Synthesis and Biological Effects of N-(2-Phosphonomethoxyethyl) Derivatives of Deazapurine Bases

Analogs of antiviral 9-(2-phosphonomethoxyethyl)adenine (PMEA,II), containing modified purine bases 1-deazaadenine (VII, 3-deazapurine (XI), 7-deaza-7-cyanoadenine (XIIIb) and 3-deazaguanine (XXIb) were prepared by alkylation of the heterocyclic bases with bis(2-propyl) 2-chloroethoxymethylphosphonate (V) in dimethylformamide in the presence of sodium hydride or cesium carbonate. The obtained protected derivatives were deblocked with bromotrimethylsilane to give the phosphonic acids. 3-DeazaPMEG (XXIb) is active against DNA viruses and exhibits a marked cytostatic effect against L-1210 leukemia.

5'-O-Alkyl-5-fluorouridines: Synthesis and biological activity

Methyl 2,3-O-isopropylidene-D-ribofuranoside (IV) was alkylated with alkyl halides in the presence of sodium hydride and the products were transformed by acid hydrolysis and glycosylation into methyl 5-O-alkyl-D-ribofuranosides VII. Benzoylation of VII followed by acetolysis afforded 1-O-acetyl-2,3-di-O-benzoyl-5-O-alkyl-D-ribofuranoses IX which on reaction with 2,4-bis(trimethylsilyloxy)pyrimidine in the presence of tin tetrachloride in acetonitrile and subsequent hydrolysis gave 5'-O-alkyl-2',3'-di-O-benzoyluridines XIa-XIe. Methanolysis of compounds XI furnished 5'-O-alkyluridines III. The 5-O-allyl derivative XII was hydroxylated in the presence OsO4 and transformed further to 5'-O-(RS)-(2,3-dihydroxypropyl)uridine (IIIg) and its tetrabenzoate XVI. Compounds XI and XVI on reaction with elemental fluorine in acetic acid afforded benzoyl derivatives of 5'-O-alkyl-5-fluorouridines XVIIa-XVIIe and XIX which were methanolyzed to give 5'-O-alkyl-5-fluorouridines II. This procedure afforded 5'-O-methyl (IIa), ethyl (IIb), n-butyl (IIc), n-hexyl (IId), n-octyl (IIe), and (RS)-(2,3-dihydroxypropyl) (IIf) derivatives of 5-fluorouridine. None of the compounds II exhibited antibacterial effect on Escherichia coli B or antiviral activity against HSV-1, HSV-2, vaccinia virus or vesicular stomatitis viruses. Compounds IIc,d,e suppressed the growth of L 1210 mice leukemic cells at concentrations of 10-5 to 10-6 mol l-1; the 5'-O-n-butyl derivative IIc has the highest activity (ID50 2·8 μmol l-1) but does not prolong the life span of L 1210 leukemia bearing mice following repeated daily doses of 80 mg/kg.

Synthesis of the sulfonamido derivatives of arabinonucleosides

Reaction of the sodium salt of 4-aminobenzenesulfonamide with cyclocytidine I and cyclouridine II led to the 2-sulfonamido derivatives V and VI while the reaction with the 5'-chloro derivatives of anhydronucleosides III and IV afforded compounds VIII and IX containing nitrogen bridge between the carbon atoms in position 2 and 5'. Kinetics of the model cyclization reaction of 5'-chloroarabinosylisocytosine (XI) was followed and the structure of prepared compounds was confirmed. Inhibition activity against L 1210 leukemia cells in the experiments in vitro was exhibited by compounds V (1.4 . 10-5 mol l-1) and VIII (3.3 . 10-6 mol l-1).