Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. II. The Synthon Approach

1995 ◽  
Vol 60 (8) ◽  
pp. 1390-1409 ◽  
Author(s):  
Antonín Holý ◽  
Hana Dvořáková ◽  
Milena Masojídková
Keyword(s):  
Subsequent Reaction ◽  
Heterocyclic Base ◽  
Benzyl Ethers ◽  
Pyrimidine Bases ◽  
Hydrolysis Of ◽  
Derivatives Of ◽  
Hydrolytic Deamination ◽  
Adenine Derivatives

Another approach to (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) I and II is described, consisting in alkylation of the heterocyclic base with (R)- and (S)-2-[bis(2-propyl)phosphonylmethoxy]propyl p-toluenesulfonates (X and XVIII) followed by transsilylation of the intermediary N-[2-bis(2-propyl)phosphonylmethoxypropyl] derivatives XI and XIX. The key intermediates X and XVIII were obtained from 1-benzyloxypropanols VI and XIV by two routes: (i) condensation with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (XIII), hydrogenolysis of the obtained 1-benzyloxy-2-bis(2-propyl)phosphonylmethoxypropanes VIII and XVI over Pd/C to 2-bis(2-propyl)phosphonylmethoxypropanols IX and XVII and tosylation of the latter or (ii) chloromethylation of compounds VI and XIV and subsequent reaction of the chloromethyl ethers VII and XV with tris(2-propyl) phosphite and further processing of the benzyl ethers VIII and XVI analogous to the enantiomeric propanols IX and XVII. This approach was used for the synthesis of derivatives of adenine (Ia, IIa), 2,6-diaminopurine (Ib, IIb) and 3-deazaadenine (Ic, IIc). Their guanine counterparts Ie and IIe were prepared by hydrolysis of 2-amino-6-chloropurine intermediates XId and XIXd. 6-Chloropurine was converted into diester XIi by reaction with tosylate X, which on reaction with thiourea and subsequent ester cleavage afforded the 6-thiopurine derivative Ij. Analogously, 2-amino-6-chloropurine derivative XId reacted with thiourea to give 9-(R)-(2-phosphonomethoxypropyl)-2-thioguanine (If), or with dimethylamine under formation of (2-phosphonomethoxypropyl)-2-amino-6-dimethylaminopurine (Ig). Hydrogenolysis of compound XId gave 9-(R)-(2-phosphonomethoxypropyl)-2-aminopurine (Ik). Hydrolytic deamination of adenine derivatives Ia and IIa led to enantiomeric (2-phosphonomethoxypropyl)hypoxanthines Ih and IIh.

Synthesis of Enantiomeric N-(2-Phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases. I. The Stepwise Approach

1995 ◽  
Vol 60 (7) ◽  
pp. 1196-1212 ◽  
Author(s):  
Antonín Holý ◽  
Milena Masojídková
Keyword(s):  
Acid Hydrolysis ◽  
High Activity ◽  
Aluminum Hydride ◽  
Heterocyclic Base ◽  
Stepwise Approach ◽  
Pyrimidine Bases ◽  
Hydrolysis Of ◽  
Derivatives Of ◽  
Very High

The (R)- and (S)-N-(2-phosphonomethoxypropyl) derivatives of purine and pyrimidine bases (PMP derivatives) exhibit very high activity against retroviruses. This paper describes the synthesis of enantiomeric 9-(2-phosphonomethoxypropyl)adenines (I and XXVII), 9-(2-phosphonomethoxypropyl)-2,6-diaminopurines (II and XXXI), 9-(2-phosphonomethoxypropyl)guanines (III and XXIX) and 1-(R)-(2-phosphonomethoxypropyl)cytosine (XIX) by alkylation of N-protected N-(2-hydroxypropyl) derivatives of the corresponding bases with bis(2-propyl) p-toluenesulfonyloxymethylphosphonate (X), followed by stepwise N- and O-deprotection of the intermediates. The key intermediates, N-(2-hydroxypropyl) derivatives IX and XXV, were obtained by alkylation of the appropriate heterocyclic base with (R)- or (S)-2-(2-tetrahydropyranyloxy)propyl p-toluenesulfonate (VII or XXIII) and acid hydrolysis of the resulting N-[2-(2-tetrahydropyranyloxy)propyl] derivatives VIII and XXII. The chiral synthons were prepared by tosylation of (R)- or (S)-2-(2-tetrahydropyranyloxy)propanol (VI or XXI) available by reduction of enantiomeric alkyl 2-O-tetrahydropyranyllactates V and XXI with sodium bis(2-methoxyethoxy)aluminum hydride. This approach was used for the synthesis of cytosine, adenine and 2,6-diaminopurine derivatives, while compounds derived from guanine were prepared by hydrolysis of 2-amino-6-chloropurine intermediates. Cytosine derivative IXe was also synthesized by alkylation of 4-methoxy-2-pyrimidone followed by ammonolysis of the intermediate IXf.

