Title: Unsymmetrical cyclotriazadisulfonamide (CADA) compounds as human CD4 receptor down-modulating agents
Authors: Demillo, Violeta G ×
Goulinet-Mateo, Florian
Kim, Jessica
Schols, Dominique
Vermeire, Kurt
Bell, Thomas W #
Issue Date: Aug-2011
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:54 issue:16 pages:5712-5721
Abstract: Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically down-modulating cell-surface and intracellular CD4. The specific biomolecular target of CADA compounds is unknown, but previous studies led to an unsymmetrical binding model. To test this model, methods were developed for effective synthesis of diverse, unsymmetrical CADA compounds. A total of 13 new, unsymmetrical target compounds were synthesized, as well as one symmetrical analogue. The new compounds display a wide range of potency for CD4 down-modulation in CHO·CD4-YFP cells. VGD020 (IC(50) = 46 nM) is the most potent CADA compound discovered to date, and VGD029 (IC(50) = 730 nM) is the most potent fluorescent analogue. Structure-activity relationships are analyzed from the standpoint of additive or nonadditive energy effects of different substituents. They appear to be consistent with the zipper-type mechanism in which entropy costs are reduced for additional stabilizing interactions between the small molecule and its protein target.
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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