Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA.
Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610, USA.
ChemMedChem. 2022 Jul 19;17(14):e202200165. doi: 10.1002/cmdc.202200165. Epub 2022 May 23.
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 IC /IC values toward HER-family overexpressing breast cancer cells.
报道了一类具有环状硫代磺酸盐结构的分子-二硫键断裂剂（DDA）的结构-性质-功能关系，这些分子能够平行下调表皮生长因子受体（EGFR）家族，并选择性诱导 EGFR+或 HER2+乳腺癌细胞凋亡。最近的研究结果表明，DDA 的作用机制涉及与蛋白二硫键异构酶（PDI）家族成员活性位点半胱氨酸残基的硫醇（ate）发生共价结合。本文报道了如何通过调节硫醇-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，研究揭示了生物效力和硫醇反应性之间的相关性。亲核进攻引发的环状硫代磺酸盐开环反应的特异性可以通过在母体支架上添加取代基来调节。还报道了先导化合物的优化工作，这导致对过表达 HER 家族的乳腺癌细胞的 IC/IC 值有了相当大的降低。
