Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-.beta.-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships

Abstract

The syntheses of several 2'-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti herpes virus activity in vitro were examined. Those arabinonucleosides containing the 2'-fluoro function exhibit, generally, more potent anti herpes virus (HSV) activity than do their 2'-chloro of 2'-bromo analogues. The importance of the fluorine in the 2'-"up" (arabino) configuration for enhancement of antiviral effectiveness is demonstrated by the superior activity of 2'-fluoro-5-iodo-ara-C [3a, FIAC] to that of 2'-fluoro-5-iodo-ribo-C. Of all the nucleosides tested herein, FIAC exhibited the most potent in vitro activity against HSV. 2'-Chloro-5-iodo- and -5-methyl-ara-C (3b and 4b) were 37 to greater than 500 times more effective in vitro against HSV type 2 than against type 1, suggesting that these latter derivatives might serve clinically as useful probes to distinguish between HSV types 1 and 2 in the diagnosis of HSV infections in man.

Activities of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine and its metabolites against herpes simplex virus types 1 and 2 in cell culture and in mice infected intracerebrally with herpes simplex virus type 2

“…The order of the therapeutic index (ID5W,/ED90) values of the drugs was as follows (in increasing order): ACV > FIAC FIAU > FMAU > FAC FAU -FHMAU >> ara-A. The relative potencies of the 2'-fluoronucleosides in cell cultures are also consistent with findings reported previously (16,17,24,34,35), with the exception of FAU and FHMAU, which previously were found to have poor antiviral activity compared with the other fluorinated compounds (15)(16)(17)24). Technical differences must account for these disparities.…”

Semiautomated Radiosynthesis and Biological Evaluation of [18F]FEAU: A Novel PET Imaging Agent for HSV1-tk/sr39tk Reporter Gene Expression

“…After cooling, the reaction was quenched with saturated sodium bicarbonate (10 mL). The organic layer was washed with brine (2×10 mL) and dried over MgSO 4 . Column chromatography with chloroform afforded pure fluoro product (0.65 g, 56%).…”

“…One of the best validated reporter genes is the Herpes Simplex Virus Type 1 thymidine kinase (HSV1-tk), which can phosphorylate various substrates. A series of 5-substituted fluoroarabinofuranosyl nucleosides with high antiviral activity was first developed by Fox et al in the late 1970s [3][4][5][6][7]. From these early studies, radiolabeled markers for HSV1-tk reporter gene expression and cell proliferation, such as 2′-deoxy-2′-fluoro-β-D-arabinofuranosyl-5-iodouracil ([ 14 [10][11][12][13].…”

Antirhinovirus activity of purine nucleoside analogs

“…The most recently developed antirhinovirus compounds (3,15,24,31) reach their MICs within the range of 0.001 to 0.01 ,ug/ml. Such low MICs are unusual for antiviral compounds and are only matched by the most potent antiherpesvirus compounds (11,42).…”