Anticancer Agents Derived from Cyclic Thiosulfonates: Structure-Reactivity and Structure-Activity Relationships.
| Autor: | Ghilardi AF; Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA., Yaaghubi E; Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA., Ferreira RB; Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA., Law ME; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610, USA., Yang Y; Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA., Davis BJ; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610, USA., Schilson CM; Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA., Ghiviriga I; Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA., Roitberg AE; Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA., Law BK; Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, 32610, USA., Castellano RK; Department of Chemistry, University of Florida, Gainesville, FL, 32611, USA. |
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| Jazyk: | angličtina |
| Zdroj: | ChemMedChem [ChemMedChem] 2022 Jul 19; Vol. 17 (14), pp. e202200165. Date of Electronic Publication: 2022 May 23. |
| DOI: | 10.1002/cmdc.202200165 |
| Abstrakt: | 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 (© 2022 Wiley-VCH GmbH.) |
| Databáze: | MEDLINE |
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