title: Unsymmetrical cyclotriazadisulfonamide (CADA) compounds as human CD4 receptor down-modulating agents.
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.
authors.affiliation: Department of Chemistry, University of Nevada, Reno, Nevada 89557-0216, USA.
authors.forename: Violeta G
authors.initials: VG
authors.lastname: Demillo
authors.forename: Florian
authors.initials: F
authors.lastname: Goulinet-Mateo
authors.forename: Jessica
authors.initials: J
authors.lastname: Kim
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Kurt
authors.initials: K
authors.lastname: Vermeire
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bell
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation / Q000187:drug effects*; D005434:Flow Cytometry; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008956:Models, Chemical; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C498074:9-benzyl-3-methylene-1,5-di-p-toluenesulfonyl-1,5,9-triazacyclododeane; D019380:Anti-HIV Agents; D015704:CD4 Antigens; D006571:Heterocyclic Compounds; D008164:Luminescent Proteins