Structure-activity studies of novel D-Ser8-cyclosporine A derivatives as potential anti-HIV drugs

A symposium report. Since the discovery of the immunosuppressive activity of cyclosporine A (CsA), considerable work has been devoted to the chem. synthesis of potent analogs. More recently, the finding of potential anti-HIV I activity of CsA raised interest for the design of CsA-derived compds. devoid of immunosuppressive activity. With this objective, the highly immunosuppressive CsA analog DSer8CsA was taken as a versatile candidate for modulating the binding mode to its receptors cyclophilin A (CypA) and calcineurin A (CnA). To this end, the functional group at position 8 of 1 is used for the chemoselective transformation to substituted pseudoproline systems and to dimers disposing variable linkers. Direct-transformation of a serine or threonine to a pseudoproline (PPro) has been shown to be a valuable method to tune the activity of bioactive compds.. Here the authors applied this strategy to DSer8CsA using various monosubstituted dimethoxyacetals in the presence of pyridium p-toluenesulfonate. In vitro activities of cyclosporin derivs. were evaluated applying the IL-2 reporter gene assay (measuring immunosuppressive activity) and the binding affinity to CypA (related to the anti-HIV activity). In conclusion, SAR studies of DSer8CsA derivs. applying the PPro concept and dimerization techniques at position 8 reveal differential effects on receptor binding, resulting in compds. of high therapeutical interest. [on SciFinder (R)]