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 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.

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.

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).

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).

Side-Chain Derivatives of Biologically Active Nucleosides. Part 2: Synthesis and anti-HIV Activity of 5′-C-Methyl Derivatives of 3′-Fluoro-3′-Deoxythymidine

1996 ◽  
Vol 7 (3) ◽  
pp. 173-177 ◽  
Author(s):  
J. Hiebl ◽  
E. Zbiral ◽  
M. von Janta-Lipinski ◽  
J. Balzarini ◽  
E. De Clercq
Keyword(s):  
Inhibitory Effect ◽  
Biologically Active ◽  
Side Chain ◽  
Dna Viruses ◽  
Immunodeficiency Virus ◽  
Methyl Derivatives ◽  
Derivatives Of ◽  
Anti Hiv

1-(3′-Fluoro-2′,3′,6′-trideoxy-β-D-allofuranosyl)thymine [7] and 1-(3′-fluoro-2′,3′,6′-trideoxy-α-L-talofuranosyl) thymine [8] were synthesized starting from the corresponding 2,3′-anhydro nucleoside derivatives. The fluorine was introduced stereoselectively by opening of the anhydro bridge in the presence of HF/AIF3. The 5′-C-methyl derivatives, [7] and [8], of 3′-fluoro-3′-deoxythymidine (FLT) were evaluated for their inhibitory effect against human immunodeficiency virus type 1 (HIV-1) and type 2 (HIV-2). The compounds [7] and [8] had antiviral activity which was three orders of magnitude lower than the reference compound 3′-fluoro-3′-deoxythymidine. None of the compounds showed appreciable activity against other RNA or DNA viruses at subtoxic concentrations.

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.

Absolute configuration at C(20) of the derivatives of 21-nor-5α-cholane-20,24-diol

1980 ◽  
Vol 45 (9) ◽  
pp. 2443-2451
Author(s):  
Vladimír Pouzar ◽  
Miroslav Havel
Keyword(s):  
Absolute Configuration ◽  
Side Chain ◽  
Chemical Correlation ◽  
The Absolute ◽  
Derivatives Of

Derivatives of 21-nor-5α-cholane-20,24-diol XI and XIX were prepared by stepwise construction of the side-chain in the position 17β. Their absolute configuration at C(20) was determined on the basis of chemical correlation with the derivatives of 21-nor-5α-cholan-20-ol, XVI and XXIV. The absolute configuration of alcohols XVI and XXIV was determined from the ratio of the yields in which they are formed during the reduction of ketone X and using the benzoate rule. To compounds XI-XVIII the configuration 20R and to compounds XIX-XXVI the configuration 20S has been assigned.

Reactions of 3-cyano-1-methylquinolinium methyl sulphate with some C-acids and with p-nitroaniline

1981 ◽  
Vol 46 (2) ◽  
pp. 503-505 ◽  
Author(s):  
Oldřich Kocián ◽  
Miloslav Ferles
Keyword(s):  
Sodium Methoxide ◽  
Ethyl Cyanoacetate ◽  
Derivatives Of

The action of malononitrile, ethyl cyanoacetate, dibenzoylmethane and/or p-nitroaniline on compound I in the presence of sodium methoxide gives rise to derivatives of 3-cyano-1-methyl-1,4-dihydroquinoline, II and III

Preparation of Chloro and Sulfanyl Derivatives of 1-(2-Deoxy-4-C-hydroxymethyl-α-L-threo-Pentofuranosyl)uracil

1997 ◽  
Vol 62 (7) ◽  
pp. 1114-1127 ◽  
Author(s):  
Hubert Hřebabecký ◽  
Jan Balzarini ◽  
Antonín Holý
Keyword(s):  
Nucleophilic Substitution ◽  
Hydrogen Chloride ◽  
Thionyl Chloride ◽  
Sodium Methoxide ◽  
Thioacetic Acid ◽  
Uracil Derivatives ◽  
Derivatives Of ◽  
Hiv 1

