Adapting decarbonylation chemistry for the development of prodrugs capable of in vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules.
Adapting decarbonylation chemistry for the development of prodrugs capable of in vivo delivery of carbon monoxide utilizing sweeteners as carrier molecules.
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DOI：
10.1039/d1sc02711e
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发表时间：
2021-08-11
期刊：
影响因子：
8.4
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
De La Cruz LK;Yang X;Menshikh A;Brewer M;Lu W;Wang M;Wang S;Ji X;Cachuela A;Yang H;Gallo D;Tan C;Otterbein L;de Caestecker M;Wang B
一氧化碳作为内源性信号分子在各种器官损伤动物模型中表现出药理学功效。为了解决使用CO气体作为广泛应用的治疗剂的困难，我们有兴趣通过在有机化合物中的CO的生物可逆性笼化来开发CO前药。具体而言，我们已经探索了1，2-二羰基化合物的脱羧-脱羰基化学。在生理条件下有利于最大CO释放的因素的检查和优化导致有机CO前药使用无热量甜味剂作为连接到1，2-二羰基核心的离去基团。连接具有适当性质的离去基团促进了导致CO产生的所需的水解-脱羧-脱羰反应顺序。选择一种这样的CO前药来概括在细胞培养研究中CO对LPS诱导的TNF-α产生的抗炎作用。小鼠口服给药将COHb水平升高至各种临床前和临床研究中确立的安全有效水平。此外，在小鼠急性肾损伤模型中证明了其药理学疗效。这些研究证明了这些具有良性载体的前药作为口服活性的基于CO的治疗剂的潜力。这代表了具有良性载体的口服活性有机CO前药的第一个例子，该良性载体是FDA批准的甜味剂，具有体内证明的安全性。具有FDA批准的甜味剂作为离去基团的1，2-二羰基化合物提供CO以保护小鼠免受急性肾损伤。
Carbon monoxide as an endogenous signaling molecule exhibits pharmacological efficacy in various animal models of organ injury. To address the difficulty in using CO gas as a therapeutic agent for widespread applications, we are interested in developing CO prodrugs through bioreversible caging of CO in an organic compound. Specifically, we have explored the decarboxylation–decarbonylation chemistry of 1,2-dicarbonyl compounds. Examination and optimization of factors favorable for maximal CO release under physiological conditions led to organic CO prodrugs using non-calorific sweeteners as leaving groups attached to the 1,2-dicarbonyl core. Attaching a leaving group with appropriate properties promotes the desired hydrolysis–decarboxylation–decarbonylation sequence of reactions that leads to CO generation. One such CO prodrug was selected to recapitulate the anti-inflammatory effects of CO against LPS-induced TNF-α production in cell culture studies. Oral administration in mice elevated COHb levels to the safe and efficacious levels established in various preclinical and clinical studies. Furthermore, its pharmacological efficacy was demonstrated in mouse models of acute kidney injury. These studies demonstrate the potential of these prodrugs with benign carriers as orally active CO-based therapeutics. This represents the very first example of orally active organic CO prodrugs with a benign carrier that is an FDA-approved sweetener with demonstrated safety profiles in vivo. 1,2-Dicarbonyl compounds with FDA-approved sweeteners as leaving groups deliver CO for protection against acute kidney injury in mice.
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影响因子：
16.6
作者：
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DOI：
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发表时间：
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影响因子：
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作者：
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DOI：
10.1097/01.asn.0000050760.87113.25
发表时间：
2003-03-01
影响因子：
13.6
作者：
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通讯作者：
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