(HHDFOE)]，且未检测到镓（III）类似物for-[Ga(HPDFOE)]。这项工作证明了MTS用于从内异羟肟酸单体组装大环铁载体的实用性和局限性。配体、铁（III）大环化合物和脱辅基大环化合物相对水溶性的间接测量方法（RP-HPLC洗脱顺序、c log P值、分子力学和密度泛函理论计算）一致地将for-DFOE鉴定为for-DFOE、ret-DFOE、for-HHDFOE、ret-HHDFOE和for-HPDFOE中水溶性最高的大环化合物。在这一组中，自然界中仅知for-DFOE，这可能表明水溶性是其在自然选择中的一个重要特性。