3'-Chloro and 3'-acetylsulfanyl derivatives of 1-(2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil were prepared by reaction of 2,3'-anhydro-1-{5'-O-benzoyl-4'-C-[(benzoyloxy)methyl]-2'-deoxy-α-L-erythro-pentofuranosyl}uracil (3) with hydrogen chloride and thioacetic acid, respectively. The reaction with hydrogen chloride gave a mixture of N-1 and N-3 substituted uracil derivatives 12 and 14. Reaction of 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-α-L-threo-pentofuranosyl}uracil (7) with thionyl chloride and subsequent debenzoylation afforded 1-(4-C-chloromethyl-2-deoxy-β-D-erythro-pentofuranosyl)uracil (19). Nucleophilic substitution with lithium thioacetate, followed by deacylation, converted 1-{3-O-benzoyl-4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (9) into 1-(2-deoxy-4-C-sulfanylmethyl-β-D-erythro-pentofuranosyl)uracil (21). The obtained thiols were oxidized with iodine or air to give 1,1'-[disulfandiylbis(2,3-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-3,1-diyl]di(pyrimidine-2,4-(1H,3H)-dione) (17) and 1,1'-[disulfandiylbis(2,5-dideoxy-4-hydroxymethyl-α-L-threo-pentofuranose-5,1-diyl]di(pyrimidine-2,4(1H,3H)-dione) (22). Reaction of 1-{3-acetylsulfanyl-5-O-methanesulfonyl-4-C-[(benzoyloxy)methyl]-2,3-dideoxy-α-L-threo-pentofuranosyl)}uracil (24) with methanolic sodium methoxide afforded 1-(3,5-anhydro-2,3-dideoxy-4-C-hydroxymethyl-3-sulfanyl-α-L-threo-pentofuranosyl)uracil (25). The same reagent was used in the preparation of 1-(3,5-anhydro-2-deoxy-4-C-hydroxymethyl-α-L-threo-pentofuranosyl)uracil (26) from 1-{4-C-[(benzoyloxy)methyl]-2-deoxy-5-O-p-toluenesulfonyl-α-L-threo-pentofuranosyl}uracil (8). From the series of 4'-substituted 2'-deoxyuridine derivatives, synthesized in this study, solely the 4'-chloromethyl derivative 19 and the oxetane derivative 26 exhibited an appreciable activity against HIV-1 and HIV-2.

scholarly journals Synthesis of New Derivatives of BEDT-TTF: Installation of Alkyl, Ethynyl, and Metal-Binding Side Chains and Formation of Tris(BEDT-TTF) Systems

2021 ◽  
Vol 7 (8) ◽  
pp. 110
Author(s):  
Songjie Yang ◽  
Matteo Zecchini ◽  
Andrew Brooks ◽  
Sara Krivickas ◽  
Desiree Dalligos ◽  
...  
Keyword(s):  
Metal Binding ◽  
Tricarboxylic Acid ◽  
Metal Salts ◽  
Side Chain ◽  
Side Chains ◽  
Ethynyl Group ◽  
X Ray ◽  
Transition Metal Salts ◽  
Alkyl Side Chains ◽  
Derivatives Of

The syntheses of new BEDT-TTF derivatives are described. These comprise BEDT-TTF with one ethynyl group (HC≡C-), with two (n-heptyl) or four (n-butyl) alkyl side chains, with two trans acetal (-CH(OMe)2) groups, with two trans aminomethyl (-CH2NH2) groups, and with an iminodiacetate (-CH2N(CH2CO2−)2 side chain. Three transition metal salts have been prepared from the latter donor, and their magnetic properties are reported. Three tris-donor systems are reported bearing three BEDT-TTF derivatives with ester links to a core derived from benzene-1,3,5-tricarboxylic acid. The stereochemistry and molecular structure of the donors are discussed. X-ray crystal structures of two BEDT-TTF donors are reported: one with two CH(OMe)2 groups and with one a -CH2N(CH2CO2Me)2 side chain.

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