Anticancer Agents Derived from Cyclic Thiosulfonates: Structure‐Reactivity and Structure‐Activity Relationships

• Published in: ChemMedChem 2022-07, Vol.17 (14), p.e202200165-n/a
• Main Authors: Ghilardi, Amanda F., Yaaghubi, Elham, Ferreira, Renan B., Law, Mary E., Yang, Yinuo, Davis, Bradley J., Schilson, Christopher M., Ghiviriga, Ion, Roitberg, Adrian E., Law, Brian K., Castellano, Ronald K.
• Format: Article
• Language: English
• Subjects: Anticancer; Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Antitumor agents; Apoptosis; Breast cancer; Chemical bonds; Cyclic thiosulfonate; Cysteine; Epidermal growth factor; ErbB-2 protein; Growth factors; Lead compounds; Optimization; Protein disulfide isomerase inhibitors; Protein disulfide-isomerase; Protein Disulfide-Isomerases; Structure-Activity Relationship; Structure-function relationships; Sulfhydryl Compounds - chemistry; Thiol reactivity; Thiosulfonate; Tunable ring opening
• ISSN: 1860-7179; 1860-7187; 1860-7187
• DOI: 10.1002/cmdc.202200165

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. Exchange dynamics: 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.