Thio Analogues Research Articles

Synthesis of ferrocenyl conjugates of thio analogs of hydroxyl-containing biomolecules via the Mitsunobu reaction with N-(ethoxycarbonyl)ferrocenecarbothioamide as the pronucleophile

A new method for attachment of a ferrocenyl moiety to hydroxyl-containing biomolecules is reported, based on the Mitsunobu reaction with N-(ethoxycarbonyl)ferrocenecarbothioamide. The reaction results in the replacement of the OH group with a (ferrocenyl)thioimidoyl moiety. Using this method, ferrocenyl conjugates of cholesterol, stigmasterol, as well as protected and nonprotected adenosine and 2′-deoxy adenosine were obtained in high yield and with high chemo- and stereoselectivity.

ChemInform Abstract: Synthesis of Azoles from 3‐[(3‐Hydrazino‐3‐oxopropyl)anilino]‐ and 3‐[(3‐Hydrazino‐3‐oxopropyl)‐4‐methylanilino]propane Hydrazides.

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Complexes of telomeric oligonucleotides with the PGEk protein vector: Internalization by target cells and antiproliferative activity

Recombinant protein PGEk, consisting of the human epidermal growth factor (hEGF) and a DNA-binding domain, proved to be capable of interacting with the hEGF receptor and inducing cell proliferation, as characteristic of hEGF. PGEk complexes with the telomere-mimic oligonucleotide d(TTAGGG)4 (TMO) and its thio analog (TMS) were efficiently and selectively internalized by cells with a high-level expression of the hEGF receptors. The extent of internalization was studied as a function of the PGEk: oligonucleotide ratio in the complex. The intracellular location of the oligonucleotides was determined. PGEk was found to ensure a more efficient delivery of the oligonucleotides and to protect them from nuclease degradation. The oligonucleotides contained in the complexes exerted a far greater cytotoxic effect as compared with the free oligonucleotides.

Studies of the Synthesis of Diethyl Cyclopropylphosphonate and Its Thio and Seleno Analogs

Two methods for the synthesis of unsubstituted diethyl cyclopropylphosphonate are described. One method is a reaction between cyclopropylmagnesium bromide and diethyl chlorophosphite to give diethyl cyclopropylphosphonite, followed by oxidation with sodium periodate to the corresponding phosphonate. Alternatively, diethyl cyclopropylphosphonite was reacted with elemental sulfur or selenium to give the thio and seleno analogs, respectively. The second method involves exclusive 1,3‐elimination of HBr from diethyl 3‐bromopropylphosphonate. This method can be directed to either the 1,2‐ or the 1,3‐elimination reaction, leading to propenylphosphonate or cyclopropylphosphonate, depending on the solvent used.

Crystal Structure of a Cyclohexylammonium Salt of the N-(2,2-Difluoro-2-phosphonoethanethioyl)aspartate: A Difluorinated N-(Phosphonoacetyl)-L-aspartate (PALA) Thio Analogue

The title compound, a cyclohexylammonium salt of N-(2,2-difluoro-2-phosphonoethanethioyl)aspartate, {(C6H4F2NO7PS)4-. 4[(C6H11-NH3)+]} crystallizes in the triclinic space group P1 with the following cell parameters: a = 11.335(2)A, b = 12.849(3)A, c = 14.353(3)A, α = 83.14(3)°, β = 86.75(3)°, γ = 84.81(3)°, V = 2064.7(7)A3, Z = 1 and Dx = 1.184 g cm-3. The structure was refined to a final R value of 0.0745 for 5790 reflections [I>2σ(I)]. This structure consists of two anionic N-(2,2-difluoro-2-phophonoethanethioyl)aspartate moieties and eight cationic cyclohexylammonium entities; among them, three are disordered. In addition, one water and one ethanol molecules are present. X-ray analysis shows that it possesses a sandwich-type layer structure, consisting of mutually stacking polar layers with an important hydrogen-bonding network and hydrophobic layers consisting of disordered cyclohexyl parts of cationic moieties.

Solvent extraction of silver from nitric acid solutions by calix[4]arene amide derivatives

Solvent extraction experiments were carried out to recover silver from nitric acid solutions using as the extractants calix[4]arene tetramide (LBC) and its thio-analogue (THIO) dissolved in dichloromethane. The stoichiometry of the formation of the silver-calixarene complex differs depending on the used extractant. It was shown that one silver ion reacts with a single molecule of LBC, while two silver ions are extracted with a single THIO molecule. Very high percent extractions (>90% with LBC and >99% with THIO) were achieved with both extractants by just adding surplus extractant (THIO: 0.6 mol/mol Ag + and LBC: 1.4–1.5 mol/mol Ag +). Based on equilibrium data, the extraction isotherm relationship and the extraction constant K ex for each extractant were derived. The extraction results show that THIO is an efficient extractant extracting silver either from acid or from neutral solutions with the same efficiency. Nitric acid, in the concentration range from 0 to 0.1 mol dm −3, strongly affects the extraction capability of LBC in less acidic solutions, reducing the percent extraction down to 40%. LBC extracts both silver and sodium collectively and with the same efficiency. The selectivity coefficient has a value close to unity ( β ≈ 1). THIO has demonstrated extremely high selectivity for silver over sodium in a mixture. Stripping of silver was performed by two-phase electrowinning from the loaded organic phase, thereby achieving a high stripping degree (50–90%) and reasonably high current efficiency (60–90%). The calixarenes did not change their extraction features during the electrowinning process and can be reused for extraction many times.

Reaction of thio and seleno phosphoric acid derivatives with O‐thioacylated hydroxylamine

AbstractThe reactivity of thio and seleno analogs of phosphoric acid 1b–f with O‐thioacylhydroxylamine 2 was examined. The experimental evidence for the proposed mechanism involving an N—O bond cleavage and a single electron transfer process (SET) from phosphate anions was collected. The influence of phosphoric acids 1 structure and their oxidation potentials on the course of the reaction and products 3, 4, 6, 7 distribution was presented. © 2007 Wiley Periodicals, Inc. Heteroatom Chem 18:767–773, 2007; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20368

Quantum-chemical study of the structure and reactivity of pyrazol-5-ones and their thio and seleno analogs: X. 1-methylpyrazol-5-one and its thio and seleno analogs in H-complex formation reactions in the gas phase and in solutions

The effects of specific solvation and self-association of chalcogenpyrazol-5-ones are assessed using nonempirical quantum-chemical, density functional theory (DFT), and MP2 second-order perturbation theory methods. The formation of H-complexes with water, methanol, and DMSO stabilizes all tautomeric forms, the NH tautomers of all hetero analogs being the most affected. The NH tautomers form with water 1:2 complexes which reveal cooperativity. The complexes of chalcogenpyrazolones with DMSO are more stable than the respective complexes with water, and, therewith, the extra stabilization in continuum is less pronounced than in the case of hydration. Quantitatively, the effects of tautomer self-association compare with the effects of interaction of chalcogenpyrazolones with proton-donor solvents.

Synthesis of azoles from 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides

Condensation of 3-[(3-hydrazino-3-oxopropyl)anilino]-and 3-[(3-hydrazino-3-oxopropyl)-4-methylanilino]propane hydrazides with 2,4-pentanedione, phenyl isocyanate or phenyl isothiocyanate (with subsequent work up of the semicarbazides obtained by base), and carbon disulfide gave respectively: 1-(3,5-dimethyl-1H-1-pyrazolyl)-3-[3-(3,5-dimethyl-1H-1-pyrazolyl)-3-oxopropylanilino]-1-propanone, 3-(2-{[2-(5-oxo-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-3-yl)ethyl]anilino}ethyl)-4-phenyl-4,5-dihydro-1H-1,2,4-triazol-5-one and its thio analog, and 5-(2-{[2-(2-thioxo-2,3-dihydro-1,3,4-oxadiazol-5-yl)ethyl]anilino}ethyl)-2,3-dihydro-1,3,4-oxadiazole-2(3H)-thione plus their methyl derivatives.

Syntheses of the 3- and 4-thio analogues of 4-nitrophenyl 2-acetamido-2-deoxy-β- d-gluco- and galactopyranoside

The syntheses of 4-nitrophenyl β-glycosides of the 3-thio and 4-thio analogues of the two principal 2-acetamido-2-deoxy-hexoses found in living systems, GlcNAc and GalNAc, are described. While synthesis of the 4-thio analogues could be achieved via nucleophilic displacements of sulfonate derivatives with thioacetate, problems with neighbouring group acetamido participation necessitated the use of sulfamidate intermediates for the 3-thio analogues. These 3- and 4-thio analogues are employed in the chemo-enzymatic synthesis of thio-oligosaccharide analogues of structures present in glycosaminoglycans, glycoproteins and glycolipids.

Structure−Activity Relationship of Uridine 5‘-Diphosphoglucose Analogues as Agonists of the Human P2Y14 Receptor

UDP-glucose (UDPG) and derivatives are naturally occurring agonists of the Gi protein-coupled P2Y14 receptor, which occurs in the immune system. We synthesized and characterized pharmacologically novel analogues of UDPG modified on the nucleobase, ribose, and glucose moieties, as the basis for designing novel ligands in conjunction with modeling. The recombinant human P2Y14 receptor expressed in COS-7 cells was coupled to phospholipase C through an engineered Galpha-q/i protein. Most modifications of the uracil or ribose moieties abolished activity; this is among the least permissive P2Y receptors. However, a 2-thiouracil modification in 15 (EC50 49 +/- 2 nM) enhanced the potency of UDPG (but not UDP-glucuronic acid) by 7-fold. 4-Thio analogue 13 was equipotent to UDPG, but S-alkylation was detrimental. Compound 15 was docked in a rhodposin-based receptor homology model, which correctly predicted potent agonism of UDP-fructose, UDP-mannose, and UDP-inositol. The hexose moiety of UDPG interacts with multiple H-bonding and charged residues and provides a fertile region for agonist modification.

