Structure requirements for anaerobe processing of azo compounds: Implications for prodrug design
Structure requirements for anaerobe processing of azo compounds: Implications for prodrug design
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DOI：
10.1016/j.bmcl.2012.10.014
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发表时间：
2012-12-15
影响因子：
2.7
通讯作者：
Gilmer, John F.
中科院分区：
文献类型：
--
作者：
Gavin, Jason;Ruiz, Juan F. Marquez;Gilmer, John F.
本文概述了产气荚膜梭菌（Clostridium perfringens）对偶氮类化合物的代谢，这是一种在人类结肠中发现的厌氧菌。最近报道的一种基于5-氨基水杨酸的强的松龙前药在与细菌孵育时显示出药物释放，而基于对氨基苯甲酸（PABA）的类似物则没有。相反，它呈现出一个新的HPLC峰，与母体的保留时间相对较近，LCMS鉴定为部分还原的联氨产物。本文研究了与paba基化合物具有不同程度的电子和空间相似性的基板上的偶氮还原。在含偶氮的芳香环上有一个供电子基团的偶氮化合物，在没有检测到联氨中间体的情况下，与母体胺立即发生歧化。只含有吸电子基团的化合物被部分可逆地还原成可检测的稳定联氨。它们与母体胺不不成比例，而是使母体偶氮化合物再生。这种不完全还原与偶氮基前药的设计和偶氮基染料的毒理学有关。(C) 2012 Elsevier Ltd.版权所有。
This Letter generalizes the metabolism of the azo class of compounds by Clostridium perfringens, an anaerobe found in the human colon. A recently reported 5-aminosalicylic acid-based prednisolone prodrug was shown to release the drug when incubated with the bacteria, while the para-aminobenzoic acid (PABA) based analogue did not. Instead, it showed a new HPLC peak with a relatively close retention time to the parent which was identified by LCMS as the partially reduced hydrazine product. This Letter investigates azoreduction across a panel of substrates with varying degrees of electronic and steric similarity to the PABA-based compound. Azo compounds with an electron donating group on the azo-containing aromatic ring showed immediate disproportionation to their parent amines without any detection of hydrazine intermediates by HPLC. Compounds containing only electron withdrawing groups are partially and reversibly reduced to produce a stable detectable hydrazine. They do not disproportionate to their parent amines, but regenerate the parent azo compound. This incomplete reduction is relevant to the design of azo-based prodrugs and the toxicology of azo-based dyes. (C) 2012 Elsevier Ltd. All rights reserved.