The synthesis and the pharmacological properties of enantiomeric derivatives of 7-(2,3-dihydroxypropyl)theophylline

1979 ◽  
Vol 44 (8) ◽  
pp. 2550-2555 ◽  
Author(s):  
Antonín Holý ◽  
Miroslav Vaněček
Keyword(s):  
Guinea Pig ◽  
Acid Hydrolysis ◽  
Sodium Salt ◽  
Blood Circulation ◽  
Pharmacological Properties ◽  
Camp Phosphodiesterase ◽  
Derivatives Of ◽  
Subsequent Acid

7-(S)-(2,3-Dihydroxypropyl)theophylline ((S)-I) and its enantiomer (R)-I were prepared by heating of the sodium salt of theophylline with 1-O-toluenesulfonyl-2,3-O-isopropylidene-D-glycerol or its L-enantiomer and subsequent acid hydrolysis. The two enantiomers I do not differ either by the inhibition of 3',5'-cAMP-phosphodiesterase, vasodilatatory activity on isolated guinea-pig aorta, or the effect on blood circulation of dogs in vivo.

Fluorescent analogues of acyclic inhibitors of S-adenosyl-L-homocysteine hydrolase

1988 ◽  
Vol 53 (8) ◽  
pp. 1779-1794 ◽  
Author(s):  
Hana Dvořáková ◽  
Antonín Holý ◽  
Milena Masojídková
Keyword(s):  
Acid Hydrolysis ◽  
Sodium Salt ◽  
Fluorescence Spectra ◽  
Inhibitory Effect ◽  
Leukemia Cells ◽  
Subsequent Acid ◽  
Fluorescent Analogues

Condensation of sodium salt of 2-aminopurine (I) with 4-chloromethyl-2,2-dimethyl-1,3-dioxolane (II) followed by acid hydrolysis afforded 9-(RS)-(2,3-dihydroxypropyl)-2-aminopurine (V). Similarly, sodium salt of lin-benzoadenine (IX) reacted with compound II to give 3-(RS)-(2,3-dihydroxypropyl)-lin-benzoadenine (Xb). Analogues of eritadenine (XVIb) derived from 2-aminopurine (VII) and lin-benzoadenine (XIV) were obtained by reaction of sodium salt of the corresponding base (I or IX) with 2,3-O-cyclohexylidene-D-erythronolactone (VI) and subsequent acid hydrolysis. By action of chloroacetaldehyde on 9-substituted acyclic analogues of adenosine or AMP (XVI) were prepared 9-(2,3-dihydroxypropyl)-1,N6-ethenoadenine (XVIIa), 1,N6-etheno derivative of eritadenine (XVIIb), 3-(1,N6-ethenoadenin-9-yl)-2-hydroxypropanoic acid (XVIIc) and its 2-methylpropyl ester (XVIId), as well as 9-(S)-(3-hydroxy-2-phosphonylmethoxypropyl)-1,N6-ethenoadenine (XVIIe) and 9-(2-phosphonylmethoxyethyl)-1,N6-ethenoadenine (XVIIf). Fluorescence spectra of all the mentioned compounds exhibit parameters corresponding to the substituted fluorophore; however, no pronounced inhibitory effect on SAH-hydrolase from L-1210 mice leukemia cells has been found for any of them.

Preparation of isomeric 3-aminopropylamino derivatives of 9-(RS)-(2,3-dihydroxypropyl)adenine

1983 ◽  
Vol 48 (7) ◽  
pp. 1910-1921 ◽  
Author(s):  
Antonín Holý
Keyword(s):  
Acid Hydrolysis ◽  
Bromo Derivative ◽  
Derivatives Of ◽  
Subsequent Acid

Treatment of 9-(RS)-(2,3-dihydroxypropyl)adenine (III) with bromine in water afforded the 8-bromo derivative IV which on reaction with acetone was converted into the 1,3-dioxolane derivative VI. Reaction of compound VI with 1,3-diaminopropane, followed by acid hydrolysis, gave 9-(RS)-(2,3-dihydroxypropyl)-8-(3-aminopropylamino)adenine (VIII). Compound IV reacts with 1,3-diaminopropane under formation of a mixture of compound VIII and isomeric 9-(RS)-[3(2)-(3-aminopropylamino)-2(3)-hydroxypropyl]-8-hydroxyadenines (IX, X). 9-(RS)-(2,3-Dihydroxypropyl)-8-hydroxyadenine (XVII) was prepared by reaction of compound VI with sodium benzoxide in dimethylformamide and subsequent acid hydrolysis. Its tosylation, followed by reaction of the obtained 3'-O-p-toluenesulfonyl derivative XVIII with 1,3-diaminopropane, furnished also the compound IX. In an analogous way, 9-(RS)-[3-(3-aminopropylamino)-2-hydroxypropyl]adenine (XXI) was prepared from 3'-O-p-toluenesulfonyl derivative of compound III (XX).

