Synthesis of chromone, quinolone, and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis.
Synthesis of chromone, quinolone, and benzoxazinone sulfonamide nucleosides as conformationally constrained inhibitors of adenylating enzymes required for siderophore biosynthesis.
复制标题
DOI：
10.1021/jo400976f
复制
发表时间：
2013-08-02
期刊：
影响因子：
--
通讯作者：
Aldrich CC
中科院分区：
文献类型：
--
作者：
Engelhart CA;Aldrich CC
MbtA催化结核分枝杆菌（Mtb）中菌素生物合成的第一步，并负责将水杨酸结合到菌素铁载体中。5 ' - o -[N-（水杨基）磺胺酰]腺苷（Sal-AMS）是一种非常有效的MbtA核苷抑制剂，对全细胞Mtb具有良好的活性，但生物利用度较差。为了提高生物利用度，我们基于计算和结构研究设计了四种构象约束的Sal-AMS类似物，去除两个可旋转键和电离的氨基甲酸酯基。本文描述了salams的色素、喹诺酮和苯并恶嗪酮-3-磺酰胺衍生物的合成、生化和微生物学评价。我们用新的化学方法从常见的β-酮磺酰胺中间体中组装了这三个杂环。铬酮和喹诺酮-3-磺酰胺中间体的合成特点是利用二甲基甲酰胺二甲基缩醛将β-酮磺酰胺甲酰化，从而得到胺酮，该胺酮可以通过加成-消除反应在分子内与苯酚反应或在分子间与伯胺反应。采用β-酮磺酰胺亚硝化和分子内亲核芳烃取代法制备了苯并恶嗪酮-3-磺酰胺。这些双环磺胺与受保护的腺苷衍生物的Mitsunobu偶联，随后进行全局去保护，提供了各自抑制剂的简明合成。
MbtA catalyzes the first committed step of mycobactin biosynthesis in Mycobacterium tuberculosis (Mtb) and is responsible for the incorporation of salicylic acid into the mycobactin siderophores. 5′-O-[N-(Salicyl)sulfamoyl]adenosine (Sal-AMS) is an extremely potent nucleoside inhibitor of MbtA that possesses excellent activity against whole-cell Mtb, but suffers from poor bioavailability. In an effort to improve the bioavailability, we have designed four conformationally constrained analogues of Sal-AMS that remove two rotatable bonds and the ionized sulfamate group based on computational and structural studies. Herein we describe the synthesis, biochemical, and microbiological evaluation of chromone-, quinolone-, and benzoxazinone-3-sulfonamide derivatives of Sal-AMS. We developed new chemistry to assemble these three heterocycles from common β-ketosulfonamide intermediates. The synthesis of the chromone- and quinolone-3-sulfonamide intermediates features formylation of a β-ketosulfonamide employing dimethylformamide dimethyl acetal to afford an enaminone that can react intramolecularly with a phenol or intermolecularly with a primary amine via addition-elimination reaction(s). The benzoxazinone-3-sulfonamide was prepared by nitrosation of a β-ketosulfonamide followed by intramolecular nucleophilic aromatic substitution. Mitsunobu coupling of these bicyclic sulfonamides with a protected adenosine derivative followed by global deprotection provides a concise synthesis of the respective inhibitors.
登录
查看更多内容
影响因子：
14.8
作者：
Ferreras, JA;Ryu, JS;Quadri, LEN
通讯作者：
Quadri, LEN
影响因子：
2.1
作者：
ABDULLA, RF;BRINKMEYER, RS
通讯作者：
BRINKMEYER, RS
影响因子：
3.5
作者：
Ikeuchi, Hideyuki;Meyer, Megan E.;Richards, Nigel G. J.
通讯作者：
Richards, Nigel G. J.
影响因子：
3.2
作者：
Chavadi, Sivagami Sundaram;Stirrett, Karen L.;Quadri, Luis E. N.
通讯作者：
Quadri, Luis E. N.
DOI：
10.1073/pnas.97.3.1252
发表时间：
2000-02-01
影响因子：
11.1
作者：
De Voss, JJ;Rutter, K;Barry, CE
通讯作者：
Barry, CE