Optimizing the Drug-Like Properties of CADA Compounds and Synthesis of Cyclic Peptides as Potential CD4 Down Modulators
AdvisorBell, Thomas W
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ABSTRACTCyclotriazadisulfonamide (CADA) is a small molecule macrocycle that was first synthesized by the Bell research group as an intermediate in the synthesis of bicyclic triamines. CADA compounds inhibit replication of various strains of HIV and simian immunodeficiency virus (SIV) by selectively down-modulating the expression of cell-surface CD4. More specifically, CADA inhibits co-translational translocation of nascent human CD4 across the endoplasmic reticulum (ER) membrane. Many CADA analogs have been synthesized and tested for CD4 down-modulation and suppression of HIV-1 replication in vitro in Dr. Bell’s group. Even though many of the synthesized CADA analogs show promising anti HIV potencies, they cannot be tested in mice (mouse models of the human immune system) due to poor drug-like properties. The compounds that are synthesized in our project will undergo in vitro pharmacokinetic data evaluation of solubility, lipophilicity, membrane permeability, and metabolic stability. Those compounds with the best properties will then be evaluated for oral bioavailability, toxicity, and blood plasma lifetimes in mice. In this project, 4 CADA analogs (VGD020, VGD027, CK204, AR001) were successfully synthesized on large scale (0.5– 1 g) for to facilitate collecting their pharmacokinetic pharmacokinetic data.Many sulfonamide drugs mimic peptides. As CADA compounds are sulfonamides, it is believed that they have the possibility to show peptidomimetic properties. Moreover, the cyclodepsipeptide compounds CAM741 and the cotransins, have similar mechanism of action in the down-modulation of proteins like CADA compounds. Therefore, in a second project, small cyclic tripeptides and tetrapeptides were chosen for synthesis. A novel approach to the synthesis of cyclic tri- and tetra-peptides is proposed and explored in this project.