Medicinal Chemistry of the Noncanonical Cyclic Nucleotides cCMP and cUMP.

After decades of intensive research on adenosine-3',5'-cyclic monophosphate (cAMP)- and guanosine-3',5'-cyclic monophosphate (cGMP)-related second messenger systems, also the noncanonical congeners cyclic cytidine-3',5'-monophosphate (cCMP) and cyclic uridine-3',5'-monophosphate (cUMP) gained more and more interest. Until the late 1980s, only a small number of cCMP and cUMP analogs with sometimes undefined purities had been described. Moreover, most of these compounds had been rather synthesized as precursors of antitumor and antiviral nucleoside-5'-monophosphates and hence had not been tested for any second messenger activity. Along with the recurring interest in cCMP- and cUMP-related signaling in the early 2000s, it became evident that well-characterized small molecule analogs with reliable purities would serve as highly valuable tools for the evaluation of a putative second messenger role of cyclic pyrimidine nucleotides. Meanwhile, for this purpose new cCMP and cUMP derivatives have been developed, and already known analogs have been resynthesized and highly purified. This chapter summarizes early medicinal chemistry work on cCMP and cUMP and analogs thereof, followed by a description of recent synthetic developments and an outlook on potential future directions.

Synthesis and cytostatic and antiviral activities of 1-beta-D-ribofuranosyl-5-alkylcytosine (5-alkylcytidine) cyclic 3',5'-monophosphates.

A series of 5-alkylcytidines and their 5'-monophosphates and cyclic 3',5'-monophosphates have been synthesized and evaluated for antiviral and antitumor activity. The 5-alkyl cyclic nucleotides were not cytostatic (ID50 greater than 200 micrograms/mL) against leukemia L1210 cells and a deoxycytidine kinase-deficient subline thereof. Certain of the corresponding nucleosides and their 5'-monophosphates did show activity within the range of 35-162 micrograms/mL, as did the unsubstituted cytidine cyclic 3',5'-monophosphate. No antiviral activity was found for any of the compounds at 400 micrograms/mL. A drug design rationale for utilization of 5-alkylcytidines based on their potential conversion to biologically active 5-alkyl-2'-deoxyuridines is not supported by these experimental findings.

Synthesis and antitumor and antiviral activities of a series of 1-beta-D-ribofuranosyl-5-halocytosine (5-halocytidine) cyclic 3',5'-monophosphates.

A series of 1-beta-ribofuranosyl-5-halocytosine cyclic 3',5'-monophosphates (1-4) has been prepared. Direct halogenation of cytidine 3',5'-monophosphate (cCMP) yielded the Cl, Br, and I compounds while 5-F-cCMP (1) was obtained on cyclization of the 5'-monophosphate. On in vitro testing of 1-4 against L1210 and P388 leukemias, only 1 showed significant low-level activity (ID50 = 3.1 X 10(-4) mmol/L). Derivatives 2-4 were inactive at 10(-1) mmol/L and also proved to have low viral ratings against a series of RNA and DNA virus strains in vitro. By contrast the 5-F-cCMP showed moderate activity against VV, HSV-1, and HSV-2 strains (VR = 0.6-0.9). Both 5-fluorocytidine and 5-fluorocytidine 5'-monophosphate had marked antiviral activity (VR = 1.0-2.1) with the above viruses as well as with parainfluenza virus type 3. The nucleoside and nucleotide also were more active than 5-F-cCMP against L1210 and P388 cells. However, comparison of the cytotoxicities and antiviral ED50 values of 5-F-cCMP, 5-fluorocytidine 5'-monophosphate, and 5-fluorocytidine suggests a potential therapeutic advantage for 5-F-cCMP. Possible rationales for these activities are discussed in terms of 5-F-cCMP and the corresponding 5'-monophosphate as potential prodrugs and as sources, following enzymatic deamination, of cytotoxic 5-fluorouridine or its 5'-monophosphate.