Investigations into the carbonic anhydrase inhibition of COS-releasing donor core motifs.
Investigations into the carbonic anhydrase inhibition of COS-releasing donor core motifs.
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DOI：
10.1016/j.bcp.2017.11.004
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发表时间：
2018-03
影响因子：
5.8
通讯作者：
Pluth MD
中科院分区：
文献类型：
--
作者：
Steiger AK;Zhao Y;Choi WJ;Crammond A;Tillotson MR;Pluth MD
通过利用碳酸酐酶（CA）介导的羰基硫（COS）水解为硫化氢（H2S），释放COS的支架作为硫化氢（H2S）供体越来越受欢迎。这类新兴供体中的大多数化合物经历可分解（通常称为自焚）以释放COS，并且已经报道了少数不同的COS释放结构。这种捐赠策略的一个好处是，许多笼状的含COS的核心基序是可能的，并准备发展成自我牺牲COS/H2S供体。由于COS在H2S供体途径中的中间释放需要CA，因此COS供体基序不直接抑制CA是重要的。在这项工作中，我们调查的细胞毒性和CA抑制性能的不同笼COS供体核心，以及笼CO2和CS2基序和非自焚控制化合物。在A549细胞中，在浓度高达100 μM时，所研究的化合物均未表现出显著的细胞毒性或增强的细胞增殖，但我们确定了四种作为CA抑制剂的核心结构，从而为自分解COS/H2S供体基序的未来开发提供了路线图。
Carbonyl sulfide (COS) releasing scaffolds are gaining popularity as hydrogen sulfide (H2S) donors through exploitation of the carbonic anhydrase (CA)-mediated hydrolysis of COS to H2S. The majority of compounds in this emerging class of donors undergo triggerable decomposition (often referred to as self-immolation) to release COS, and a handful of different COS-releasing structures have been reported. One benefit of this donation strategy is that numerous caged COS-containing core motifs are possible and are poised for development into self-immolative COS/H2S donors. Because the intermediate release of COS en route to H2S donation requires CA, it is important that the COS donor motifs do not inhibit CA directly. In this work, we investigate the cytotoxicity and CA inhibition properties of different caged COS donor cores, as well as caged CO2 and CS2 motifs and non-self-immolative control compounds. None of the compounds investigated exhibited significant cytotoxicity or enhanced cell proliferation at concentrations up to 100 μM in A549 cells, but we identified four core structures that function as CA inhibitors, thus providing a roadmap for the future development of self-immolative COS/H2S donor motifs.
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