title: Tuning Side Arm Electronics in Unsymmetrical Cyclotriazadisulfonamide (CADA) Endoplasmic Reticulum (ER) Translocation Inhibitors to Improve their Human Cluster of Differentiation 4 (CD4) Receptor Down-Modulating Potencies.
abstract: Cyclotriazadisulfonamide prevents HIV entry into cells by down-modulating surface CD4 receptor expression through binding to the CD4 signal peptide. According to a two-site binding model, 28 new unsymmetrical analogues bearing a benzyl tail group and nine bearing a cyclohexylmethyl tail have been designed and synthesized. The most potent new CD4 down-modulator (40 (CK147); IC50 63 nM) has a 4-dimethylaminobenzenesulfonyl side arm. One of the two side arms was varied with substituents in different positions. This gave a range of CD4 down-modulation potencies that correlated well with anti-HIV-1 activities. The side arms of 21 of the new benzyl-tailed analogues were modeled by means of quantum mechanical calculations. For CADA analogues with arenesulfonamide side arms, the pIC50 values for CD4 down-modulation correlated with the component of the electric dipole moment in the aromatic ring, suggesting that an attractive electronic interaction is a major factor determining the stability of the complex between the molecule and its target.
authors.affiliation: Department of Chemistry, University of Nevada , 1664 North Virginia Street, Reno, Nevada 89557-0216 United States.
authors.forename: Reena
authors.initials: R
authors.lastname: Chawla
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven-University of Leuven , 3000 Leuven, Belgium.
authors.forename: Victor
authors.initials: V
authors.lastname: Van Puyenbroeck
authors.affiliation: Department of Chemistry, University of Nevada , 1664 North Virginia Street, Reno, Nevada 89557-0216 United States.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Pflug
authors.affiliation: Department of Chemistry, University of Nevada , 1664 North Virginia Street, Reno, Nevada 89557-0216 United States.
authors.forename: Alekhya
authors.initials: A
authors.lastname: Sama
authors.affiliation: Department of Chemistry, University of Nevada , 1664 North Virginia Street, Reno, Nevada 89557-0216 United States.
authors.forename: Rameez
authors.initials: R
authors.lastname: Ali
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven-University of Leuven , 3000 Leuven, Belgium.
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.affiliation: Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, KU Leuven-University of Leuven , 3000 Leuven, Belgium.
authors.forename: Kurt
authors.initials: K
authors.lastname: Vermeire
authors.affiliation: Department of Chemistry, University of Nevada , 1664 North Virginia Street, Reno, Nevada 89557-0216 United States.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Bell
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000187:drug effects*; D016466:CHO Cells; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D015536:Down-Regulation / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D023581:HIV Fusion Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006573:Heterocyclic Compounds, 1-Ring / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D021381:Protein Transport / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D015704:CD4 Antigens; C000609914:CK147 compound; D023581:HIV Fusion Inhibitors; D006573:Heterocyclic Compounds, 1-Ring; D013449:Sulfonamides