Syntheses of Enantiomeric N-(3-Hydroxy-2-phosphonomethoxypropyl) Derivatives of Purine and Pyrimidine Bases

1993 ◽  
Vol 58 (3) ◽  
pp. 649-674 ◽  
Author(s):  
Antonín Holý
Keyword(s):  
Benzoyl Chloride ◽  
Sodium Hydride ◽  
Cesium Carbonate ◽  
Amino Groups ◽  
Heterocyclic Base ◽  
Pyrimidine Bases ◽  
Derivatives Of ◽  
General Method

Methods of preparation of N-(3-hydroxy-2-phosphonomethoxypropyl) (HPMP) derivatives of (2S)- and (2R)-configuration (compounds I and XXVII, respectively) are described. The general method starts from the corresponding N-(2,3-dihydroxypropyl) derivatives which were converted either into the (R)-enantiomers XIII by reaction of the base with (R)-glycidol butyrate (XII) in the presence of cesium carbonate and subsequent methanolysis, or into the (S)-enantiomers XI by alkylation of the base with (R)-2,2-dimethyl-4-tosyloxymethyl-1,3-dioxolane (V) in the presence of the same reagent. The amino groups on the heterocyclic base in compounds XI and XIII were benzoylated by silylation followed by reaction with benzoyl chloride and the obtained N-benzoates XV and XVII on reaction with trityl chloride afforded the corresponding 3'-O-trityl derivatives XVI and XVIII. These compounds were condensed with bis(2-propyl) p-sulfonyloxymethylphosphonate (XXIII) in dimethylformamide in the presence of sodium hydride to give the fully protected diesters XXIV and XXVIII. These compounds could be selectively acid-hydrolyzed to remove the trityl group only under formation of compounds XXXV, or methanolyzed and then acid-hydrolyzed to remove the trityl and N-benzoyl groups and lead to compounds XXVI and XXX, or treated with bromotrimethylsilane to remove the trityl and 2-propyl group to give phosphonates of the type XXXI. All the three types of compounds were then converted into free phosphonates of the (S)-series (I) and the (R)-series (XXVII). Derivatives of cytosine (Ia, XXVIIa), adenine (Ib, XXVIIb), 2,6-diaminopurine (Ic, XXVIIc) and guanine (Id, XXVIId) were prepared. Condensation of the partially blocked adenine deriavtive XXXV with the tosyl derivative XXIII and subsequent deprotection afforded 9-(S)-(2,3-diphosphonomethoxy propyl)adenine (XLIII). Reaction of the same compound XXXV or its (R)-enantiomer XXXVIII with diethyl phosphonate , followed by deblocking, afforded 3'-O-phosphoryl derivatives (S)-HPMPA (XXXVII) and (R)-HPMPA (XL).

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.

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

1993 ◽  
Vol 58 (7) ◽  
pp. 1645-1667 ◽  
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.

Theoretical Study of the Process of Passage of Glycoside Amides through the Cell Membrane of Cancer Cell

2020 ◽  
Vol 20 ◽  
Author(s):  
Vasil Tsanov ◽  
Hristo Tsanov
Keyword(s):  
Cell Membrane ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Quantum Chemical ◽  
Density Functional ◽  
Enzyme Regulation ◽  
Amide Derivatives ◽  
Pass Through ◽  
Hydrolysis Of ◽  
Derivatives Of

Background:: This article concentrates on the processes occurring in the medium around the cancer cell and the transfer of glycoside amides through their cell membrane. They are obtained by modification of natural glycoside-nitriles (cyano-glycosides). Hydrolysis of starting materials in the blood medium and associated volume around physiologically active healthy and cancer cells, based on quantum-chemical semi-empirical methods, is considered. Objective:: Based on the fact that the cancer cell feeds primarily on carbohydrates, it is likely that organisms have adapted to take food containing nitrile glycosides and / or modified forms to counteract "external" bioactive activity. Cancers, for their part, have evolved to create conditions around their cells that eliminate their active apoptotic forms. This is far more appropriate for them than changing their entire enzyme regulation to counteract it. In this way, it protects itself and the gene sets and develops according to its instructions. Methods:: Derived pedestal that closely defines the processes of hydrolysis in the blood, the transfer of a specific molecular hydrolytic form to the cancer cell membrane and with the help of time-dependent density-functional quantum- chemical methods, its passage and the processes of re-hydrolysis within the cell itself, to forms causing chemical apoptosis of the cell - independent of its non-genetic set, which seeks to counteract the process. Results:: Used in oncology it could turn a cancer from a lethal to a chronic disease (such as diabetes). The causative agent and conditions for the development of the disease are not eliminated, but the amount of cancer cells could be kept low for a long time (even a lifetime). Conclusion:: The amide derivatives of nitrile glycosides exhibit anti-cancer activity, the cancer cell probably seeks to displace hydrolysis of these derivatives in a direction that would not pass through its cell membrane and the amide- carboxyl derivatives of nitrile glycosides could deliver extremely toxic compounds within the cancer cell itself and thus block and / or permanently damage its normal physiology.

