The small molecule cyclotriazadisulfonamide (CADA) is known to down-modulate expression of the cell-surface protein CD4 by blocking its co-translational translocation across the ER membrane. This way, CADA prevents 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 an unsymmetrical conformation of the 12-membered ring. We propose that other head groups might also effectively pre-organize the proposed bioactive conformation.  For this reason, a series of novel CADA analogs with either saturated or unsaturated head groups have been synthesized and tested for CD4 down-modulation and anti-HIV activity. In general, modification of the head group resulted in decreased activity of the analog as compared to the isobutylene head group analog. Compound RA003 with a 2-hydroxymethyl-1,3-propylene head group was found to have highest potency for CD4 down-modulation (IC50= 380 nM).

Effect of head group variation on human CD4 down-modulating and anti-HIV potencies of CADA analogs

248th National Meeting (2014)

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