The synthesis of a new acyclic analogue of deoxyguanosine, 9-[(1,3-dihydroxy-2-propoxy)methyl]guanine (DHPG, 1), is described starting from epichlorohydrin via condensation of 2-O-(acetoxymethyl)-1,3-di-O-benzylglycerol (5) with N2,9-diacetylguanine (6). In vitro studies indicate that DHPG is a potent and broad-acting (herpes simplex virus types 1 and 2, cytomegalovirus, and Epstein-Barr virus) antiherpetic agent. In vivo studies indicate its lack of toxicity [LD50 (mice) = 1-2 g/kg, ip] and its superiority over acyclovir [oral ED50 = 7 (mg/kg)/day vs. 550 (mg/kg)/day in HSV-2 infected mice].
A series of nucleosides were synthesized in which the 4'-hydrogen was substituted with either an azido or a methoxy group. The key steps in the syntheses of the 4'-azido analogues were the stereo- and regioselective addition of iodine azide to a 4'-unsaturated nucleoside precursor followed by an oxidatively assisted displacement of the 5'-iodo group. The 4'-methoxynucleosides were made via epoxidation of 4'-unsaturated nucleosides with in suit epoxide opening by methanol. Reaction-mechanism considerations, empirical conformation rules, NMR-based conformational calculations, and NOE experiments suggest that the 4'-azidonucleosides prefer a 3'-endo (N-type) conformation of the furanose moiety. When evaluated for their inhibitory effect on HIV in A3.01 cell culture, all the 4'-azido-2'-deoxy-beta-D-nucleosides exhibited potent activity. IC50's ranged from 0.80 microM for 4'-azido-2'-deoxyuridine (6c) to 0.003 microM for 4'-azido-2'-deoxyguanosine (6e). Cytotoxicity was detected at 50-1500 times the IC50's in this series. The 4'-methoxy-2'-deoxy-beta-D-nucleosides were 2-3 orders of magnitude less active and less toxic than their azido counterparts. Modifications at the 2'- or 3'-position of the 4'-substituted-2'-deoxynucleosides tended to diminish activity. Further evaluation of 4'-azidothymidine (6a) in H9, PBL, and MT-2 cells infected with HIV demonstrated a similar inhibitory profile to that of AZT. However, 4'-azidothymidine (6a) retained its activity against HIV mutants which were resistant to AZT.
Reactions of the 5'-hydroxyl group of suitably substituted pyrimidine nucleosides with methyltriphenoxyphosphonium iodide (1) in DMF are very rapid and give the corresponding 5'-deoxy-o'-iodo nucleosides in high yield. Selective iodination of only the primary hydroxyl function in a series of unprotected pyrimidine nucleosides can also be achieved in a number of cases. Iodination of 2',3'-O-isopropylideneuridine can also be accomplished in pyridine, but in the presence of N,N-diisopropylethylamine there is also formation of 2',3'-0isopropylidene-Oz,5'-cyclouridine. The reaction of thymidine with an excess of 1 in pyridine gives 5'-deoxy-5'iodo-O2,3 '-cyclothymidine, which is an intermediate in the formation of 3',5 '-dideoxy-3', 5 '-diiodothymidine via a similar reaction in DMF. In certain cases, the formation of phenyl methylphosphonate esters of secondary c, R = ß-l (9) (a) K.
The replacement of various hydroxyl functions in the sugar moiety of nucleosides by chlorine or bromine can be achieved through reaction with carbon tetrahalides and triphenylphosphine in DMF or DMAC. The reactions with primary hydroxyl groups are rapid and efficient while reactions of the secondary hydroxyl groups of 2'-deoxy nucleosides are slower. In the latter case, the chlorination reaction occurs principally with inversion of configuration while bromination proceeds mainly with retention of configuration. Pyrimidine nucleosides containing a free, as-2',3'-diol undergo quite selective chlorination of the 2'-hydroxyl function with retention of configuration. Mechanisms are discussed for these reactions. The nature of some side reactions between carbon tetrahalides, triphenylphosphine, and DMF are discussed. A recently described preparation of 3 '-chloro-3 '-deoxyuridine has been reexamined and found to give predominantly 5 '-O-acetyluridine and derivatives of 2'-chloro-2'deoxyuridine.
The reaction of l-(5-deoxy-2,3-0-isopropylidene-i?-D-eryf/zro-pent-4-enofuranosyl)uracil (1) with iodine fluoride in methylene chloride leads to the stereospecific formation of 5'-deoxy-4'-fluoro-5'-iodo-2',3'-0-isopropylideneuridine (4a) in almost quantitative yield. The 5'-iodo function of 4a can be converted into the analogous 5'azido derivative (5a) by vigorous treatment with lithium azide in dimethylformamide. Treatment of 5a with nitrosyl tetrafluoroborate leads to the isolation of 2,5,-anhydro-4'-fluoro-2,,3,-0-isopropylideneuridine (6a) which can be readily hydrolyzed to 4'-fluoro-2,,3'-0-isopropylideneuridine (7a). The latter compound has been converted into 4'-fluoro-5,-0-sulfamoyluridine (8b), the uracil analogue of nucleocidin, by treatment with sulfamoyl chloride followed by mild acidic hydrolysis. The synthesis of 4'-fluorouridine '-phosphate (8d] has also been achieved via conversion of 7a to its bis(2,2,2-trichloroethyl)phosphate ester followed by careful removal of protecting groups. The unusual stabilities of 4'-fluorouridine derivatives are discussed. In addition, it has been shown that treatment of 2',3'-methoxymethylene-and 2',3'-methoxyethylideneuridine derivatives with nitrosyl tetrafluoroborate leads to the formation of 2,2'-anhydro-1 -ß-D-arabinofuranosyluracils, presumably via 2',3'-acyloxonium ions.Recent work from this laboratory has explored methods for the introduction of substituents at C4> of the furanose ring in both purine and pyrimidine nucleosides.3 While other types
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