Uno H, Meyer R B, Shuman D A, Robins R K, Simon L N, Miller J P
J Med Chem. 1976 Mar;19(3):419-22. doi: 10.1021/jm00225a017.
1, 8-Disubstituted derivatives of adenosine cyclic 3', 5'-phosphate (cAMP) were synthesized by N-oxidation or N-methylation of previously reported 8-substituted cAMP derivatives to yield 8-bromoadenosine cyclic 3', 5'-phosphate 1-oxide and 8-(benzylthio)-1-methyladenosine cyclic 3', 5'-phosphate. Substituents were introduced into the 8 position of 2-methyladenosine cyclic 3', 5'-phosphate and 2-butyladenosine cyclic 3', 5'-phosphate by bromination, followed by treatment with sodium benzylmercaptide, sodium p-chlorothiophenolate, or, in the former case, sodium azide. Each of the 1,8- and 2,8-disubstituted derivatives of cAMP was tested as activators of cAMP-dependent protein kinase and as substrates for the inhibitors of cyclic nucleotide phosphodiesterases. Depending on the substitutions, examples were found where the disubstituted derivatives were either more active, equally as active or less active than the monosubstituted parent compounds as protein kinase activators. For the compounds reported, 8-substitution completely or substantially eliminated the ability of 1- or 2-substituted derivatives of cAMP to serve as substrates for phosphodiesterase and diminished the ability of these latter derivatives to inhibit cAMP hydrolysis.
通过对先前报道的8-取代环磷酸腺苷（cAMP）衍生物进行N-氧化或N-甲基化反应，合成了1,8-二取代的环磷酸腺苷衍生物，得到了8-溴代环磷酸腺苷1-氧化物和8-（苄硫基）-1-甲基环磷酸腺苷。通过溴化反应将取代基引入到2-甲基环磷酸腺苷和2-丁基环磷酸腺苷的8位，随后用苄基硫醇钠、对氯苯硫酚钠处理，或者在前一种情况下用叠氮化钠处理。对cAMP的1,8-和2,8-二取代衍生物分别进行了测试，考察它们作为环磷酸腺苷依赖性蛋白激酶激活剂的活性以及作为环核苷酸磷酸二酯酶抑制剂底物的特性。根据取代情况发现，在某些例子中，二取代衍生物作为蛋白激酶激活剂的活性比单取代母体化合物更高、相当或更低。对于所报道的化合物，8位取代完全或基本上消除了cAMP的1-或2-取代衍生物作为磷酸二酯酶底物的能力，并降低了这些衍生物抑制cAMP水解的能力。
