Total synthesis and evaluation of [ψ[CH2NH]Tpg4]vancomycin aglycon:: Reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding
Total synthesis and evaluation of [ψ[CH2NH]Tpg4]vancomycin aglycon:: Reengineering vancomycin for dual D-Ala-D-Ala and D-Ala-D-Lac binding
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DOI：
10.1021/ja0572912
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发表时间：
2006-03-08
影响因子：
15
通讯作者：
Boger, DL
中科院分区：
文献类型：
--
作者：
Crowley, BM;Boger, DL
介绍了[Psi[CH_2NH]Tpg（4）]万古霉素苷元（5）的有效合成方法，其中万古霉素苷元的4位酰胺羰基被亚甲基取代。进行该单个原子的去除以增强与D-Ala-D-Lac的结合，对抗赋予细菌的抗性，所述细菌通过类似的单个原子变化（酯0酰胺NH）来重塑其D-Ala-D-Ala肽聚糖细胞壁前体。该方法的关键要素包括合成修饰的万古霉素ABCD环系统，其特征在于残基4和5的还原胺化偶联，用于安装深位酰胺修饰，用于形成修饰的CID环系统的两个二芳基醚闭合中的第一个（76%，2.5-3：1动力学阻转非对映体选择性），用于安装受阻AB联芳基键（90%）的Suzuki偶联，阻转异构体立体化学可以在其上热调节，AB环系统的大环内酰胺化闭合（70%）。随后的DE环系统引入引起了室温芳族亲核取代反应，用于形成剩余的二芳基醚（86%，6-7：1动力学阻转非对映选择性），完成5的碳骨架。与预期一致并且相对于万古霉素糖苷配基，5表现出对D-Ala-D-Lac的亲和力增加40倍（K-a = 5.2 × 10（3）M-1），对D-Ala-D-Ala的亲和力降低35倍（K-a = 4.8 × 10（3）M-1），提供了具有平衡的双重结合特征的糖肽类似物。令人满意的是，5对VanA抗性生物体表现出抗微生物活性（MIC = 31 μ g/mL），所述VanA抗性生物体在糖肽抗生素攻击后将其D-Ala-D-Ala细胞壁前体重构为D-Ala-D-Lac，显示出反映这些结合特征的效力。
An effective synthesis of [Psi[CH2NH]Tpg(4)]vancomycin aglycon (5) is detailed in which the residue 4 amide carbonyl of vancomycin aglycon has been replaced with a methylene. This removal of a single atom was conducted to enhance binding to D-Ala-D-Lac, countering resistance endowed to bacteria that for remodel their D-Ala-D-Ala peptidoglycan cell wall precursor by a similar single atom change (ester 0 amide NH). Key elements of the approach include a synthesis of the modified vancomycin ABCD ring system featuring a reductive amination coupling of residues 4 and 5 for installation of the deep-seated amide modification, the first of two diaryl ether closures for formation of the modified CID ring system (76%, 2.5-3:1 kinetic atropodiastereoselectivity), a Suzuki coupling for installation of the hindered AB biaryl bond (90%) on which the atropisomer stereochemistry could be thermally adjusted, and a macrolactamization closure of the AB ring system (70%). Subsequent DE ring system introduction enlisted a room-temperature aromatic nucleophilic substitution reaction for formation of the remaining diaryl ether (86%, 6-7:1 kinetic atropodiastereoselectivity), completing the carbon skeleton of 5. Consistent with expectations and relative to the vancomycin aglycon, 5 exhibited a 40-fold increase in affinity for D-Ala-D-Lac (K-a = 5.2 x 10(3) M-1) and a 35-fold reduction in affinity for D-Ala-D-Ala (K-a = 4.8 x 10(3) M-1), providing a glycopeptide analogue with balanced, dual binding characteristics. Beautifully, 5 exhibited antimicrobial activity (MIC = 31 mu g/mL) against a VanA-resistant organism that remodels its D-Ala-D-Ala cell wall precursor to D-Ala-D-Lac upon glycopeptide antibiotic challenge, displaying a potency that reflects these binding characteristics.