Synthesis of Novel CADA Analog Prodrugs and Ring-Size Variants Designed to Act as anti-HIV Agents via Down-Modulation of the CD4 Receptor
AuthorScarbrough, Emily Desiree
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Cyclotriazadisulfonamide (CADA) inhibits HIV replication by selectively down-modulating expression of the CD4 receptor protein on host cells. Current studies are aimed at developing a prodrug approach involving various CADA analog prodrug parent compounds bearing dipeptide chains that are covalently bonded to two amino or two hydroxyl groups attached to the para position of the methylbenzenesulfonyl side arms. Cleavage of these chains by dipeptidyl-peptidase IV is expected to convert the prodrugs into various active CADA analogs. For this purpose, prodrug parent compound ES04 in which the methyl groups of CADA are replaced by aminomethyl groups has been synthesized. According to a 3D-QSAR model, ES04 is expected to have a CD4 down-modulation potency that is similar to that of CADA. The second objective of this work is to determine if the size of the macro ring is a contributing factor to potency for CD4 down-modulation. The CADA analog VGD020 possesses great potency for CD4 down-modulation and HIV inhibition to date. The 12-membered ring size of VGD020 has been reduced to 11-membered to produce novel analogs that retain CD4 down-modulating activity. Previous studies were aimed at determining where CADA analogs are localized in the cell and whether they bind to specific biomolecules. For this purpose, compound ES-KKD-024 in which the tosyl sidearms of CADA are replaced with fluorescent dansyl sidearms has been synthesized.