Design and synthesis of biphenyl and biphenyl ether inhibitors of sulfatases
| Autor: | Bernard T. Golding, Alfie Brennan, Tristan Reuillon, Miller Duncan Charles, Celine Cano, Gary S. Beale, Annalisa Bertoli, Sari F. Alhasan, Helen L. Reeves, David R. Newell, Roger J. Griffin |
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| Rok vydání: | 2016 |
| Předmět: |
Biphenyl
chemistry.chemical_classification endocrine system 010405 organic chemistry Stereochemistry organic chemicals Amino derivatives Ether General Chemistry 01 natural sciences Small molecule humanities 0104 chemical sciences Chemistry 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Aryl sulfatase Enzyme chemistry 030220 oncology & carcinogenesis bacteria heterocyclic compounds Carboxylate Pharmacophore |
| Zdroj: | Chemical Science |
| ISSN: | 2041-6539 2041-6520 |
| Popis: | Two series of inhibitors of sulfatase 2, ARSA and ARSB were designed based on biphenyl and biphenyl ether scaffolds substituted with e.g. sulfamate and carboxylate groups. Inhibitors of sulfatase-2 are putative anticancer agents, but the discovery of potent small molecules targeting this enzyme has proved challenging. Based on molecular modelling, two series of sulfatase-2 inhibitors have been developed with biphenyl and biphenyl ether scaffolds judiciously substituted with sulfamate, carboxylate and other polar groups (e.g. amino). Inhibition of aryl sulfatase A and B was also determined. The biphenyl ether derivatives were less selective for sulfatase-2 over aryl sulfatase B than the biphenyl series. All biphenyl ether derivatives inhibited aryl sulfatase A, whereas only amino derivatives inhibited aryl sulfatase B significantly. In the biphenyl series few derivatives exhibited activity against aryl sulfatase B. The trichloroethylsulfamate group was identified as a new pharmacophore enabling potent inhibition of all of the sulfatases studied. |
| Databáze: | OpenAIRE |
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