Cyclic nucleotide analogs as biochemical tools and prospective drugs.
Cyclic AMP (cAMP) and cyclic GMP (cGMP) are key second messengers involved in a multitude of cellular events. From the wealth of synthetic analogs of cAMP and cGMP, only a few have been explored with regard to their therapeutic potential. Some of the first-generation cyclic nucleotide analogs were promising enough to be tested as drugs, for instance N(6),O(2)'-dibutyryl-cAMP and 8-chloro-cAMP (currently in clinical Phase II trials as an anticancer agent). Moreover, 8-bromo and dibutyryl analogs of cAMP and cGMP have become standard tools for investigations of biochemical and physiological signal transduction pathways. The discovery of the Rp-diastereomers of adenosine 3',5'-cyclic monophosphorothioate and guanosine 3',5'-cyclic monophosphorothioate as competitive inhibitors of cAMP- and cGMP-dependent protein kinases, as well as subsequent development of related analogs, has proven very useful for studying the molecular basis of signal transduction. These analogs exhibit a higher membrane permeability, increased resistance against degradation, and improved target specificity. Furthermore, better understanding of signaling pathways and ligand/protein interactions has led to new therapeutic strategies. For instance, Rp-8-bromo-adenosine 3',5'-cyclic monophosphorothioate is employed against diseases of the immune system. This review will focus mainly on recent developments in cyclic nucleotide-related biochemical and pharmacological research, but also highlights some historical findings in the field.
Schwede
F
F
Center for Environmental Research and Environmental Technology, Department of Bioorganic Chemistry, University of Bremen, Leobener Strasse, D-28359, Bremen, Germany.
Maronde
E
E
Genieser
H
H
Jastorff
B
B
D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy; D002986:Clinical Trials as Topic; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006152:Cyclic GMP / Q000502:physiology; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism* / Q000493:pharmacokinetics / Q000627:therapeutic use; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D009369:Neoplasms / Q000188:drug therapy; D011953:Receptors, Cyclic AMP / Q000502:physiology*; D015398:Signal Transduction
D000970:Antineoplastic Agents; D011953:Receptors, Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP