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

Lorenzo Cianni; Fernanda Dos Reis Rocho; Vinícius Bonatto; Felipe Cardoso Prado Martins; Jerônimo Lameira; Andrei Leitão; Carlos A Montanari; Anwar Shamim

doi:10.1016/j.bmc.2020.115827

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

Bioorg Med Chem. 2021 Jan 1:29:115827. doi: 10.1016/j.bmc.2020.115827. Epub 2020 Nov 16.

Authors

Lorenzo Cianni¹, Fernanda Dos Reis Rocho¹, Vinícius Bonatto¹, Felipe Cardoso Prado Martins¹, Jerônimo Lameira², Andrei Leitão¹, Carlos A Montanari³, Anwar Shamim⁴

Affiliations

¹ Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, Avenue Trabalhador Sancarlense, 400, 23566-590, São Carlos, SP, Brazil.
² Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, Avenue Trabalhador Sancarlense, 400, 23566-590, São Carlos, SP, Brazil; On leave from Drug Designing and Development Laboratory. Federal University of Pará, Rua Augusto Correa S/N, Belém, PA, Brazil.
³ Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, Avenue Trabalhador Sancarlense, 400, 23566-590, São Carlos, SP, Brazil. Electronic address: carlos.montanari@usp.br.
⁴ Medicinal and Biological Chemistry Group, Institute of Chemistry of São Carlos, University of São Paulo, Avenue Trabalhador Sancarlense, 400, 23566-590, São Carlos, SP, Brazil. Electronic address: shamim.hej@gmail.com.

PMID: 33254069
DOI: 10.1016/j.bmc.2020.115827

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.

Keywords: Human cysteine proteases; Nitrile inhibitors; cathepsin B; cathepsin L.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemical synthesis
Amides / chemistry
Amides / pharmacology*
Amines / chemical synthesis
Amines / chemistry
Amines / pharmacology*
Cathepsin B / antagonists & inhibitors*
Cathepsin B / metabolism
Cathepsin L / antagonists & inhibitors*
Cathepsin L / metabolism
Dose-Response Relationship, Drug
Drug Design*
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology*
Humans
Molecular Dynamics Simulation
Molecular Structure
Structure-Activity Relationship

Substances

Amides
Amines
Enzyme Inhibitors
CTSB protein, human
Cathepsin B
CTSL protein, human
Cathepsin L