Synthesis and Biological Effects of 9-(3-Hydroxy-2-phosphonomethoxypropyl) Derivatives of Deazapurine Bases

1993 ◽  
Vol 58 (6) ◽  
pp. 1403-1418 ◽  
Author(s):  
Hana Dvořáková ◽  
Antonín Holý ◽  
Petr Alexander
Keyword(s):  
Acid Hydrolysis ◽  
Sodium Methoxide ◽  
Potent Inhibitor ◽  
Biological Effects ◽  
Side Chain ◽  
Cesium Carbonate ◽  
Phosphonic Acids ◽  
Dna Viruses ◽  
Derivatives Of ◽  
Subsequent Acid

Analogs of antiviral 9-(S)-(3-hydroxy-2-phosphonomethoxypropyl)adenine (HPMPA, I), containing modified purine bases 3-deazaadenine XII, 1-deazaadenine XIV, 7-deaz-7-cyanoaadenine XXXII and 3-deazaguanine XXXVIII, were prepared by alkylation of the bases with synthon XVII, containing preformed structure of the side chain, in the presence of cesium carbonate. The obtained protected derivatives were deblocked successively with sodium methoxide and bromotrimethylsilane to give phosphonic acids XII, XIV, XXXII and XXXVIII. Compounds XII, XIV and XVI were also prepared from (S)- or (R)-9-(2,3-dihydroxypropylderivatives VI, VII and XV by the reaction with chloromethanephosphonyl dichloride, isomerization of the arising 2'- and 3'-chloromethanephosphonates and conversion of the 3'-isomers into the phosphonic acids in alkaline medium. The 3-deaza analog XII was also prepared by ditritylation of VI, reaction with bis(2-propyl) tosyloxymethanephosphonate (XXII), subsequent acid hydrolysis and reaction with bromotrimethylsilane. 3-DeazaHPMPA (XII) is a potent inhibitor of DNA viruses (HSV-1, HSV-2, VZV, CMV) and exhibits activity against Plasmodium sp.

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

1992 ◽  
Vol 57 (7) ◽  
pp. 1466-1482 ◽  
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.

Preparation of enantiomeric and racemic 2,3,4,5-tetrahydroxypentyl derivatives of adenine, cytosine and uracil

1982 ◽  
Vol 47 (10) ◽  
pp. 2786-2805 ◽  
Author(s):  
Antonín Holý
Keyword(s):  
Acid Hydrolysis ◽  
Sodium Borohydride ◽  
Catalytic Hydrogenation ◽  
Protecting Groups ◽  
Sodium Salts ◽  
Hydrolysis Of ◽  
Derivatives Of ◽  
Subsequent Acid

1-(Adenin-9-yl)-1-deoxy-DL-ribitol (III), -D-arabitol (IXa), -L-arabitol (XIVa), -DL-xylitol (XXIVa), 1-(cytosin-L-yl)-1-deoxy-D-arabitol (IXb), -L-arabitol (XIVb), 1-(uracil-1-yl)-1-deoxy-D-arabitol (IXc), -L-arabitol (XIVc) and -DL-xylitol (XXIVb) were prepared by reaction of 1-O-p-toluenesulfonyl-2,3:4,5-di-O-isopropylidenealditols Ib, VIIb, XIIb and XXIIb with sodium salts of adenine, N4-benzoylcytosine or 4-methoxy-2-pyrimidone followed by removal of the protecting groups. Condensation of the mentioned sodium salts with methyl 5-O-p-toluenesulfonyl-2,3-O-isopropylidene-β-D-ribofuranoside (IV) with subsequent acid hydrolysis and reduction with sodium borohydride afforded 1-(adenin-9-yl)-1-deoxy-L-ribitol (VIa) and 1-(cytosin-1-yl)-1-deoxy-L-ribitol (VIb). 1-(Adenin-9-yl)-1-deoxy-L-lyxitol (XVII), -L-lyxitol (XVIII) and -2-O-methyl-D-lyxitol (XXI) were prepared analogously. Acid hydrolysis of 5-(adenin-9-yl)-5-deoxy-4-O-benzyl-1,2-O-isopropylidene-α-D-xylofuranose (XXVa), followed by reduction with sodium borohydride and catalytic hydrogenation, gave 1-(adenin-9-yl)-1-deoxy-L-xylitol (XXVIb).

