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Cyclic thioether peptide mimetics as VCAM-VLA-4 antagonists
N Fotouhi1, P Joshi, J W Tilley
1Roche Research Center, Hoffmann-La Roche Inc, Nutley, NJ 07110, USA. nader.fotouhi@roche.com
Bioorganic & Medicinal Chemistry Letters
|June 24, 2000
Summary
Researchers selectively replaced sulfur with carbon in a cyclic disulfide, creating potent thioethers. Their effectiveness in the VCAM/VLA-4 assay varied with ring size and sulfur placement.
Area of Science:
- Medicinal Chemistry
- Organic Synthesis
- Biochemistry
Background:
- Cyclic disulfides are important pharmacophores.
- The VCAM/VLA-4 interaction is a key target in inflammatory diseases.
Purpose of the Study:
- To synthesize novel cyclic thioethers by replacing sulfur with carbon.
- To evaluate the biological activity of these compounds in the VCAM/VLA-4 assay.
Main Methods:
- Intramolecular displacement of bromide in a 13-membered cyclic disulfide.
- Synthesis of cyclic thioethers.
- VCAM/VLA-4 binding assay.
Main Results:
- Selective substitution of sulfur by carbon was achieved.
- The resulting thioethers demonstrated potent activity in the VCAM/VLA-4 assay.
- Activity was dependent on the macrocyclic ring size and sulfur atom position.
Conclusions:
- Novel cyclic thioethers can be synthesized with tunable potency.
- Macrocyclic ring size and sulfur atom position are critical for VCAM/VLA-4 inhibitory activity.