Synthesis and CD4 down-modulation potencies of CADA head analogs

by Ali, Rameez, Ph.D., UNIVERSITY OF NEVADA, RENO, 2015, 215 pages; 3724114

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 (IC 50 = 110 nM).

AdviserThomas W. Bell
SchoolUNIVERSITY OF NEVADA, RENO
Source TypeDissertation
SubjectsChemistry
Publication Number3724114

About ProQuest Dissertations & Theses
With nearly 4 million records, the ProQuest Dissertations & Theses (PQDT) Global database is the most comprehensive collection of dissertations and theses in the world. It is the database of record for graduate research.

PQDT Global combines content from a range of the world's premier universities - from the Ivy League to the Russell Group. Of the nearly 4 million graduate works included in the database, ProQuest offers more than 2.5 million in full text formats. Of those, over 1.7 million are available in PDF format. More than 90,000 dissertations and theses are added to the database each year.

If you have questions, please feel free to visit the ProQuest Web site - http://www.proquest.com - or contact ProQuest Support.