Branched-chain derivatives of acyclic adenosine analogs: Alkyl and hydroxymethyl derivatives of S-adenosyl-L-homocysteinase inhibitors substituted at the 2- and 3-position of the side chain

1989 ◽  
Vol 54 (1) ◽  
pp. 248-265
Author(s):  
Antonín Holý
Keyword(s):  
Acid Hydrolysis ◽  
Sodium Borohydride ◽  
Sodium Salt ◽  
Osmium Tetroxide ◽  
Sodium Perchlorate ◽  
Side Chain ◽  
Isopropylidene Derivative ◽  
Branched Chain ◽  
Hydrolysis Of ◽  
Derivatives Of

Reaction of 1,3-dichloro-2-propanone (VII) with methylmagnesium chloride, followed by alkaline hydrolysis, afforded 2-methylpropane-1,2,3-triol (VIII) which on treatment with 2,2-dimethoxypropane and subsequent tosylation gave 4-(p-toluenesulfonyloxymethyl)-2,2,4-trimethyl-1,3-dioxolane (IXb). Compound IXb was condensed with sodium salt of adenine and the intermediate X was acid-hydrolysed to give 9-(RS)-(2,3-dihydroxy-2-methylpropyl)adenine (XI). Oxidation of XI with sodium periodate led to 9-(2-oxopropyl)adenine (XII). 9-(RS)-(2-Hydroxy-2-hydroxymethyloctyl)adenine (XVI) was obtained analogously from compound VII and hexylmagnesium bromide via triol XIV. Methyl 2-bromomethyl-2-propenoate (XVII) reacted with sodium salt of adenine and the resulting methyl 2-(adenin-9-ylmethyl)-2-propenoate (XVIII) was hydroxylated with sodium perchlorate and osmium tetroxide. The obtained methyl (RS)-2-(adenin-9-ylmethyl)-2,3-dihydroxypropanoate (XIX) was alkali-hydrolysed to give sodium salt of the acid XX. Reduction of ester XIX with sodium borohydride furnished 9-(RS)-(2,3-dihydroxy-2-hydroxymethylpropyl)adenine (XXI). 1-Nonen-3-ol (XXIII), obtained by reaction of propenal with hexylmagnesium bromide, was converted by hydroxylation with osmium tetroxide into nonane-1,2,3-triol (XXIVa) and further into its 1-O-p-toluenesulfonate XXIVb which reacted with 2,2-dimethoxypropane to give 2,2-dimethyl-4-hexyl-5-(p-toluenesulfonyloxymethyl)-1,3-dioxolane (XXV). Compound XXV reacted with adenine and the resulting intermediate XXVI was converted into 9-(RS)-(2,3-dihydroxynonyl)adenine (XXVII) by acid hydrolysis. 9-(3-Methyl-2-buten-1-yl)adenine (XXVIII), obtained by alkylation of sodium salt of adenine with 1-bromo-3-methyl-2-butene, was oxidized with potassium permanganate in an acid medium to give 9-(3-hydroxy-2-oxo-3-methylbutyl)adenine (XXIX). This compound was converted into 9-(RS)-(2,3-dihydroxy-3-methylbutyl)adenine (XXX) by reduction with sodium borohydride. 4-C-Hydroxymethyl-1,2-O-isopropylidene-α-D-xylofuranose (XXXII) reacted with 2,2-dimethoxypropane under formation of 4-C-hydroxymethyl-1,2:3,5-di-O-isopropylidene derivative XXXIIIa whose p-toluenesulfonyl derivative XXXIIIb on treatment with adenine afforded 4-C-(adenin-9-yl)methyl-1,2:3,5-di-O-isopropylidene-α-D-xylofuranose (XXXIV). Acid hydrolysis of this compound, followed by oxidation in an alkaline medium, gave (2S,3R)-4-(adenin-9-yl)-3-hydroxymethyl-2,3-dihydroxybutanoic acid, isolated as its ethyl ester XXXVI.

