A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (Ki = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4′-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (Ki = 35.5 nM; selectivity ratio cathepsin S/K = 57; S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S.

N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S. In silico design, synthesis and biochemical characterization / Lemke, Carina; Cianni, Lorenzo; Feldmann, Christian; Gilberg, Erik; Yin, Jiafei; Dos Reis Rocho, Fernanda; De Vita, Daniela; Bartz, Ulrike; Bajorath, Jürgen; Montanari, Carlos A.; Gütschow, Michael. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 30:18(2020). [10.1016/j.bmcl.2020.127420]

N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S. In silico design, synthesis and biochemical characterization

De Vita, Daniela;
2020

Abstract

A library of cathepsin S inhibitors of the dipeptide nitrile chemotype, bearing a bioisosteric sulfonamide moiety, was synthesized. Kinetic investigations were performed at four human cysteine proteases, i.e. cathepsins S, B, K and L. Compound 12 with a terminal 3-biphenyl sulfonamide substituent was the most potent (Ki = 4.02 nM; selectivity ratio cathepsin S/K = 5.8; S/L = 67) and 24 with a 4′-fluoro-4-biphenyl sulfonamide substituent the most selective cathepsin S inhibitor (Ki = 35.5 nM; selectivity ratio cathepsin S/K = 57; S/L = 31). In silico design and biochemical evaluation emphasized the impact of the sulfonamide linkage on selectivity and a possible switch of P2 and P3 substituents with respect to the occupation of the corresponding binding sites of cathepsin S.
2020
cathepsin S; nitriles; reversible inhibition; sulfonamides
01 Pubblicazione su rivista::01a Articolo in rivista
N-Sulfonyl dipeptide nitriles as inhibitors of human cathepsin S. In silico design, synthesis and biochemical characterization / Lemke, Carina; Cianni, Lorenzo; Feldmann, Christian; Gilberg, Erik; Yin, Jiafei; Dos Reis Rocho, Fernanda; De Vita, Daniela; Bartz, Ulrike; Bajorath, Jürgen; Montanari, Carlos A.; Gütschow, Michael. - In: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS. - ISSN 0960-894X. - 30:18(2020). [10.1016/j.bmcl.2020.127420]
File allegati a questo prodotto
File Dimensione Formato  
Lemke_N-Sulfonyl_2020.pdf

solo gestori archivio

Tipologia: Versione editoriale (versione pubblicata con il layout dell'editore)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 2.12 MB
Formato Adobe PDF
2.12 MB Adobe PDF   Contatta l'autore

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1477075
Citazioni
  • ???jsp.display-item.citation.pmc??? 0
  • Scopus 4
  • ???jsp.display-item.citation.isi??? 4
social impact