Advanced search
Start date
Betweenand
Related content
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

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

Full text
Author(s):
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]
Total Authors: 8
Affiliation:
[1] Univ Sao Paulo, Inst Chem Sao Carlos, Med & Biol Chem Grp, Ave Trabalhador Sancarlense 400, BR-23566590 Sao Carlos, SP - Brazil
Total Affiliations: 1
Document type: Journal article
Source: Bioorganic & Medicinal Chemistry; v. 29, JAN 1 2021.
Web of Science Citations: 0
Abstract

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)

FAPESP's process: 13/18009-4 - Molecular design, synthesis and trypanocidal activity of cruzain reversible covalent inhibitors
Grantee:Carlos Alberto Montanari
Support Opportunities: Research Projects - Thematic Grants
FAPESP's process: 18/03985-1 - Molecular design, synthesis, and trypanocidal activity of reversible covalent inhibitors of cruzain enzyme
Grantee:Anwar Shamim
Support Opportunities: Scholarships in Brazil - Post-Doctoral
FAPESP's process: 16/07946-5 - Synthesis and evaluation of trypanocidal activity of potential reversible covalent inhibitors of cruzain enzyme
Grantee:Lorenzo Cianni
Support Opportunities: Scholarships in Brazil - Doctorate (Direct)