Green asymmetric synthesis of epoxypeptidomimetics and evaluation as human cathepsin K inhibitors

Autor(es)

Silva, Taynara L. ^{[1, 2, 3]} ; dos Santos, Deborah A. ^[4] ; de Jesus, Hugo C. R. ^[1] ; Bromme, Dieter ^{[2, 3]} ; Fernandes, Joao B. ^[1] ; Paixao, Marcio W. ^[4] ; Correa, Arlene G. ^[4] ; Vieira, Paulo C. ^{[5, 4]}

Afiliação do(s) autor(es)

^[1] Univ Fed Sao Carlos, Dept Chem, BR-13565905 Sao Carlos, SP - Brazil

^[2] Fac Dent, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3 - Canada

^[3] UBC Ctr Blood Res, 2350 Hlth Sci Mall, Vancouver, BC V6T 1Z3 - Canada

^[4] Univ Fed Sao Carlos, Ctr Excellence Res Sustainable Chem, Dept Chem, BR-13565905 Sao Carlos, SP - Brazil

^[5] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry; v. 28, n. 15 AUG 1 2020.
• Citações Web of Science: 0

Resumo

Cathepsin K (CatK) is a cysteine protease known for its potent collagenolytic activity, being recognized as an important target to the development of therapies for the treatment of bone disorders. Epoxypeptidomimetics have been reported as potent inhibitors of cathepsins, thus in this work we present a green synthesis of new peptidomimetics by using a one-pot asymmetric epoxidation/Ugi multicomponent reaction. The compounds were evaluated against CatK showing selectivity when compared with cathepsin L, with an inhibition profile in the low micromolar IC50 range. Investigation of the mechanism of action carried out for compounds LSPN428 and LSPN694 suggested a mixed inhibition mode and docking studies allowed a better understanding about interactions of inhibitors with the enzyme. (AU)

• Processo FAPESP: 14/50249-8 - Green chemistry: sustainable synthetic methods employing benign solvents, safer reagents, and bio-renewable feedstock
• Beneficiário: Arlene Gonçalves Corrêa
• Modalidade de apoio: Auxílio à Pesquisa - Programa Centros de Pesquisa em Engenharia
• Processo FAPESP: 13/07600-3 - CIBFar - Centro de Inovação em Biodiversidade e Fármacos
• Beneficiário: Glaucius Oliva
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 17/15455-4 - Contribuição aos estudos integrados para o controle de formigas cortadeiras - busca de novos inseticidas e fungicidas - nanoencapsulamento
• Beneficiário: Hugo César Ramos de Jesus
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado