Acyclic purine phosphonate analogs as antiviral agents. Synthesis and structure-activity relationships

Abstract

A series of 9-(phosphonoalkyl)purines, which are analogues of 9-[2-(phosphonomethoxy)ethyl]purines (guanine, PMEG, 1; adenine, PMEA, 2), were synthesized. The analogues were tested for activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), human cytomegalovirus (HCMV), Rauscher murine leukemia virus (R-MuLV), and human immunodeficiency virus type 1 (HIV-1). With variations in the length of the alkyl chain, the optimal activity was achieved with two carbons between the purine base and the phosphonomethoxy functionality. Despite the structural similarity and the close pKa2 value of 8 to that of PMEG, no phosphorylation of 8 was observed by the bovine brain guanylate kinase. Since all isosteric analogues of PMEG (7-9) were not inhibitory against HSV-1 and HSV-2, the presence of the 3'-oxygen atom in the PME purines proved critical for anti-HSV activity. Introduction of the 1'-methyl group on the PMEG side chain significantly reduced its anti-HSV activity. Analogue 11, which is a mimic of the phosphate by incorporation of the alpha,alpha-difluoro carbon, was ineffective against HSV-1 and HSV-2. These results suggest that the structural requirements of PME purines for anti-HSV activity appear to be very strict.

Synthesis of Novel 2'-Spirocyclopropanoid 4'-Deoxythreosyl Phosphonic Acid Nucleoside Analogues

“…The supernatant was clarified, and the viral particles were then pelleted at 40,000 rpm for 30 min by using a rotor (70.1 Ti; Bechman Instruments, Inc., Fullerton, Calif.) and suspended in virus-disrupting buffer. The RT assay was performed by a modification of the method of Spira et al 24 in 96-well microdilution plates by using (rA) n ·(dT) [12][13][14][15][16][17][18] as the template primer. The RT results were expressed in disintegrations per minute per milliliter of originally clarified supernatant.…”

Synthesis and Conformation of Novel 4'-Fluorinated 5'-Deoxythreosyl Phosphonic Acid Nucleosides as Antiviral Agents

“…A solution of the allylic alcohol 10 (1.17 g, 3.41 mmol) in triethyl orthoacetate (15 mL) and 0.1 mL of propionic acid was heated at 135-140 o C overnight with constant stirring to allow for the removal of ethanol. An excess of triethyl orthoacetate was removed by distillation, and the residue was purified by silica gel column chromatography (EtOAc/hexane, 1:30) to give compound 11 (1.06 g, 75%) as a colorless oil: (±)-Acetic Acid 4-Fluoro-4-vinyl-tetrahydrofuran-2-yl Ester (14). To a solution of compound 13 (233 mg, 1.76 mmol) in anhydrous pyridine (10 mL) and DMAP (10 mg), Ac 2 O (267 mg, 2.62 mmol) was slowly added, and the mixture was stirred overnight under nitrogen.…”

Synthesis and Some Properties of 4'-Phenyl-5'-Norcarbocyclic Adenosine Phosphonic Acid Analogues

“…This oxygen atom for antiviral activity may be attributed to the increased binding capacity of the phosphonate analogues to target enzymes. 8 Actually, the exact role of substituent in 4'-position in nucleoside analogues in inhibiting reverse transcriptase (RT) has not been explored clearly. In continuation of our effort to find more detailed structure activity relationship of branched nucleoside as RT inhibitor, we have designed and prepared a novel class of nucleosides comprising branched-5'-norcarbocyclic phosphonic acid analogues bearing phenyl group which has bigger van der Waals radius than ethynyl or ethenyl functional group.…”