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

Abstract

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.

Discovery of Novel Ribonucleoside Analogs with Activity against Human Immunodeficiency Virus Type 1

“…The observed drug potentiation by 3-deazauridine, a CTP synthase inhibitor, was associated with a decrease of dCTP pool levels. The antiviral activity of 5-fluorocytidine against RNA and DNA viruses has been previously reported (29), as has the anti-HIV-1 activity of the reduced form of 5-fluorocytidine, 2=-deoxy-5-fluorocytidine (30), and that of the derivative 2=,3=-dideoxy-beta-L-5-fluorocytidine (30). Previous reports have demonstrated the antiviral activity of 2=-C-methylcytidine as a delayed chain terminator against RNA viruses, such as hepatitis C virus (HCV) and footand-mouth disease virus (FMDV) (31)(32)(33).…”

Bis(carbamoyloxymethyl) Esters of 2?,3?-Dideoxyuridine 5?-monophosphate (ddUMP) as Potential ddUMP Prodrugs

“…The solvent was evaporated under reduced pressure (30 mmHg) at <30°C to give (N,NЈ-dimethyl)carbamoyloxymethyl chloride, 6b, as a light yellow viscous liquid in 83% yield. 1 …”

“…5Ј-Mononucleotides are obligatory intermediates in the activation of most anticancer and antiviral nucleoside analogues (1)(2)(3)(4). However, their utility as chemotherapeutic agents is severely compromised because they are charged at physiologic pH and penetrate poorly into cells (5)(6).…”

Fluorinated [1,2,4]triazolo[1,5-a]pyrimidines and [1,2,4]triazolo[5,1-c][1,2,4]triazines*

“…The antitumor action of fluoroazines [3] is the most wellknown although recently antimicrobial [4], fungicidal [4], anti-candida [5], antiandrogen [6], and antiviral effects [7][8][9][10] have also been found for these compounds. The biological activity of these fluoroheterocycles has been attributed to their structural similarity to natural pyrimidine bases such as uracil, cytosine, and thymine.…”

“…This could be probably due to the electronwithdrawing effect of the triazine nitrogen atom N-5, which shifts the fluorine peak downfield. An attempt to obtain compounds 8a,c from hydrazones 7a,c by heating in pyridine at reflux [18] led to the product of two reactions, namely, nucleophilic substitution of the fluorine atom and cyclization, to Zwitter-ions 9a,c were also obtained by counter synthesis, namely, by the reaction of triazolyldiazonium salts 6a,c prepared by the diazotization of 3-aminotriazoles 4a,c with the diethyl pyridinium malonate bromide (10) in the presence of pyridine.…”