2′,5′-dd-3′-AMP-bis(t-Bu-SATE)

2′,5′-dd-3′-AMP-bis(t-Bu-SATE) is a potent, cell-permeable adenylyl cyclase inhibitor. IC50 = 30 nM.9-substituted adenine derivatives with protected phosphoryl groups were synthesized and tested as inhibitors of adenylyl cyclase in isolated enzyme and intact cell systems. Protected 3′-phosphoryl derivatives of 2′,5′-dideoxyadenosine (2′,5′-dd-Ado) and beta-l-2′,5′-dd-Ado, protected 5′-phosphoryl derivatives of beta-l-2′,3′-dd-Ado, and protected phosphoryl derivatives of two 9-(2-phosphonomethoxy-acyl)-adenines were synthesized. Protection was afforded by two cyclosaligenyl- or three S-acyl-2-thioethyl-substituents. These pro-nucleotides were tested for their capacity to block forskolin-induced increases in [³H]cAMP in OB1771 and F442A preadipocytes and human macrophages prelabeled with [³H]adenine. A striking selectivity for 2′,5′-dd-Ado-3′-phosphoryl derivatives was observed. Cyclosaligenyl-derivatives (IC₅₀ approximately 2 microm) were much less potent than S-acyl-2-thioethyl-derivatives. Best studied of these was 2′,5′-dd-Ado-3′-O-bis(S-pivaloyl-2-thioethyl)-phosphate, which blocked [³H]cAMP formation in preadipocytes (IC₅₀ approximately 30 nm) and suppressed opening of cAMP-dependent Cl(-) channels in cardiac myocytes (IC₅₀ approximately 800 nm). The availability and characteristics of these prodrugs should make them useful for blocking cAMP-mediated pathways in intact cell systems, in biochemical, pharmacological, and potentially therapeutic contexts.

2′,5′-dd-3′-AMP-bis(t-Bu-SATE) is a potent, cell-permeable adenylyl cyclase inhibitor. IC₅₀ = 30 nM.