Design, synthesis and stepwise optimization of nitrile-based inhibitors of cathepsins B and L

Autor(es)

Cianni, Lorenzo ^[1] ; Rocho, Fernanda Dos Reis ^[1] ; Bonatto, Vinicius ^[1] ; Prado Martins, Felipe Cardoso ^[1] ; Lameira, Jeronimo ^[1] ; Leitao, Andrei ^[1] ; Montanari, Carlos A. ^[1] ; Shamim, Anwar ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Chem Sao Carlos, Med & Biol Chem Grp, Ave Trabalhador Sancarlense 400, BR-23566590 Sao Carlos, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Bioorganic & Medicinal Chemistry; v. 29, JAN 1 2021.
• Citações Web of Science: 0

Resumo

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. (AU)

• Processo FAPESP: 13/18009-4 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Carlos Alberto Montanari
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/03985-1 - Planejamento, síntese e atividade tripanossomicida de inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Anwar Shamim
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 16/07946-5 - Síntese e atividade tripanossomicida de potenciais inibidores covalentes reversíveis da enzima cruzaína
• Beneficiário: Lorenzo Cianni
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto