J. J. Fox

A practical synthesis of 2-deoxy-2-fluoro-D-arabinofuranose derivatives.

A seven-step synthesis of 1,3-di-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-D-arabinofuranose, a versatile intermediate in the synthesis of chemotherapeutically important nucleosides, was achieved from 1,2:5,6-di-O-isopropylidene-3-O-tosyl-alpha-D-allofuranose. The crucial steps were the fluorination by use of potassium fluoride in acetamide and the conversion of 6-O-benzoyl-3-deoxy-3-fluoro-D-glucofuranose into 5-O-benzoyl-2-deoxy-2-fluoro-3-O-formyl-D-arabinofuranose by periodate oxidation. Also described is the synthesis of 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)cytosine. This procedure affords good overall yields of products without formation of undesirable, isomeric intermediates and is suitable for large-scale preparations.

Synthesis of the pyrrolo[3,2-d]pyrimidine C-nucleoside isostere of inosine

Abstract The synthesis of “9-deazainosine,” a new C-nucleoside analog of inosine and of formycin B is described. It involves conversion of a ribosylated 3-amino-2-carboalkoxypyrrole intermediate to the desired pyrrolo[3,2-d]pyrimidine system.

Nucleosides LXXXIX. Synthesis of 1-(2-chloro-2-deoxy-α- and -β-D-arabinofuranosyl)cytosines☆

1-(2-Chloro-2-deoxy-β-D-arabinofuranosyl)cytosine (16) and its α anomer (18) were synthesized by direct condensation of 3,5-di-O-acetyl-2-chloro-2-deoxy-α-D-arabinofuranosyl bromide with trimethylsilylated N4-acetylcytosine in the absence of catalyst. A new and convenient method for the synthesis of 1,3,5-tri-O-acetyl-2-chloro-2-deoxy-α-D-arabinofuranose from methyl 3,5-di-O-benzyl-α,β-D-ribofuranoside is described.

2′-Fluoro-arabinosyl Pyrimidine Nucleosides: Chemistry, Antiviral, and Potential Anticancer Activities

ABSTRACT A series of 2′-fluoro-5-substituted-arabinofuranosyl-cytosines and -uracils were synthesized. Two of these, FIAC and FMAU, were found to be very potent and highly selective against herpes simplex virus (HSV) types 1 and 2 at very low drug levels. Cytotoxicity to uninfected Vero or human fibroblast cell proliferation was minimal. The selectivity of FIAC against HSV versus its low cytotoxicity against Vero cells is shown to be due, at least in part, to a virus-specified thymidine kinase. Structure-activity studies demonstrate that the 2′-fluoro substituent in the up (arabino) configuration is essential for this potent antiviral activity. Substitution of the 2′-fluoro group by chloro or bromo reduces the antiviral potency. FIAC is also active in a plaque reduction assay against herpes zoster virus at concentrations of 0.01 μM and against cytomegalovirus plaque formation at 0.1 μM. In vivo studies in mice inoculated with 20 LD50 of HSV-1 show that FIAC and FMAU are effective, the latter giving 60% cures at dose levels as low as 1 mg/kg/day x5. The selective cytotoxicity of FIAC against human tumor cell lines but not against normal human cells is discussed.

EXPERIMENTAL AND CLINICAL STUDIES ON NUCLEOSIDE ANALOGS AS ANTITUMOR AGENTS

I-fl-D-arabinofuranosykytosine (ara-C) (FIGURE l)’.’ is the mainstay of the treatment of acute myeloblastic leukemia in a d ~ l t s . ~ It has, however, several drawbacks, in that it has a n extremely short half-life4 and is very schedule-~pecific,~ which makes it less than ideal for clinical use. For this reason, attempts have been made to find other derivatives that might act as masked precursors, have longer half-lives as well as less schedule-dependency, give less toxicity, and perhaps achieve better clinical results. The 2,2‘-anhydro derivatives of ara-C6 and ara-5-fluoro~ytosine~ have been synthesized. 2.2’-Anhydro-l-fl-~-arabinofuranosyI-5-fluorocytos~ne (AAFC) is

