2′ Derivatives of Guanosine and Inosine Cyclic 3′, 5′-Phosphates. Synthesis, Enzymic Activity, and the Effect of 8-Substituents

Jon P. Miller, Kay H. Boswell, Roland K. Robins, Rich B. Meyer, Amohsin Mian, Tasneema Khwaja

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8 Scopus citations


A series of representative derivatives of guanosine cyclic 3′,5′-phosphate (cGMP) and inosine cyclic 3′,5′-phosphate (cIMP) which contained modifications in either the 2′ position or the 8 and 2′ positions were synthesized. Three types of derivatives were investigated: (1) derivatives in which the 2′ position has been altered to produce a 2′-deoxynucleoside cyclic 3′,5′-phosphate or a 9-β-D-arabinofuranosylpurine cyclic 3′,5′-phosphate; (2) 2′-O-acyl derivatives; and (3) doubly modified derivatives containing a 2′ modification [as in (1) and (2)] and an 8-substitution. 2′-Deoxyinosine cyclic 3′,5′-phosphate and 9-β-D-arabinofuranosylhypoxanthine cyclic 3′,5′-phosphate were obtained by HNO2 deamination of 2′-deoxyadenosine cyclic 3′,5′-phosphate and 9-β-D-arabinofuranosyladenine cyclic 3′,5′-phosphate (ara-cAMP), respectively. Treatment of 8-bromo-2′-O-(p-toluenesulfonyl)adenosine cyclic 3′,5′-phosphate with NaSH yielded the intermediate 8,2′-anhydro-9-β-D-arabinofuranosyl-8-mercaptoadenine cyclic 3′,5′-phosphate, which was converted directly to 2′-deoxyadenosine cyclic 3′,5′-phosphate (dcAMP) by treatment with Raney nickel. 8-Bromo-2'-O-(/>-toluenesulfonyl)guanosine cyclic 3′,5′-phosphate was converted to 8,2′-anhydro-9-β-D-arabinofuranosyl-8-mercaptoguanine cyclic 3′,5′-phosphate, and the latter was desulfurized with Raney nickel to give 2′-deoxyguanosine cyclic 3′,5′-phosphate. Ara-cAMP, 9-β-D-arabinofuranosylguanine cyclic 3′,5′-phosphate, and 9-β-D-arabinofuranosyl-8-mercaptoguanine cyclic 3′,5′-phosphate have been previously reported (Mian et al. (1974), J. Med. Chem. 17, 259). 8-Bromo-2′-O-acetylinosine cyclic 3′,5′-phosphate and 8-[(p-chlorophenyl)thio]-2′-O-acetylinosine cyclic 3′,5′-phosphate were produced by acylation of 8-bromoinosine cyclic 3′,5′-phosphate and 8-[(p-chlorophenyl)thio]inosine cyclic 3′,5′-phosphate, respectively; while 8-bromo-2′-O-butyrylguanosine cyclic 3′,5′-phosphate was synthesized by bromination of 2′-O-butyrylguanosine cyclic 3′,5′-phosphate. The enzymic activities of these derivatives were investigated (1) as activators of cAMP-dependent (bovine brain) and cGMP-dependent (lobster tail muscle) protein kinases, (2) as substrates for a cyclic nucleotide phosphodiesterase (rabbit kidney), and (3) as inhibitors of the hydrolysis of both cAMP and cGMP by two cyclic nucleotide phosphodiesterase preparations (rabbit lung and beef heart). Both the 2′ derivatives and 8-substituted 2′ derivatives of both cIMP and cGMP were less than one-hundredth as active as cAMP or cGMP at activating the cAMP-dependent protein kinase or the cGMP-dependent protein kinase, respectively. All of the 2′ derivatives of cIMP and cGMP were hydrolyzed at significant rates by phosphodiesterase, while the 8-substituted.2′ derivatives were completely or substantially resistant to enzymic hydrolysis. The results of the studies of the inhibition of cAMP and cGMP hydrolysis by these derivatives showed that (1) 2′ derivatives were, in general, better inhibitors than the corresponding 8-substituted 2′ derivatives; (2) O2′ -acyl derivatives and 2′-deoxy derivatives were similar in inhibitory properties and in turn were better inhibitors than the ara derivatives; and (3) all the derivatives inhibited cGMP hydrolysis to an equal or greater extent than they inhibited cAMP hydrolysis.

Original languageEnglish (US)
Pages (from-to)217-223
Number of pages7
Issue number1
StatePublished - Jan 1 1976

ASJC Scopus subject areas

  • Biochemistry


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