Benzyl ethers of methyl α-D-glucopyranoside

1980 ◽  
Vol 45 (7) ◽  
pp. 1959-1963 ◽  
Author(s):  
Dušan Joniak ◽  
Božena Košíková ◽  
Ludmila Kosáková
Keyword(s):  
Kinetic Study ◽  
Spectrophotometric Determination ◽  
Reductive Cleavage ◽  
Ether Bond ◽  
Benzyl Ethers ◽  
Acid Catalyzed ◽  
Model Substances ◽  
Hydrolysis Of

Methyl 4-O-(3-methoxy-4-hydroxybenzyl) and methyl 4-O-(3,5-dimethoxy-4-hydroxybenzyl)-α-D-glucopyranoside and their 6-O-isomers were prepared as model substances for the ether lignin-saccharide bond by reductive cleavage of corresponding 4,6-O-benzylidene derivatives. Kinetic study of acid-catalyzed hydrolysis of the compounds prepared was carried out by spectrophotometric determination of the benzyl alcoholic groups set free, after their reaction with quinonemonochloroimide, and it showed the low stability of the p-hydroxybenzyl ether bond.

Cyclization and acid-catalyzed hydrolysis of O-benzoylbenzamidoximes

1986 ◽  
Vol 51 (12) ◽  
pp. 2786-2797
Author(s):  
František Grambal ◽  
Jan Lasovský
Keyword(s):  
Reaction Rate ◽  
Kinetic Isotope ◽  
Acid Base Equilibrium ◽  
Mineral Acids ◽  
Kinetics Of Formation ◽  
Acid Catalyzed ◽  
Ph Scale ◽  
Kinetics Of ◽  
Hydrolysis Of ◽  
Derivatives Of

Kinetics of formation of 1,2,4-oxadiazoles from 24 substitution derivatives of O-benzoylbenzamidoxime have been studied in sulphuric acid and aqueous ethanol media. It has been found that this medium requires introduction of the Hammett H0 function instead of the pH scale beginning as low as from 0.1% solutions of mineral acids. Effects of the acid concentration, ionic strength, and temperature on the reaction rate and on the kinetic isotope effect have been followed. From these dependences and from polar effects of substituents it was concluded that along with the cyclization to 1,2,4-oxadiazoles there proceeds hydrolysis to benzamidoxime and benzoic acid. The reaction is thermodynamically controlled by the acid-base equilibrium of the O-benzylated benzamidoximes.

The melanocyte stimulating activity of N-nitroso-2-chloroethyl-carbamoyl derivatives of α-melanotropin fragments

1988 ◽  
Vol 53 (11) ◽  
pp. 2574-2582 ◽  
Author(s):  
Hedvig Medzihradszky-Schweiger ◽  
Helga Süli-Vargha ◽  
József Bódi ◽  
Kálmán Medzihradszky
Keyword(s):  
Biological Activity ◽  
Active Site ◽  
Frog Skin ◽  
Terminal Sequence ◽  
Subsequent Reaction ◽  
Affinity Labels ◽  
Derivatives Of

A number of N-nitroso-2-chloroethyl-carbamoyl (Q(NO)) derivatives of α-melanotropin fragments have been synthesized and their effect on the frog skin melanocytes studied. Peptides substituted in this way possess the biological activity of the parent compounds, indicating that they preserved their receptor recognizing ability. These compounds can therefore serve as affinity labels. Some of these derivatives, related to the C-terminal sequence of α-melanotropin show prolonged darkening reaction, which does not influence the subsequent reaction of melanocytes with α-melanotropin. The Q(NO)-derivative of a fragment derived from the classical active site of the hormone shows, however, inhibition of the effect of α-melanotropin. It can be concluded that the latter peptide acts through the melanotropin receptor, while others, related to the C-terminal sequence of the hormone through another mechanism.

scholarly journals Novel Amino Acid Derivatives of Quinolines as Potential Antibacterial and Fluorophore Agents

2020 ◽  
Vol 88 (4) ◽  
pp. 57
Author(s):  
Oussama Moussaoui ◽  
Rajendra Bhadane ◽  
Riham Sghyar ◽  
El Mestafa El Hadrami ◽  
Soukaina El Amrani ◽  
...  
Keyword(s):  
Amino Acid ◽  
Methyl Esters ◽  
Amino Acid Derivatives ◽  
Bacterial Strains ◽  
Fluorescent Properties ◽  
Topoisomerase Iv ◽  
Microdilution Method ◽  
Hydrolysis Of ◽  
Derivatives Of

A new series of amino acid derivatives of quinolines was synthesized through the hydrolysis of amino acid methyl esters of quinoline carboxamides with alkali hydroxide. The compounds were purified on silica gel by column chromatography and further characterized by TLC, NMR and ESI-TOF mass spectrometry. All compounds were screened for in vitro antimicrobial activity against different bacterial strains using the microdilution method. Most of the synthesized amino acid-quinolines show more potent or equipotent inhibitory action against the tested bacteria than their correspond esters. In addition, many of them exhibit fluorescent properties and could possibly be utilized as fluorophores. Molecular docking and simulation studies of the compounds at putative bacterial target enzymes suggest that the antimicrobial potency of these synthesized analogues could be due to enzyme inhibition via their favorable binding at the fluoroquinolone binding site at the GyrA subunit of DNA gyrase and/or the ParC subunit of topoisomerase-IV.

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