Novel peptidyl aryl vinyl sulfones as highly potent and selective inhibitors of cathepsins L and B

ChemMedChem
Laura MendietaErnest Giralt

Abstract

Herein we present the design, synthesis, and evaluation of a structurally novel library of 20 peptidyl 3-aryl vinyl sulfones as inhibitors of cathepsins L and B. The building blocks, described here for the first time, were synthesized in a highly efficient and enantioselective manner, starting from 3-aryl-substituted allyl alcohols. The corresponding vinyl sulfones were prepared by a new approach, based on a combination of solid-phase peptide synthesis using the Fmoc/tBu strategy, followed by solution-phase coupling to the corresponding (R)-3-amino-3-aryl vinyl sulfones as trifluoroacetate salts. The inhibitory activity of the resulting compounds against cathepsins L and B was evaluated, and the compound exhibiting the best activity was selected for enzymatic characterization. Finally, docking studies were performed in order to identify key structural features of the aryl substituent.

References

Aug 18, 1995·Journal of Medicinal Chemistry·J T PalmerD Brömme
Aug 1, 1996·Journal of Computer-aided Molecular Design·G M MorrisA J Olson
Feb 1, 1997·Nature Structural Biology·M E McGrathD Brömme
Jun 26, 1998·The Biochemical Journal·R XingR W Mason
Aug 26, 1998·The Journal of Experimental Medicine·J C EngelJ H McKerrow
Dec 22, 1998·Journal of Cancer Research and Clinical Oncology·V KolkhorstB Wiederanders
Jun 3, 1999·Bioorganic & Medicinal Chemistry·J H McKerrowC R Caffrey
Jul 9, 1999·Biochimica Et Biophysica Acta·M SöderströmE Vuorio
Jan 5, 2001·Journal of Medicinal Chemistry·J P FalgueyretM D Percival
Jan 30, 2002·Bioorganic & Medicinal Chemistry Letters·Minoru YamamotoShintaro Inoue
Jul 2, 2002·Critical Reviews in Oral Biology and Medicine : an Official Publication of the American Association of Oral Biologists·D P Dickinson
Jun 21, 2003·The Journal of Organic Chemistry·Anna PicóMiquel A Pericàs
Sep 8, 2004·Bioorganic & Medicinal Chemistry·Marion G GötzJames C Powers
Nov 13, 2004·Cell Cycle·Johanna A Joyce, Douglas Hanahan
Oct 8, 2005·The Journal of Organic Chemistry·Thomas D AveryEdward R T Tiekink
Feb 17, 2006·Genes & Development·Vasilena GochevaJohanna A Joyce
Apr 22, 2006·Chembiochem : a European Journal of Chemical Biology·Teresa TarragóErnest Giralt
Nov 27, 2007·Trends in Pharmacological Sciences·Carmela Palermo, Johanna A Joyce
Feb 1, 2008·Journal of Medicinal Chemistry·Roberta EttariMaria Zappalà

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Citations

Feb 24, 2011·Parasitology Research·Yan-ping HanZhi-yue Lv
Oct 26, 2011·Biochimica Et Biophysica Acta·Vito TurkDušan Turk
Mar 22, 2014·Chembiochem : a European Journal of Chemical Biology·Matthias D MertensMichael Gütschow
Mar 10, 2015·Chemical Communications : Chem Comm·Cécile M J OuairyHerman S Overkleeft
Aug 1, 2018·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Angela RampaAlessandra Bisi
Feb 12, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Dibyendu Dana, Sanjai K Pathak
Aug 14, 2020·International Journal of Molecular Sciences·Rolando CannalireVincenzo Summa

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