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Pyridine-fused Cyclotriazadisulfonamide (CADA) Compounds: Synthesis and CD4 Down-Modulation Potency
AuthorLumangtad, Liezel A.
AdvisorBell, Thomas W.
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Macrocyclic polyamine cyclotriazadisulfonamide (CADA) is a small molecule that down-modulates expression of human CD4 (hCD4). The mechanism of action involves binding to the signal peptide (SP) of hCD4, locking it in the channel across the membrane of the endoplasmic reticulum (ER), preventing its translocation into the ER lumen and subsequent transport of the mature protein to the cell membrane. Several structural modifications and structure-activity relationship (SAR) studies have been done on CADA but the most potent analogs that have been synthesized suffer from poor drug-like properties. SH28 (IC50 5.9 µM), the first pyridine-fused CADA analog, represents a novel molecular scaffold which may be promising for improving the potency and water solubility of CADA as pyridine is completely miscible with water, mildly basic, and can be protonated under gastrointestinal tract (GIT) pH level, imparting some hydrophilicity in CADA. Pyridines are also easily metabolized by the body via N-oxidation or methylation to give secondary metabolites that are quickly excreted through the kidneys. Pyridine-fused analogs of SH28 were synthesized following different synthetic routes. These compounds were tested for CD4 down-modulation and anti-HIV activities. Of the compounds tested, LAL018, a pyridine-fused CADA analog with a para-benzyloxy substituent, was found to be the most potent towards CD4 down-modulation, with an IC50 value of 0.42 µM in CHO·CD4-YFP cells. It was also tested for anti-HIV activity against three different HIV strains and it was found to be the most potent compound against HIV-2 (ROD) and the second most potent against HIV-1 X4. Copper (II) and gold (III) complexes of some open-chain pyridine-fused disulfonamides were also synthesized as potential gp160 binding agents. These compounds will also be tested for other therapeutic applications, including broad antiviral, antimalarial, and as anticancer agents.