Synthesis of Novel 9-Benzyl-3-methylene-1,5-bis(p-toluenesulfonyl)-1,5,9-triazacyclododecane (CADA) Analogs

Abstract

Cyclotriazadisulfonamide (CADA) inhibits the entry of HIV and HHV-7 by specific down-modulation of the CD4 receptor expression on the surface of lymphocytes and monocytes/macrophages. In this work synthesis and biological activities of novel CADA head group analogs SA01, SA02, SA03, SA04, SA06, SA07, SA08, SA40, SA41 with polar and good leaving groups are reported. The structural modifications of CADA were made to increase potency, reduce cytotoxicity, and improve physical properties. IsoCADA (SA05), an isomer of CADA, was synthesized involving cyclization of 1,5,7-triazabicyclo[4.4.0]dec-5- ene (TBD), a guanidinium base, and tested for its antiviral properties. An alternate method for the macrocyclization of disulfonamide using a palladium catalyst has been successfully developed. This new method obviates the necessity of high dilution, slow addition of the reagent and formation of polymer side products which have limited the synthetic utility of the classical Richman-Atkins macrocyclization method.