Cyano substituent effects on enol and enethiol acidity and basicity: The protonation and deprotonation of 3-hydroxy-2-propenenitrile and its thio analogue

The gas-phase basicity and acidity of 3-hydroxy-2-propenenitrile (3-hydroxyacrylonitrile) and its sulfur-containing analogue, 3-mercapto-2-propenenitrile, have been determined by means of high-level G3B3 ab initio calculations and, in the case of the latter compound, compared with the experimental values obtained by means of FT-ICR mass spectrometry techniques, and with previous reported values for the N C–CH CH–X (X = CH 3, NH 2, SiH 3, PH 2) analogues. For both compounds the Z-isomer is the dominant species in the gas-phase. Protonation takes place in both cases at the cyano group. The loss of the proton from the substituent, was found to be systematically much more favorable than the deprotonation at the HC CH group. 3-Hydroxy-2-propenenitrile is predicted to be a stronger base by ca. 5 kJ mol −1 than its thio analogue, but a weaker acid by 26 kJ mol −1. Both compounds are stronger acids than the corresponding unsubstituted vinyl compounds, because cyano substitution stabilizes much more the deprotonated species than the corresponding neutral compound. There is a clear disagreement between our theoretical estimates for both the gas-phase basicity and the gas-phase acidity of 3-mercapto-2-propenenitrile and the corresponding experimental values, which is consistent with its isomerization to yield isothiazole.

Synthesis of 4-Aryl-3(5)-(2-hydroxyphenyl)pyrazoles by Reaction of Isoflavones and their 4-Thio Analogues with Hydrazine Derivatives

4-Aryl-3(5)-2-(hydroxyphenyl)pyrazoles have been prepared by the reaction of isoflavones and their 4-thio analogues with hydrazine hydrate and phenylhydrazine in hot pyridine. The reaction mechanism for the formation of these pyrazoles is discussed. All the new compounds have been fully characterized by NMR spectroscopy. In [D6]DMSO, a 1H NMR study allows observation of the presence of both pyrazole annular tautomers, due to the presence of intramolecular hydrogen bonds in each tautomer (OH···N and NH···O). Theoretical calculations have been carried out on tautomers and conformers of compounds 20 (3(5)-(2-hydroxy-4-methoxyphenyl)-5(3)-methyl-4-phenylpyrazole) and 21 (3(5)-(2-hydroxy-4-methoxyphenyl)-4-(2-methoxyphenyl)-5(3)-methylpyrazole), including the absolute shieldings (GIAO/B3 LYP/6–311++G**) of 21.

Thio analogs of pyrimidine bases: Syntheses and EIMS study of new ortho‐(meta‐ and para‐)bromobenzyl s‐mono and S‐N‐1‐disubstituted 5‐morpholinomethyl(5‐piperidinomethyl)‐2‐thiouracils

Abstractmagnified imageEleven new ortho‐(meta‐ and para‐)bromobenzyl S‐mono and S‐N‐1‐disubstituted derivatives of 5‐morpholinomethyl‐2‐thiouracil (MMTU) and 5‐piperidinomethyl‐2‐thiouracil (PMTU) have been prepared and their EI induced mass spectral fragmentation has been investigated. It has been shown that the data derived from EIMS spectra can be used to differentiate the isomers

Synthesis and Anti-Human Immunodeficiency Virus Activity of 4‘-Branched (±)-4‘-Thiostavudines

Motivated by our recent finding that 4'-ethynylstavudine (4) is a promising anti-human immunodeficiency virus type 1 (HIV-1) agent, we synthesized its 4'-thio analogue, as well as other 4'-thiostavudines having a carbon substituent at the 4'-position, as racemates in this study. Methyl 3-oxo-tetrahydrothiophen-2-carboxylate (5) was used as a starting material to construct the requisite 4-thiofuranoid glycal (13). Introduction of a thymine base was carried out by an electrophilic addition reaction to 13 using N-iodosuccinimide (NIS) and bis(trimethylsilyl)thymine. The desired beta-anomer (16beta) obtained as a major product in this reaction underwent ready elimination with activated Zn to give the 4'-carbomethoxy derivative (18). By using 18 as a common intermediate, 4'-carbon-substituted (CH2OH, CO2Me, CONH2, CH=CH2, CN, and C(triple bond)CH) 4'-thiostavudines were prepared. Among these six compounds, 4'-cyano (28) and 4'-ethynyl (29) analogues were found to show inhibitory activity against HIV-1 with ED50 values of 7.6 and 0.74 microM, respectively. The activity of 29 was comparable to that of stavudine, but 29 was not as active as 4. Optical resolution of 29 was briefly examined.

