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Carboxylate isosteres for caspase inhibitors : the acylsulfonamide case revisited

Y Adriaenssens, Daniel Jiménez Fernandez, Lieselotte Vande Walle UGent, F Elvas, J Joossens, A Lambeir, K Augustyns, Mohamed Lamkanfi UGent and P Van der Veken (2017) ORGANIC & BIOMOLECULAR CHEMISTRY. 15(35). p.7456-7473
abstract
As part of an ongoing effort to discover inhibitors of caspase-1 with an optimized selectivity and bio-pharmaceutical 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 H-1-and C-13-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.
Please use this url to cite or link to this publication:
author
organization
year
type
journalArticle (original)
publication status
published
subject
keyword
INTERLEUKIN-1-BETA CONVERTING-ENZYME, UNNATURAL AMINO-ACIDS, CONVENIENT, SYNTHESIS, SELECTIVE DETECTION, SULFONAMIDE GROUP, PRODRUG FORMS, DRUG, DESIGN, POTENT, DISCOVERY, ICE
journal title
ORGANIC & BIOMOLECULAR CHEMISTRY
Org. Biomol. Chem.
volume
15
issue
35
pages
7456 - 7473
Web of Science type
Article
Web of Science id
000411462600031
ISSN
1477-0520
1477-0539
DOI
10.1039/c7ob01403a
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
8534182
handle
http://hdl.handle.net/1854/LU-8534182
date created
2017-10-13 12:04:11
date last changed
2017-11-21 09:44:03
@article{8534182,
  abstract     = {As part of an ongoing effort to discover inhibitors of caspase-1 with an optimized selectivity and bio-pharmaceutical 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 H-1-and C-13-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.},
  author       = {Adriaenssens, Y and Jim{\'e}nez Fernandez, Daniel and Vande Walle, Lieselotte and Elvas, F and Joossens, J and Lambeir, A and Augustyns, K and Lamkanfi, Mohamed and Van der Veken, P},
  issn         = {1477-0520},
  journal      = {ORGANIC \& BIOMOLECULAR CHEMISTRY},
  keyword      = {INTERLEUKIN-1-BETA CONVERTING-ENZYME,UNNATURAL AMINO-ACIDS,CONVENIENT,SYNTHESIS,SELECTIVE DETECTION,SULFONAMIDE GROUP,PRODRUG FORMS,DRUG,DESIGN,POTENT,DISCOVERY,ICE},
  language     = {eng},
  number       = {35},
  pages        = {7456--7473},
  title        = {Carboxylate isosteres for caspase inhibitors : the acylsulfonamide case revisited},
  url          = {http://dx.doi.org/10.1039/c7ob01403a},
  volume       = {15},
  year         = {2017},
}

Chicago
Adriaenssens, Y, Daniel Jiménez Fernandez, Lieselotte Vande Walle, F Elvas, J Joossens, A Lambeir, K Augustyns, Mohamed Lamkanfi, and P Van der Veken. 2017. “Carboxylate Isosteres for Caspase Inhibitors : the Acylsulfonamide Case Revisited.” Organic & Biomolecular Chemistry 15 (35): 7456–7473.
APA
Adriaenssens, Y., Jiménez Fernandez, D., Vande Walle, L., Elvas, F., Joossens, J., Lambeir, A., Augustyns, K., et al. (2017). Carboxylate isosteres for caspase inhibitors : the acylsulfonamide case revisited. ORGANIC & BIOMOLECULAR CHEMISTRY, 15(35), 7456–7473.
Vancouver
1.
Adriaenssens Y, Jiménez Fernandez D, Vande Walle L, Elvas F, Joossens J, Lambeir A, et al. Carboxylate isosteres for caspase inhibitors : the acylsulfonamide case revisited. ORGANIC & BIOMOLECULAR CHEMISTRY. 2017;15(35):7456–73.
MLA
Adriaenssens, Y, Daniel Jiménez Fernandez, Lieselotte Vande Walle, et al. “Carboxylate Isosteres for Caspase Inhibitors : the Acylsulfonamide Case Revisited.” ORGANIC & BIOMOLECULAR CHEMISTRY 15.35 (2017): 7456–7473. Print.