Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships.
Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships.
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DOI：
10.1002/cmdc.202200165
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发表时间：
2022-07-19
期刊：
影响因子：
3.4
通讯作者：
中科院分区：
文献类型：
--
作者：
报道了与一类环状硫代磺酸盐分子-二硫键破坏剂（DDA）-相关的结构-性质-功能关系，其具有平行下调表皮生长因子受体（HER）家族并选择性诱导EGFR+或HER 2+乳腺癌细胞凋亡的能力。最近的研究结果表明，DDA的作用机制涉及共价结合的巯基（酸）从蛋白质二硫键异构酶（PDI）家族成员的活性位点半胱氨酸残基。报道了药效团的结构修饰如何通过调节硫醇-硫代磺酸盐交换反应的动力学来改变环状硫代磺酸盐的抗癌活性，并且研究揭示了生物学效力与硫醇反应性之间的相关性。通过亲核攻击的环状硫代磺酸盐开环反应的特异性可以通过向母体支架添加取代基来调节。还报道了先导化合物优化的努力，并导致对HER家族过表达乳腺癌细胞的IC 50/IC 90值显著降低。报道了环状硫代磺酸盐分子-二硫键破坏剂（DDA）-的结构-性质-功能关系，其平行下调表皮生长因子受体（HER）家族并选择性诱导EGFR+或HER 2+乳腺癌细胞凋亡。最近显示，DDA共价结合至选定蛋白质二硫键异构酶（PDI）的活性位点半胱氨酸残基。这里显示，对DDA的结构修饰可以调节硫醇-硫代磺酸盐交换反应的动力学，并产生更有效的化合物。
Reported are structure-property-function relationships associated with a class of cyclic thiosulfonate molecules—disulfide-bond disrupting agents (DDAs)—with the ability to downregulate the Epidermal Growth Factor Receptor (HER) family in parallel and selectively induce apoptosis of EGFR+ or HER2+ breast cancer cells. Recent findings have revealed that the DDA mechanism of action involves covalent binding to the thiol(ate) from the active site cysteine residue of members of the protein disulfide isomerase (PDI) family. Reported is how structural modifications to the pharmacophore can alter the anticancer activity of cyclic thiosulfonates by tuning the dynamics of thiol-thiosulfonate exchange reactions, and the studies reveal a correlation between the biological potency and thiol-reactivity. Specificity of the cyclic thiosulfonate ring-opening reaction by a nucleophilic attack can be modulated by substituent addition to a parent scaffold. Lead compound optimization efforts are also reported, and have resulted in a considerable decrease of the IC50/IC90 values toward HER-family overexpressing breast cancer cells. Reported are structure-property-function relationships of cyclic thiosulfonate molecules—disulfide-bond disrupting agents (DDAs)—that downregulate the Epidermal Growth Factor Receptor (HER) family in parallel and selectively induce apoptosis of EGFR+ or HER2+ breast cancer cells. Shown recently, the DDAs covalently bind to the active site cysteine residue(s) of selected protein disulfide isomerases (PDIs). Shown here, structural modifications to the DDAs can tune the dynamics of thiol-thiosulfonate exchange reactions and lead to more potent compounds.
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