Effects of atom pairs O and S on the stability of zwitterionic tetrahedral intermediate: A theoretical study

Ab initio and DFT studies have been carried out on the structure and stability of the zwitterionic complexes formed in water in the aminolysis of phenyl acetate, CH 3C( O)–OAr (O, O), and its thio analogues (O, S), (S, O) and (S, S) with ammonia by explicitly solvating 0–5 water molecules. Formation of the zwitterionic tetrahedral structure in water was found to be more facile and more stable for the thio derivatives in the order (O, O) < (O, S) < (S, O) < (S, S). This is in good agreement with the experimental rates of the aminolysis in water, which indicates that the proclivity to form, and the stability of, the zwitterionic intermediate constitute major factors in determining the reaction rate.

Identification of the novel thio‐arsenosugars DMThioAsSugarCarboxyl, DMThioAsSugarCarbamate and DMThioAsSugarAdenine in extracts of giant clam tissues by high‐performance liquid chromatography online with electrospray tandem mass spectrometry

Recently, the identification of four thio-arsenosugars in extracts of marine samples was reported. The biosynthesis of these arsenic species is most likely closely related to the well known oxo-arsenosugars. Due to their symbiotic algae giant clams contain oxo-arsenosugars with Carboxyl-, Carbamate- and Adenine-aglycone in significant amounts. Now we provide evidence for the presence of the thio analogues of these three arsenosugars in tissue extracts of the giant clams Tridacna maxima and Tridacna derasa. Anion-exchange high-performance liquid chromatography (HPLC) online with electrospray tandem mass spectrometry was applied for the identification of the thio-arsenosugars and the indirect quantification via their oxo analogues.

Efficient Syntheses of Thiono and Dithio Analogues of Tetronic Acid

Thiono and dithio lactone analogues of 4-hydroxyfuran-2(5H)-one (tetronic acid) were synthesized in three steps from tetronic acid and thiolotetronic acid. Their usefulness in pharmacomodulation were exemplified by the synthesis of thio analogues of 4-aza-2,3-didehydropodophyllotoxins.

Synthesis of ethriolophospholipids of acetal type

New analogues of acetal-type phospholipids were obtained on the basis of ethriol (2-hydroxymethyl-2-ethyl-1,3-propanediol). The starting triol originally was condensed with decanal or dodecanal to form acetals, which were then phosphorylated with tetraethyldiamidophosphorous acid chloride. The amidophosphites were further oxidized with iodosobenzene or sulfurized to the corresponding acetal-type phospholipids and their thio analogues.

Structure-activity relationships of uridine 5'-diphosphate analogues at the human P2Y6 receptor.

The structure-activity relationships and molecular modeling of the uracil nucleotide activated P2Y6 receptor have been studied. Uridine 5'-diphosphate (UDP) analogues bearing substitutions of the ribose moiety, the uracil ring, and the diphosphate group were synthesized and assayed for activity at the human P2Y6 receptor. The uracil ring was modified at the 4 position, with the synthesis of 4-substituted-thiouridine 5'-diphosphate analogues, as well as at positions 2, 3, and 5. The effect of modifications at the level of the phosphate chain was studied by preparing a cyclic 3',5'-diphosphate analogue, a 3'-diphosphate analogue, and several dinucleotide diphosphates. 5-Iodo-UDP 32 (EC50 = 0.15 microM) was equipotent to UDP, while substitutions of the 2'-hydroxyl (amino, azido) greatly reduce potency. The 2- and 4-thio analogues, 20 and 21, respectively, were also relatively potent in comparison to UDP. However, most other modifications greatly reduced potency. Molecular modeling indicates that the beta-phosphate of 5'-UDP and analogues is essential for the establishment of electrostatic interactions with two of the three conserved cationic residues of the receptor. Among 4-thioether derivatives, a 4-ethylthio analogue 23 displayed an EC50 of 0.28 microM, indicative of favorable interactions predicted for a small 4-alkylthio moiety with the aromatic ring of Y33 in TM1. The activity of analogue 19 in which the ribose was substituted with a 2-oxabicyclohexane ring in a rigid (S)-conformation (P = 126 degrees , 1'-exo) was consistent with molecular modeling. These results provide a better understanding of molecular recognition at the P2Y6 receptor and will be helpful in designing selective and potent P2Y6 receptor ligands.