Synthesis of N-(2-(2-phosphonylethoxy)ethyl) derivatives of heterocyclic bases

Reaction of bis(2-chloroethyl) ether (II) with triethyl phosphite afforded diethyl 2-chloroethoxyethylphosphonate (III). This compound reacts with sodium salts of heterocyclic bases to give diethyl esters of N-(2-(2-phosphonylethoxy)ethyl) derivatives of purine and pyrimidine bases IV. Compounds IV on reaction with bromotrimethylsilane and subsequent hydrolysis were converted into N-(2-(phosphonylethoxy)ethyl) derivatives IV.

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Synthesis of 2-Deoxy-β-D-ribonucleosides and 2,3-Dideoxy-β-D-pentofuranosides on Immobilized Bacterial Cells

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19942303 ◽

1994 ◽

Vol 59 (10) ◽

pp. 2303-2330 ◽

Cited By ~ 18

Author(s):

Ivan Votruba ◽

Antonín Holý ◽

Hana Dvořáková ◽

Jaroslav Günter ◽

Dana Hocková ◽

...

Keyword(s):

The Other ◽

Bacterial Cells ◽

Amino Groups ◽

E Coli ◽

Pyrimidine Series ◽

Acceptor Activity ◽

Dependent Strain ◽

Pyrimidine Bases ◽

Heterocyclic Bases ◽

Derivatives Of

Alginate gel-entrapped cells of auxotrophic thymine-dependent strain of E. coli catalyze the transfer of 2-deoxy-D-ribofuranosyl moiety of 2'-deoxyuridine to purine and pyrimidine bases as well as their aza and deaza analogs. All experiments invariably gave β-anomers; in most cases, the reaction was regiospecific, affording N9-isomers in the purine and N1-isomers in the pyrimidine series. Also a 2,3-dideoxynucleoside can serve as donor of the glycosyl moiety. The acceptor activity of purine bases depends only little on substitution, the only condition being the presence of N7-nitrogen atom. On the other hand, in the pyrimidine series the activity is limited to only a narrow choice of mostly short 5-alkyl and 5-halogeno uracil derivatives. Heterocyclic bases containing amino groups are deaminated; this can be avoided by conversion of the base to the corresponding N-dimethylaminomethylene derivative which is then ammonolyzed. The method was verified by isolation of 9-(2-deoxy-β-D-ribofuranosyl) derivatives of adenine, guanine, 2-chloroadenine, 6-methylpurine, 8-azaadenine, 8-azaguanine, 1-deazaadenine, 3-deazaadenine, 1-(2-deoxy-β-D-ribofuranosyl) derivatives of 5-ethyluracil, 5-fluorouracil, and 9-(2,3-dideoxy-β-D-pentofuranosyl)hypoxanthine, 9-(2,3-dideoxy-β-D-pentofuranosyl)-6-methylpurine, and other nucleosides.

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General Method of Preparation of N-[(S)-(3-Hydroxy-2-phosphonomethoxypropyl)] Derivatives of Heterocyclic Bases

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19931151 ◽

1993 ◽

Vol 58 (5) ◽

pp. 1151-1163 ◽

Cited By ~ 6

Author(s):

Petr Alexander ◽

Antonín Holý

Keyword(s):

Sodium Salt ◽

Boron Trifluoride ◽

Boron Trifluoride Etherate ◽

Cesium Carbonate ◽

Analogous Reaction ◽

Sodium Salts ◽

Heterocyclic Bases ◽

Derivatives Of ◽

General Method ◽

Methanolic Ammonia

Reaction of (R)-1-O-p-toluenesulfonyl-1,2,3-propanetriol (IV) with N-trimethylacetylimidazole (II) afforded (R)-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (V) which was reacted with dimethoxymethane in the presence of phosphorus pentoxide to give (R)-2-O-methoxymethyl-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (VI). Compound VI was treated with acetic anhydride and boron trifluoride etherate and the obtained 2-acetoxy derivative VII reacted with bromotrimethylsilane to give the intermediary bromomethyl ether VIII. Compound VIII on reaction with tris(2-propyl) phosphite afforded (R)-2-O-bis(2-propyl)phosphonomethyl-1-O-p-toluenesulfonyl-3-O-trimethyacetyl-1,2,3-propanetriol (IX). Condensation of synthon IX with sodium salts of adenine, 2,6-diaminopurine, or with cytosine, 6-azacytosine or 2-chloroadenine in the presence of cesium carbonate, afforded fully protected diesters X and XIIIb which on methanolysis and reaction with bromotrimethylsilane gave N-[(S)-(3-hydroxy-2-phosphonomethoxypropyl)] derivatives of adenine (XIa), 2- chloroadenine (XIb), 2,6-diaminopurine (XIc), cytosine (XIVa) and 6-azacytosine (XIVb). In an analogous reaction, sodium salt of 4-methoxy-2-pyrimidone reacted with compound IX to give an intermediate XIIIa which on treatment with methanolic ammonia and subsequent deblocking under the same conditions also afforded the cytosine derivative XIVa. Sodium salt of 2-amino-6-chloropurine was in this way converted into the corresponding 2-aminopurine derivative XVIII. Deprotection of this compound gave 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)-2-aminopurine (XIX).

