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

Anticancer Agents Derived from Cyclic Thiosulfonates: Structure‐Reactivity and Structure‐Activity... 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png ChemMedChem Wiley

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

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References (6)

Publisher
Wiley
Copyright
© 2022 Wiley‐VCH GmbH
ISSN
1860-7179
eISSN
1860-7187
DOI
10.1002/cmdc.202200165
Publisher site
See Article on Publisher Site

Abstract

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.

Journal

ChemMedChem – Wiley

Published: Jul 19, 2022

Keywords: Anticancer; Breast cancer; Cyclic thiosulfonate; Thiol reactivity; Protein disulfide isomerase inhibitors; Thiosulfonate; Tunable ring opening

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