Inhibition of Human and Animal Platelet Adhesiveness to Glass Bead Columns by Adenosine, Dipyridamole, Chlorpromazine and Acetylsalicylic Acid

1976 ◽  
Vol 36 (02) ◽  
pp. 401-410 ◽  
Author(s):  
Buichi Fujttani ◽  
Toshimichi Tsuboi ◽  
Kazuko Takeno ◽  
Kouichi Yoshida ◽  
Masanao Shimizu
Keyword(s):  
Guinea Pig ◽  
Acetylsalicylic Acid ◽  
Guinea Pigs ◽  
Glass Bead ◽  
Animal Species ◽  
Inhibitory Effect ◽  
Rabbit Platelet ◽  
Platelet Adhesiveness

SummaryThe differences among human, rabbit and guinea-pig platelet adhesiveness as for inhibitions by adenosine, dipyridamole, chlorpromazine and acetylsalicylic acid are described, and the influence of measurement conditions on platelet adhesiveness is also reported. Platelet adhesiveness of human and animal species decreased with an increase of heparin concentrations and an increase of flow rate of blood passing through a glass bead column. Human and rabbit platelet adhesiveness was inhibited in vitro by adenosine, dipyridamole and chlorpromazine, but not by acetylsalicylic acid. On the other hand, guinea-pig platelet adhesiveness was inhibited by the four drugs including acetylsalicylic acid. In in vivo study, adenosine, dipyridamole and chlorpromazine inhibited platelet adhesiveness in rabbits and guinea-pigs. Acetylsalicylic acid showed the inhibitory effect in guinea-pigs, but not in rabbits.

Acyl-Enzymes as Thrombolytic Agents in Dog Models of Venous Thrombosis and Pulmonary Embolism

1984 ◽  
Vol 51 (02) ◽  
pp. 248-253 ◽  
Author(s):  
R J Dupe ◽  
P D English ◽  
R A G Smith ◽  
J Green
Keyword(s):  
Pulmonary Embolism ◽  
Side Effects ◽  
Venous Thrombosis ◽  
Active Site ◽  
Acute Pulmonary Embolism ◽  
Quantitative Model ◽  
Beagle Dog ◽  
Thrombosis Model ◽  
Derivatives Of

SummaryA quantitative model of venous thrombosis in the beagle dog is described. The model was adapted to permit ageing of isolated experimental clots in vivo. A model of acute pulmonary embolism in this species is also described. In the venous thrombosis model, infusion of streptokinase (SK) or SK-activated human plasmin gave significant lysis but bolus doses of SK. plasmin complex were ineffective. Active site anisoylated derivatives of SK. plasminogen complex, SK-activated plasmin and activator-free plasmin were all active when given as bolus doses in both models. At lytic doses, the acyl-enzymes caused fewer side-effects attributable to plasminaemia than the corresponding unmodified enzymes.

In vivo activity of pyrimidine-dispirotripiperaziniumin in the male guinea pig model of genital herpes

2020 ◽  
Vol 09 (01) ◽  
Author(s):  
Novoselova EA ◽  
Alimbarova LM ◽  
Monakhova NS ◽  
Lepioshkin AY ◽  
Ekins S ◽  
...  
Keyword(s):  
Guinea Pig ◽  
Genital Herpes ◽  
Pig Model ◽  
Guinea Pig Model

Tamarix articulata (T. articulata) - An Important Halophytic Medicinal Plant with Potential Pharmacological Properties

2019 ◽  
Vol 20 (4) ◽  
pp. 285-292 ◽  
Author(s):  
Abdullah M. Alnuqaydan ◽  
Bilal Rah
Keyword(s):  
Medicinal Plant ◽  
Biological Activities ◽  
Wide Spectrum ◽  
Biological Properties ◽  
In Vivo Model ◽  
Drug Candidate ◽  
Phytochemical Analysis ◽  
Pharmacological Properties

Background:Tamarix Articulata (T. articulata), commonly known as Tamarisk or Athal in Arabic region, belongs to the Tamaricaece species. It is an important halophytic medicinal plant and a good source of polyphenolic phytochemical(s). In traditional medicines, T. articulata extract is commonly used, either singly or in combination with other plant extracts against different ailments since ancient times.Methods:Electronic database survey via Pubmed, Google Scholar, Researchgate, Scopus and Science Direct were used to review the scientific inputs until October 2018, by searching appropriate keywords. Literature related to pharmacological activities of T. articulata, Tamarix species, phytochemical analysis of T. articulata, biological activities of T. articulata extracts. All of these terms were used to search the scientific literature associated with T. articulata; the dosage of extract, route of administration, extract type, and in-vitro and in-vivo model.Results:Numerous reports revealed that T. articulata contains a wide spectrum of phytochemical(s), which enables it to have a wide window of biological properties. Owing to the presence of high content of phytochemical compounds like polyphenolics and flavonoids, T. articulata is a potential source of antioxidant, anti-inflammatory and antiproliferative properties. In view of these pharmacological properties, T. articulata could be a potential drug candidate to treat various clinical conditions including cancer in the near future.Conclusion:In this review, the spectrum of phytochemical(s) has been summarized for their pharmacological properties and the mechanisms of action, and the possible potential therapeutic applications of this plant against various diseases discussed.

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