Solution and solid-phase synthesis of unsymmetrical cyclotriazadodecanedisulfonamide (CADA) analogs as novel antiviral agents

This is a report on the synthesis and antiviral properties of analogs of 9-benzyl-3-methylene-1,5-di-(4-methylbenzenesulfonyl)-1,5,9-triazacyclododecane, (CADA). The study was divided into two main sections, traditional solution-phase chemistry and solid-phase synthesis of the CADA analogs. In the solution chemistry segment, 10 molecules of the half-CADA subgroup were synthesized and tested. They exhibit little or no antiviral activity. Two unsymmetrical cyclic analogs 9-benzyl-1-(5-dimethylaminonaphthalene-1-sulfonyl)-3-methylene-5-(4-methylbenzenesulfonyl)-1,5,9-triazacyclododecane (28a) and 9-cyclohexylmethyl-1-(5-dimethylaminonaphthalene-1-sulfonyl)-3-methylene-5-(4-methylbenzenesulfonyl)-1,5,9-triazacyclododecane (28b) were synthesized and found to be as active as CADA in the down-modulation of CD4 receptor on T-cell surface (IC50∼ 0.6--1.5 muM). Eight symmetrical cyclic analogs were also synthesized and are yet to be tested. Eleven linear unsymmetrical CADA analogs were made, with three of them, 5-dimethylamino-naphthalene-1-sulfonic acid [3-(benzyl-3-[(2-methylallyl)-(4-methylbenzenesulfonyl)amino]propyl]amide (34a), N-[3-(benzyl-{3-[2-methylallyl)-(4-methylbenzenesulfonyl)amino]propyl}amino)propyl]-4-methoxy-N-(2-methylallyl)-benzenesulfonamide (34e), and N-(3-{benzyl-[3-(4-methylbenzene-sulfonyl)propyl]-amino}propyl)-4-methoxy-N-(2-methylailyl)benzene-sulfonamide (34d) showing anti-HCMV activities (IC50∼ 0.5--1.6 muM). Thirty-five other novel compounds were generated in the process of synthesizing the CADA analogs.;As a test of concept, two linear CADA analogs N-benzyl-N-[3-(N '-2-methyl-2-propenyl(4-methylbenzenesulfonyl))propyl]-N-(3-(4-methylbenzenesulfonyl)propyl)]-amine (95--214), and N-benzyl-N-[2-(N'-2-methyl-2-propenyl(4-methylbenzene-sulfonyl))ethyl]-N-2-(4-methylbenzenesulfonyl)]amine (64) were synthesized in 10 steps on a Rink amide resin. The success of this solid-phases synthetic attempt has now opened the way for the combinatorial synthesis of linear CADA analogs in the future.