Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L
| Autor: | Carlos A. Montanari, Jerônimo Lameira, Felipe Cardoso Prado Martins, Vinícius Bonatto, Fernanda dos Reis Rocho, Andrei Leitão, Lorenzo Cianni, Anwar Shamim |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
Nitrile
Stereochemistry Cathepsin L Clinical Biochemistry Pharmaceutical Science Molecular Dynamics Simulation 01 natural sciences Biochemistry Cathepsin B Structure-Activity Relationship chemistry.chemical_compound Drug Discovery Humans Peptide bond INIBIDORES DE ENZIMAS Amines Enzyme Inhibitors Molecular Biology Cathepsin chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology 010405 organic chemistry Chemistry Organic Chemistry Amides 0104 chemical sciences 010404 medicinal & biomolecular chemistry Enzyme Drug Design Lipophilicity biology.protein Molecular Medicine Cysteine |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| ISSN: | 0968-0896 |
| Popis: | Human cathepsin B (CatB) is an important biological target in cancer therapy. In this work, we performed a knowledge-based design approach and the synthesis of a new set of 19 peptide-like nitrile-based cathepsin inhibitors. Reported compounds were assayed against a panel of human cysteine proteases: CatB, CatL, CatK, and CatS. Three compounds (7h, 7i, and 7j) displayed nanomolar inhibition of CatB and selectivity over CatK and CatL. The selectivity was achieved by using the combination of a para biphenyl ring at P3, halogenated phenylalanine in P2 and Thr-O-Bz group at P1. Likewise, compounds 7i and 7j showed selective CatB inhibition among the panel of enzymes studied. We have also described a successful example of bioisosteric replacement of the amide bond for a sulfonamide one [7e → 6b], where we observed an increase in affinity and selectivity for CatB while lowering the compound lipophilicity (ilogP). Our knowledge-based design approach and the respective structure–activity relationships provide insights into the specific ligand-target interactions for therapeutically relevant cathepsins. |
| Databáze: | OpenAIRE |
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