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

1984 ◽  
Vol 49 (11) ◽  
pp. 2541-2550 ◽  
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.

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

1993 ◽  
Vol 58 (6) ◽  
pp. 1419-1429 ◽  
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.

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

1993 ◽  
Vol 58 (5) ◽  
pp. 1151-1163 ◽  
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).

Semisynthetic cephalosporins. The synthesis of 7-(heteroarylacetamido)-3-acetoxycephalosporanic acids

1985 ◽  
Vol 50 (2) ◽  
pp. 482-491 ◽  
Author(s):  
Ľubomír Janda ◽  
Zdeno Votický ◽  
Ján Šipoš ◽  
Marta Múčková
Keyword(s):  
Gram Positive ◽  
Sodium Salts ◽  
Gram Negative ◽  
Derivatives Of ◽  
Better Than

7-(5-(5-Aryl-2-furyl)-1- and -2-tetrazolylacetamido)cephalosporanic acids and their sodium salts were prepared by N-acylation of 7-aminocephalosporanic acid with derivatives of 5-(5-aryl-2-furyl)-1- and -2-tetrazolylacetic acids. The final products tested in vitro on the Gram-positive and Gram-negative strains of microorganisms showed an activity comparable or better than that of reference substances.

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

1990 ◽  
Vol 55 (3) ◽  
pp. 809-818 ◽  
Author(s):  
Antonín Holý ◽  
Ivan Rosenberg ◽  
Hana Dvořáková
Keyword(s):  
Triethyl Phosphite ◽  
Sodium Salts ◽  
Subsequent Hydrolysis ◽  
Pyrimidine Bases ◽  
Heterocyclic Bases ◽  
Derivatives Of

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.

scholarly journals Synthesis and Antiviral Evaluation of SATE-Foscarnet Prodrugs and New Foscarnet—AZT Conjugates

1998 ◽  
Vol 9 (1) ◽  
pp. 41-52 ◽  
Author(s):  
C Meier ◽  
A-M Aubertin ◽  
M de Monte ◽  
A Faraj ◽  
J-P Sommadossi ◽  
...  
Keyword(s):  
Culture Medium ◽  
Chromatographic Purification ◽  
Alkyl Esters ◽  
Chemical Hydrolysis ◽  
B Virus ◽  
Immunodeficiency Virus ◽  
Hydrolysis Of ◽  
Derivatives Of ◽  
Anti Hiv

The synthesis of a range of di- and triester derivatives of phosphonoformate (PFA; foscarnet) as potential lipophilic, membrane-soluble prodrugs is described. In addition to normal alkyl esters in the carboxylate and phosphonate residues of PFA, the bioreversible S-(pivaloyl)thioethyl ( t-butyl-SATE) group was introduced in an attempt to deliver PFA after bioactivation inside the cells. Furthermore, PFA—AZT conjugates were prepared in order to develop combinational drugs. The key synthetic step was in all cases the formation of the P—C bond to build up the different PFA esters. In contrast to the diester derivatives, the triesters of PFA showed high hydrolytic instability during chromatographic purification. The compounds were evaluated in vitro for their ability to inhibit viruses in several tissue culture systems. All PFA alkyl di- and triesters proved poorly active or inactive against human immunodeficiency virus (HIV) and inactive against hepatitis B virus. In contrast, the PFA—AZT conjugates exhibited significant anti-HIV activity. However, this activity was nearly completely lost in thymidine kinase-deficient cells, suggesting a fast unselective chemical hydrolysis of the conjugates to yield the nucleoside analogue AZT in the cell culture medium. Furthermore, no synergistic effect of PFA and AZT was observed.

Ultrastructural Changes in Three Different Mammalian Cells Following Ultraviolet Laser Irradiation

1972 ◽  
Vol 30 ◽  
pp. 350-351
Author(s):  
K. Shankar Narayan ◽  
Kailash C. Gupta ◽  
Tohru Okigaki
Keyword(s):  
Ultraviolet Light ◽  
Mammalian Cells ◽  
Biological Effects ◽  
Survival Rates ◽  
Chinese Hamster ◽  
Cell Types ◽  
Differential Sensitivity ◽  
Ultrastructural Changes ◽  
Ultraviolet Laser

The biological effects of short-wave ultraviolet light has generally been described in terms of changes in cell growth or survival rates and production of chromosomal aberrations. Ultrastructural changes following exposure of cells to ultraviolet light, particularly at 265 nm, have not been reported.We have developed a means of irradiating populations of cells grown in vitro to a monochromatic ultraviolet laser beam at a wavelength of 265 nm based on the method of Johnson. The cell types studies were: i) WI-38, a human diploid fibroblast; ii) CMP, a human adenocarcinoma cell line; and iii) Don C-II, a Chinese hamster fibroblast cell strain. The cells were exposed either in situ or in suspension to the ultraviolet laser (UVL) beam. Irradiated cell populations were studied either "immediately" or following growth for 1-8 days after irradiation.Differential sensitivity, as measured by survival rates were observed in the three cell types studied. Pattern of ultrastructural changes were also different in the three cell types.

CONTRIBUTION TO THE EXISTENCE OF REGULATORY MECHANISMS AT THE ADRENAL LEVEL

1972 ◽  
Vol 70 (4) ◽  
pp. 741-757
Author(s):  
Otto Linèt
Keyword(s):  
Orotic Acid ◽  
Adrenal Glands ◽  
Actinomycin D ◽  
Delay Period ◽  
Regulatory Mechanisms ◽  
Leucine Incorporation ◽  
Total Period ◽  
Free Media

ABSTRACT Rat adrenal glands atrophied by the administration of cortisol acetate in vivo were used as a model for the study of early metabolic processes occurring in vitro. Atrophied adrenals incubated in the presence of 14C-leucine incorporated subnormal quantities of this amino acid per mg of protein for the first 120 min. When the incubation lasted for a total period of 180 or 240 min a supranormal rise in the 14C-leucine incorporation was observed. Similar changes occurred with some delay with regard to corticosterone production as expressed per 100 mg of tissue. No differences in 14C-leucine incorporation were observed between the control and atrophied adrenals in vivo. Homogenates from atrophied glands incorporated 14C-leucine to a greater extent than the control homogenates. The in vitro incorporation of 14C-orotic acid into the RNA was also higher in atrophied adrenals. The in vitro use of actinomycin D, cycloheximide and amphenone indicated that corticosterone production depended on the incorporation of 14C-leucine. The addition of cortisol to the incubation media markedly decreased the enhancement of 14C-lysine incorporation into the protein of atrophied adrenals. These, as well as additional results suggest rebound phenomena: once atrophic adrenals are transferred to cortisol-free media, reparative processes begin after a delay period. Such phenomena seem to be mediated by regulatory mechanisms at the adrenal level.

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