Khwaja T A, Boswell K H, Robins R K, Miller J P
Biochemistry. 1975 Sep 23;14(19):4238-44. doi: 10.1021/bi00690a014.
Derivatives of adenosine 3',5'-cyclic phosphate (cAMP) with modifications in both the 2' and the 8 positions were synthesized and their enzymic activities as activators of cAMP-dependent protein kinase and as substrates for and inhibitors of cAMP phosphodiesterases were determined. Three types of derivatives were investigated: 8-substituted derivatives of O2'-Bt-cAMP, 8-substituted derivatives of 9-beta-D-arabinofuranosyladenine 3',5'-cyclic phosphate (ara-cAMP), and 8-substituted derivatives of 8,2'-anhydro-9-beta-D-arabinofuranosyladenine 3,'5'-cyclic phosphate (8,2'-anhydro-cAMP). The 8-substituted O2'-Bt-cAMP derivatives were synthesized by acylation of the preformed 8-substituted cAMP (8-HS-cAMP, 8-MeS-cAMP, and 8-PhCH2S-cAMP). 8-Br-O2'-tosyl-cAMP was sued as an intermediate for the preparation of 8,2'-anhydro-cAMP derivatives (8-HO-, 8-SH-, 8-H2N-, and 8-H3 CHN derivatives of 8,2'-anhydro-cAMP). 8-Substituted ara-cAMP derivatives were obtained by ring opening of 8-HO-8,2'-anhydro-cAMP with H+/H2O, NH3/MeOH, or MeONa/MeOH (to yield the 8-HO-, 8-H2N-, and 8-MeO-ara-cAMP derivatives). All of these doubly modified derivatives of cAMP are less than one-hundredth as active as cAMP at activating protein kinase and did not serve as substrates for the phosphodiesterase. These data show that the general inactivity of 2' derivatives of cAMP with kinase was not overcome by addition of an 8-substituent, even though many 8-substituted derivatives of cAMP activate the kinase more efficiently than does cAMP itself. In addition they show that while 2'-modification were tolerated by the phosphodiesterase, addition of an 8-substituent countermanded the allowable 2'-modification. The 8-substituted derivates of 02'-Bt-cAMP were found in general to be slightly better inhibitors of phosphodiesterase than the parent compounds containing no o2'-Bt substitution. As a group, the 8-substituted ara-cAMP derivatives were poorer inhibitors of phosphodiesterase than 8-substituted cAMP derivatives while the 8,2'-anhydro-cAMP derivatives were much poorer inhibitors than the 8-substituted ara-cAMP derivatives.
合成了腺苷 3',5'-环磷酸（cAMP）在 2'和 8 位均有修饰的衍生物，并测定了它们作为 cAMP 依赖性蛋白激酶激活剂以及作为 cAMP 磷酸二酯酶底物和抑制剂的酶活性。研究了三种类型的衍生物：O2'-Bt-cAMP 的 8-取代衍生物、9-β-D-阿拉伯呋喃糖基腺嘌呤 3',5'-环磷酸（ara-cAMP）的 8-取代衍生物以及 8,2'-脱水-9-β-D-阿拉伯呋喃糖基腺嘌呤 3',5'-环磷酸（8,2'-脱水-cAMP）的 8-取代衍生物。通过对预先形成的 8-取代 cAMP（8-HS-cAMP、8-MeS-cAMP 和 8-PhCH2S-cAMP）进行酰化反应合成了 8-取代的 O2'-Bt-cAMP 衍生物。8-溴-O2'-甲苯磺酰基-cAMP 被用作制备 8,2'-脱水-cAMP 衍生物（8,2'-脱水-cAMP 的 8-HO-、8-SH-、8-H2N-和 8-H3CHN 衍生物）的中间体。8-取代的 ara-cAMP 衍生物通过用 H+/H2O、NH3/MeOH 或 MeONa/MeOH 使 8-HO-8,2'-脱水-cAMP 开环得到（得到 8-HO-、8-H2N-和 8-MeO-ara-cAMP 衍生物）。所有这些 cAMP 的双重修饰衍生物在激活蛋白激酶方面的活性不到 cAMP 的百分之一，并且不作为磷酸二酯酶的底物。这些数据表明，即使许多 cAMP 的 8-取代衍生物比 cAMP 本身更有效地激活激酶，但在 cAMP 的 2'衍生物中加入 8-取代基并不能克服其与激酶的普遍无活性。此外，数据表明虽然磷酸二酯酶能耐受 2'-修饰，但加入 8-取代基会抵消允许的 2'-修饰。一般发现，02'-Bt-cAMP 的 8-取代衍生物作为磷酸二酯酶抑制剂比不含 o2'-Bt 取代的母体化合物略好。作为一个整体，8-取代的 ara-cAMP 衍生物作为磷酸二酯酶抑制剂比 8-取代的 cAMP 衍生物差，而 8,2'-脱水-cAMP 衍生物作为磷酸二酯酶抑制剂比 8-取代的 ara-cAMP 衍生物差得多。