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Synthesis of N-(2-phosphonylmethoxyethyl) derivatives of heterocyclic bases

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19892190 ◽

1989 ◽

Vol 54 (8) ◽

pp. 2190-2210 ◽

Cited By ~ 46

Author(s):

Antonín Holý ◽

Ivan Rosenberg ◽

Hana Dvořáková

Keyword(s):

Alkali Metal ◽

Metal Salts ◽

Alkali Metal Salts ◽

Phosphonic Acids ◽

Pyrimidine Bases ◽

Methyl Derivatives ◽

Heterocyclic Bases ◽

Derivatives Of

The preparation of N-(2-phosphonylmethoxyethyl) derivatives of purine and pyrimidine bases, IV, as analogs of the antiviral 9-(2-phosphonylmethoxyethyl)adenine (PMEA, I), is described. The synthesis consists in alkylation of alkali metal salts of heterocyclic bases or their N- or O-substituted derivatives with diethyl 2-p-toluenesulfonyloxyethoxymethylphosphonate (IIa), 2-chloroethoxymethylphosphonate (IIb) or 2-bromoethoxymethylphosphonate (IIc). The obtained N-(2-diethoxyphosphonylmethoxyethyl) derivatives of heterocyclic bases (III) were treated with bromotrimethylsilane to give phosphonic acids IV. Compounds IV were prepared from pyrimidines (uracil, cytosine and their 5-methyl derivatives), purines (adenine and its N6- and C(2)-substituted derivatives, hypoxanthine, guanine, 6-hydrazinopurine and 6-methylthiopurine etc.) and their analogs (3-deazaadenine etc.).

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Synthesis of Isomeric N-(3-Fluoro-2-hydroxypropyl) and N-(2-Fluoro-3-hydroxypropyl) Derivatives of Purine and Pyrimidine Bases

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19921466 ◽

1992 ◽

Vol 57 (7) ◽

pp. 1466-1482 ◽

Cited By ~ 11

Author(s):

Jindřich Jindřich ◽

Hana Dvořáková ◽

Antonín Holý

Keyword(s):

Hydrogen Fluoride ◽

Potassium Carbonate ◽

Sodium Salt ◽

Methyl Derivative ◽

Chloro Derivative ◽

Pyrimidine Bases ◽

Heterocyclic Bases ◽

Hydrolysis Of ◽

Derivatives Of ◽

Subsequent Acid

Reaction of fluoromethyloxirane (III) with heterocyclic bases in the presence of potassium carbonate afforded N-(3-fluoro-2-hydroxypropyl) derivatives of adenine (VI), 3-deazaadenine (VII), 2-amino-6-chloropurine (XII), 6-nitro-1-deazapurine (IX), 4-methoxy-2-pyrimidone (XVIII) and its 5-methyl derivative (XIX). Acid hydrolysis of compounds XII, XVIII, and XIX gave 9-(3-fluoro-2-hydroxypropyl)guanine (XIII), 1-(3-fluoro-2-hydroxypropyl)uracil (XX) and -thymine (XXI). The intermediates XVIII and XIX were ammonolyzed to give 1-(3-fluoro-2-hydroxypropyl)cytosine (XXII) and -5-methylcytosine (XXIII). Reaction of chloro derivative XII with sodium azide followed by hydrogenation of the formed 2-amino-6-azidopurine (XIV) led to 9-(3-fluoro-2-hydroxypropyl)-2,6-diaminopurine (XV). 9-(3-Fluoro-2-hydroxypropyl)-1-deazaadenine (X) was obtained by hydrogenation of compound IX. Benzyloxymethyloxirane (XXIV) was reacted with pyridine-hydrogen fluoride adduct to give 3-benzyloxy-2-fluoropropanol (XXV) whose tosylate XXVI on reaction with sodium salt of adenine and subsequent hydrogenolysis of the intermediate XXVII afforded 9-(2-fluoro-3-hydroxypropyl)adenine (XXVIII). The same compound was obtained by reaction of 3-benzyloxy-1-bromo-2-fluoropropanol (XXX) with sodium salt of adenine followed by methanolysis. Condensation of sodium salt of XI, XVI, and XVII with synthon XXX and subsequent acid deblocking gave 9-(2-fluoro-3-hydroxypropyl)guanine (XXXIII), 1-(2-fluoro-3-hydroxypropyl)uracil (XXXVI), and 1-(2-fluoro-3-hydroxypropyl)thymine (XXXVII). 1-(2-Fluoro-3-hydroxypropyl) derivatives of cytosine (XXXVIII) and 5-methylcytosine (XXXIX) were obtained by ammonolysis of the corresponding 4-methoxypyrimidine intermediates XXXIV and XXXV.

