Lipophilic bis-arylsulfonates as inhibitors of the CD4-GP120 interaction

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 24, 1996, Pages 2983-2988

  Patch, Raymond J ^a   Roberts, John C ^a   Gao, Huai ^a   Shi, Zhan ^a   Gopalsamy, Ariamala ^a   Kongsjahju, Azis ^a   Daniels, Kevin ^a   Kowalczyk, Paul J ^a   Van Schravendijk, Marie Rose ^a   Gordon, Kristin A ^a   Pallai, Peter V ^a  

^a Procept Inc   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTIVIRUS AGENT; CD4 ANTIGEN; CHOLESTANE DERIVATIVE; COSALANE; GLYCOPROTEIN GP 120; NAPHTHALENESULFONIC ACID DERIVATIVE; PRO 2000; SULFONIC ACID DERIVATIVE; UNCLASSIFIED DRUG;

ARTICLE; CELL FUSION; CYTOTOXICITY; DRUG DESIGN; DRUG STRUCTURE; DRUG SYNTHESIS; ENZYME LINKED IMMUNOSORBENT ASSAY; HUMAN; HUMAN CELL; HUMAN IMMUNODEFICIENCY VIRUS; LIPOPHILICITY; NUCLEAR MAGNETIC RESONANCE; PROTEIN PROTEIN INTERACTION; STRUCTURE ACTIVITY RELATION; VIRUS INFECTION;

EID: 0030591832     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(96)00552-5     Document Type: Article

References (23)

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18. 18. The assignment of β-configuration to the major isomer is made by analogy to Cushman's observations and analysis (ref. 11) of the structurally similar cosalane intermediate.
19. -).
20. 50 values from different experiments were within a factor of 2 or less.
21. 6 cells per ml) were suspended in RPMI 1640 (Whittaker-Bioproducts, Walkersville, MD) with 10% fetal bovine serum (FBS) (JRH Biosciences, Lenexa, KS) plus sodium azide. 100 uL of the suspension were added to individual tubes. Generally, test compounds were dissolved in water to a concentration of 4 mg/mL. Various dilutions of the compounds (1:40, 1:100, 1:200, 1:400, 1:800) were added to the tubes which were then incubated for 2 h at 25 °C. After this time, gp120 (American Bio-Technologies, Inc., Cambridge, MA), diluted in RPMI 1640 buffer, was added to a final concentration of 10 nM and the resulting mixture was incubated overnight (∼ 16 hrs.) at 37 °C. Cells were then washed thoroughly with phosphate-buffered saline containing 10% FBS and 0.1% sodium azide. Bound gp120 was detected using a monoclonal antibody specific for gp120 (DuPont-NEN, NEA-9284 or NEA-9205) which was incubated with the cells at a concentration of 1 ug/mL (10Oul per tube) for 30 min. on ice. The cells were then washed thoroughly as before; bound NEA-9284 was detected by staining with goat anti-mouse immunoglobulin (Boehringer Mannheim Biochemicals, Indianapolis, IN) which was labeled with fluorescein (50 uL per tube) for 30 min. on ice. The washed cells were analyzed for fluorescence on a FACScan™ instrument (Becton Dickinson).
22. 22. Since activities are determined indirectly by V3 loop antibody capture, compounds that bind to the V3 region with slow dissociation may not be distinguished from true CD4-gp120 inhibitors in these formats. Thus, for the more potent compounds, inhibition was confirmed independently by a C-terminal detecting antibody.
23. 23. The naphthalenesulfonate systems were excluded from these calculations (replaced with hydrogen atoms) for simplification purposes. Thus, for example, the log P value calculated for the hydrophobic portion of compound 1400 is based on structure i: (equation presented) Assuming that the naphthylenesulfonates do not interact with the linkers, contributions from these groups to the partition constant would be uniform throughout the series and would be expected to be additive.