Jump to main content
Jump to site search

Issue 35, 2017
Previous Article Next Article

Carboxylate isosteres for caspase inhibitors: the acylsulfonamide case revisited

Author affiliations

Abstract

As part of an ongoing effort to discover inhibitors of caspase-1 with an optimized selectivity and biopharmaceutical profile, acylsulfonamides were explored as carboxylate isosteres for caspase inhibitors. Acylsulfonamide analogues of the clinically investigated caspase-1 inhibitor VRT-043198 and of the pan-caspase inhibitor Z-VAD-CHO were synthesized. The isostere-containing analogues with an aldehyde warhead had inhibitory potencies comparable to the carboxylate references. In addition, the conformational and tautomeric characteristics of these molecules were determined using 1H- and 13C-based NMR. The propensity of acylsulfonamides with an aldehyde warhead to occur in a ring-closed conformation at physiological pH significantly increases the sensitivity to hydrolysis of the acylsulfonamide moiety, yielding the parent carboxylate containing inhibitors. These results indicate that the acylsulfonamide analogues of the aldehyde-based inhibitor VRT-043198 might have potential as a novel type of prodrug for the latter. Finally, inhibition of caspase 1 and 11 mediated inflammation in mouse macrophages was found to correlate with the potencies of the compounds in enzymatic assays.

Graphical abstract: Carboxylate isosteres for caspase inhibitors: the acylsulfonamide case revisited

Back to tab navigation

Supplementary files

Publication details

The article was received on 09 Jun 2017, accepted on 17 Aug 2017 and first published on 17 Aug 2017


Article type: Paper
DOI: 10.1039/C7OB01403A
Org. Biomol. Chem., 2017,15, 7456-7473

  •   Request permissions

    Carboxylate isosteres for caspase inhibitors: the acylsulfonamide case revisited

    Y. Adriaenssens, D. Jiménez Fernández, L. Vande Walle, F. Elvas, J. Joossens, A. Lambeir, K. Augustyns, M. Lamkanfi and P. Van der Veken, Org. Biomol. Chem., 2017, 15, 7456
    DOI: 10.1039/C7OB01403A

Search articles by author

Spotlight

Advertisements