Pyrimidines-19: Ring transformation of 5-nitrouracil into nitroresorcinols

The first intermolecular right transformation of a uracil derivative into the benzene system is reported. Treatment of 1,3-dimethyl-5-nitrouracil (1) with acetone in NaOMe/MeOH afforded 6-acetonyl-5,6-dihydro-1,3-dimethyl-5-nitrouracil (6) which was converted into 4-nitroresorcinol (5) upon treatment with NaOEt/EtOH at reflux. Reaction of1 with butanone gave two major products, 3-(5,6-dihydro-1,3-dimethyl-5-nitrouracil-6-yl)butanone (7) and the 1-(uracil-6-yl)butanone isomer (8). Prolonged treatment of7 with NaOEt/EtOH afforded 4-methyl-6-nitro-resorcinol (9) whereas8 was converted into 2-methyl-4-nitro-resorcinol (10). Treatment of1 with diethyl acetonedicar☐ylate in NaOEt/EtOH afforded diethyl-2-(5,6-dihydro-1,3-dimethyl-5-nitrouracil-6-yl)-acetonedicar☐ylate (2). Prolonged treatment of2 with NaOEt/EtOH at reflux afforded (5,6-dihydro-1,3-dimethyl-6-nitrouracil-6-yl)-acetate (3). Apparently,2 underwent a retroClaisen reaction to give3. Reaction of1 with ethyl acetoacetate in NaOEt/EtOH gave adduct isomers4 which underwent transformation reaction to give eventually 6-nitroresorcinol (5).

Inosine analogs as anti-Leishmanial agents

Several criteria were used to select a number of inosine analogs as potential growth inhibitors of the protozoan parasite Leishmania tropica. Of nine compounds tested, seven showed a high degree of selective toxicity towards L. tropica promastigotes as compared to mouse L1210 cells; these include analogs of formycin B, 7-substituted analogs of 7-deazainosine and analogs of inosine in which the sugar moiety has been modified to confer metabolic stability. The metabolism of 7-deazainosine in L. tropica promastigotes was shown to involve conversion to cytotoxic adenosine nucleotide analogs (tubercidin derivatives) that become incorporated into RNA. The results suggest several new classes of compounds which have potential as anti-leishmanial agents.

Nucleosides LXXXIII. Synthetic studies on nucleoside antibiotics. 11. Synthesis of methyl 4-amino-3,4-dideoxy-β-D-ribo-hexopyranoside and -hexopyranosiduronic acid (derivatives related to the carbohydrate moiety of gougerotin)☆

Abstract Methyl 4-amino-3,4-dideoxy-β- D - ribo -hexopyranoside ( 17 ) and its uronic acid ( 19 ) were synthesized via a series of reactions starting from 1,2:5,6-di- O -isopropylidene-3- O -tosyl-α- D -glucofuranose. A method suitable for the large scale preparation of 3,4-dideoxy- 1,2:5,6-di- O -isopropylidene-α- D - erythro -hex-3-enofuranose( 2 ) was devised.

Nucleosides-126: Selective methylation of the C-nucleoside, ψ-isocytidine and its 2

Abstract Methods were developed to prepare 1 -methyl-, 3-methyl- and 4-0-methyl-ψ-isocytidine by selective methylation.3 , 5 - O-Tetraisopropyldisiloxanyl-ψ isocytidine (8) was trimethylsilylated and then treated with MeI and, after deprotection, 1 -methyl-ψ isocytidine (6) was obtained. The 2 - deoxy analog (7) was also prepared in a similar manner from the 2 - deoxy analog (10) of 8. Treatment of 8 with CH2N2 afforded the 3-methyl-ψ-isocytidine derivative (19) as the major product. Methylation with diazomethane also occurred mainly on N3 of the 2 - deoxy analog 10 to form 20. Removal of the 3 , 5 - O-protecting group from 19 and 20 afforded 3-methyl-ψ-isocytidine (14) and its 2-deoxy analog (15), respectively. 2-N-Acetyl- 3 , 5 - O-tetraisopropyldisiloxanyl-ψ-isocytidine (24), on the other hand, gave the 4-O-methyl derivative (25) as the major product upon CH2N2 treatment. Subsequent deprotection of 25 afforded 4-O-methyl-ψ-isocytidine (29). aiv51b1p33b

́-deoxy analog. Synthesis of 1-methyl, 3-methyl and 4-o-methyl derivatives

Abstract 1-(4-Amino-3,4-dideoxy-β- d - ribo hexopyranosyluronic acid)cytosine was synthesized and its identity with the natural product pentopyranamine D was established.