Synthesis and CD4 down-modulation potencies of CADA head analogs
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Authors
Ali, Rameez
Issue Date
2015
Type
Dissertation
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Abstract
The small molecule cyclotriazadisulfonamide (CADA) is known to down-modulate expression of the transmembrane protein CD4 by blocking its co-translational translocation across the ER membrane. By this mechanism, CADA compounds prevent entry of HIV into host cells. Previous studies of solid-state conformations and structure-activity relationships suggest that CADA compounds bind to the target in an unsymmetrical manner. The isobutylene head group of CADA is believed to favor this unsymmetrical conformation of the 12-membered ring. We proposed that other head groups might more effectively pre-organize the proposed bioactive conformation and may yield very potent CADA analogs. The goal of this study is to synthesize various CADA analogs with both saturated and unsaturated head groups to test for their CD4 down-modulation and anti-HIV activities. CADA compounds are synthesized in a six step sequence in which the last palladium catalyzed-macrocylization is the limiting step due to its inconsistent and relatively poor yields. As a part of this project, the palladium catalyzed-macrocylization step was first optimized to find conditions that double its yield. VGD020, as one of the most potent CADA analogs identified thus far, was chosen as the parent compound for head group modifications. In general, modification of the isobutylene head group resulted in a decreased activity of the analog. Compound RA016 containing a methyl head group was found to have highest potency towards CD4 down-modulation (IC50 = 110 nM).
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In Copyright(All Rights Reserved)