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Preparation and biological effects of N-tris(hydroxymethyl)methylaminocarbonylmethyl derivatives of heterocyclic bases

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19842541 ◽

1984 ◽

Vol 49 (11) ◽

pp. 2541-2550 ◽

Cited By ~ 5

Author(s):

Helmut Pischel ◽

Antonín Holý ◽

Jiří Veselý ◽

Günther Wagner

Keyword(s):

Acid Derivative ◽

Orotic Acid ◽

Biological Effects ◽

Leukemic Cells ◽

Alkyl Esters ◽

Sodium Salts ◽

Heterocyclic Bases ◽

Derivatives Of

The title compounds were synthetized by the reaction of TRIS with p-nitrophenyl or alkyl esters of N-carboxymethyl derivatives of uracil, 5-chloro-, 5-bromo-, 5-iodouracil, thymine, cytosine, 6-azauracil, 2-pyridone, 2-pyrimidone, 3-pyridazone and orotic acid. The following novel N-carboxymethyl derivatives are also described: 6-azauracil derivative VIIa by condensation of 4-thio-6-azauracil with methyl bromoacetate followed by hydrolysis, 5-chloruracil derivative IIIa by chlorination of uracil compound IIa, 2-pyrimidone (IXa) and 3-pyridazone derivative Xa by the reaction of the sodium salts of the bases with sodium chloracetate. Of all the amides tested, only the 3-pyridazone derivative Xd and orotic acid derivative XIId inhibited the growth of L-1210 mouse leukemic cells in vitro with 1D50 approx. 10-4 mol l-1.

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Synthesis of N-(3-Fluoro-2-phosphonomethoxypropyl) (FPMP) Derivatives of Heterocyclic Bases

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19931645 ◽

1993 ◽

Vol 58 (7) ◽

pp. 1645-1667 ◽

Cited By ~ 26

Author(s):

Jindřich Jindřich ◽

Antonín Holý ◽

Hana Dvořáková

Keyword(s):

Heterocyclic Ring ◽

Hydroxyl Group ◽

Subsequent Removal ◽

Heterocyclic Base ◽

Primary Hydroxyl ◽

Pyrimidine Bases ◽

Ether Treatment ◽

Heterocyclic Bases ◽

Derivatives Of ◽

Chiral Synthon

A new group of compounds has been prepared: N-(3-fluoro-2-phosphonomethoxypropyl) (FPMP) derivatives of purine and pyrimidine bases which exhibit a significant selective activity against a broad spectrum of retroviruses. Racemic N-(3-fluoro-2-phosphonomethoxypropyl) derivatives of adenin (V), guanine (IX), cytosine (XIII), 2,6-diaminopurine (XXI), 3-deazaadenin e(XVII), xanthine (X) and hypoxanthin (VI) were prepared from the corresponding N-(3-fluoro-2-hydroxypropyl) derivatives after protection of amino group at the heterocyclic ring by selective benzoylation, reaction with diisopropyl p-toluenesulfonyloxymethylphosphonate (II), and subsequent removal of the protecting groups. Chiral FPMP derivatives were prepared by reaction of heterocyclic base with the corresponding chiral synthon (XXX, XXXVII) followed by deprotection. The required chiral synthons were obtained from enantiomeric 3-fluoro-1,2-propanediols by two methods. In the first, the primary hydroxyl group was tritylated, the obtained derivative was reacted with compound II, the trityl group was removed and the product was mesylated to give synthon XXXVII. The second pathway consisted in selective tosylation of the primary hydroxyl group and conversion of the secondary hydroxyl into the acetoxymethyl ether via the methoxymethyl ether; treatment of the acetoxy compound with bromotrimethylsilane and triisopropyl phosphite afforded the desired synthon XXX.

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Oligonucleotidic compounds. XXXII. Phosphorylation of 1-lyxofuranosyl, 1-xylofuranosyl and 1-arabinofuranosyl derivatives of uracil and thymine with triethyl phosphite and hexachloroacetone

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19691929 ◽

1969 ◽

Vol 34 (7) ◽

pp. 1929-1953 ◽

Cited By ~ 6

Author(s):

A. Holý ◽

F. Šorm

Keyword(s):

Triethyl Phosphite ◽

Derivatives Of

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

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19931419 ◽

1993 ◽

Vol 58 (6) ◽

pp. 1419-1429 ◽

Cited By ~ 14

Author(s):

Hana Dvořáková ◽

Antonín Holý

Keyword(s):

Biological Effects ◽

Sodium Hydride ◽

Cesium Carbonate ◽

Cytostatic Effect ◽

Phosphonic Acids ◽

Dna Viruses ◽

Purine Bases ◽

Heterocyclic Bases ◽

L 1210 Leukemia ◽

Derivatives Of

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.

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