Oxidative hydrolysis of a cyclic 1,N-propano-2′-deoxyguanosine, an adduct of 2′-deoxyguanosine with acetaldehyde or crotonaldehyde

The SO₄⁻-oxidation of cyclic 1,N²-propano-2′-deoxyguanosine, chemo- and regioselectively produced in the reaction of 2′-deoxyguanosine with excessive acetaldehyde or crotonaldehyde, resulted in the smooth formation of (4-hydroxy-5-hydroxymethyltetrahydrofuran-2-ylimino)-(4-hydroxy-6-methyltetrahydropyrimidin-2-ylideneamino)acetic acid, 3-(4-hydroxy-5-hydroxymethyltetrahydrofuran-2-yl)-6-methyl-3H-1,3,4,5,8a-pentaazacyclopenta[b]naphthalen-9-one, and 2′-deoxyguanosine even under neutral conditions. The formation of the guanine-ring opened product during the reaction is very interesting and appears to closely relate to the mechanisms for the point-mutations of DNA by these mutagenic and carcinogenic aldehydes.     

Synthesis of 1′-aryl-2′-(2-oxoindolin-3-yl)spiro[indoline-3,5′-pyrroline]-2,3′-dione via one-pot reaction of arylamines, acetone, and isatins

An efficient synthetic method for 1′-aryl-2′-(2-oxoindolin-3-yl)spiro[indoline-3,5′-pyrroline]-2,3′-diones was successfully developed via the one-pot domino reaction of arylamines, acetone, and isatins in acetic acid. The reaction mechanism involved the sequential Michael addition and ring closure of the in situ formed 3-N-aryliminoisatin and isatylidene acetone.     

Synthesis and antimicrobial activity of 10-(5-arylamino-1,3,4-oxadiazol-2-ylmethyl)acridin-9(10<Emphasis Type="Italic">H</Emphasis>)-ones

Intramolecular cyclization of N-aryl-2-[(9-oxoacridin-10(9H)-yl)acetyl]hydrazinecarboxamides afforded new 10-(5-arylamino-1,3,4-oxadiazol-2-ylmethyl)acridin-9(10H)-ones. Some of the synthesized compounds showed a moderate antimicrobial activity against gram-positive and gram-negative bacteria. Keywords: acridone, hydrazide, semicarbazide, 1,3,4-oxadiazole, antibacterial activity     

Chemical and Pharmacological Properties of 3-(Thiophen-2-yl)-4-substituted-Δ 2-1,2,4-triazoline-5-thiones

Three 3-(thiophen-2-yl)-4-substituted-Δ ² -1,2,4-triazoline-5-thiones were synthesized by intramolecular cyclization of 1-(thiophen-2-ylcarbonyl)-4-substituted thiosemicarbazides in alkaline medium. Their effects on the central nervous system (CNS) of mice in some behavioral tests were investigated. All investigated compounds displayed antinociceptive activity. The correlation between the structural features and bioactivity has been discussed.     

Unexpected course of rearrangement of substituted S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides

Three series of S-(1(3H)-isobenzofuranone-3-yl)isothiuronium bromides differing in substitution at the isothiuronium moiety (none, one or two methyl groups) and at the benzene ring were prepared and characterized. These salts were then treated with various bases (acetate, triethylamine, Na₂CO₃) to give either 1-hydroxy-3-oxo-1,3-dihydro-2H-isoindol-2-carbothioamides or the product of S to N isobenzofuranone-3-yl migration, i.e., 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas. If ammonia was used in reaction with N,N′-dimethyl isothiuronium salts then 3-hydroxy-2,3-dihydro-1H-isoindol-1-ones were formed together with 1,3-dimethyl-1-(3-oxo-1,3-dihydro-2-benzofuran-1-yl)thioureas in parallel reaction with the yields increasing with ammonia concentration. The formation of isoindolones takes place in two steps with an aldehyde intermediate, which can be trapped with N,N-dimethylhydrazine.     

H NMR studies on the reductively triggered release of heterocyclic and steroid drugs from 4,7-dioxoindole-3-methyl prodrugs

Hypoxia is a feature of several disease states, including cancer and rheumatoid arthritis. Prodrug systems which, after bioreduction, selectively release active drugs in these tissues may be important in therapy. An improved preparation of 1,2-dimethyl-3-hydroxymethyl-5-methoxyindole-4,7-dione was developed. Mitsunobu coupling with (5-substituted) isoquinolin-1-ones (potent inhibitors of poly(ADP-ribose)polymerase) gave 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and N-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethyl)isoquinolin-1-ones. Similar coupling with the anticancer drug pentamethylmelamine gave its potential prodrug 1,2-dimethyl-3-(N-(4,6-bis(dimethylamino)-1,3,5-triazin-2-yl)-N-methylaminomethyl)-5-methoxyindole-4,7-dione. Treatment of sodium prednisolone hemisuccinate with 3-chloromethyl-1,2-dimethyl-5-methoxyindole-4,7-dione gave an analogous candidate prodrug of the anti-inflammatory drug prednisolone. In a chemical model system for bioreduction, SnCl₂ in CDCl₃/CD₃OD triggered rapid stoichiometric release of isoquinolin-1-ones from the O-linked prodrugs but not from the N-linked analogues. Use of this system allowed the release process to be monitored in situ by ¹H NMR spectroscopy. Diethyl hydrazine-1,2-dicarboxylate was found to reduce Sn^IV to Sn^II, making the overall reductive release catalytic in tin. The reduced (hydroquinone) prodrug may have a short lifetime under these reductive conditions, meaning that only good leaving groups are expelled. Thus 1-(1,2-dimethyl-4,7-dioxo-5-methoxyindol-3-ylmethoxy)isoquinolines and analogues may be useful as reductively triggered prodrugs.     

Facile synthesis of spiro[benzo[e]indole-2,2′-piperidine] derivatives and their transformation to novel fluorescent scaffolds

The reaction of azaheterocyclic enamines with acrylamide was employed for the preparation of novel fluorescent scaffolds possessing a benzo[e]indoline moiety. Reaction of 3-substituted 2-methylidene-1H-benzo[e]indole with acrylamide gave rise to spiro[benzo[e]indole-2,2′-piperidin]-6′-ones. Ring opening reactions of the latter spiro compounds were investigated. Benzo[e]indoline derivatives possessing 2-(3-carbamoylpropyl), 2-[3-(ethoxycarbonyl)propyl] and 2-(4-aminobutyl) side chains were synthesised. The optical properties of the benzo[e]indoline derivatives were studied by UV-vis and fluorescence spectroscopy.     

Stepwise solid phase synthesis of uridylylated viral genome-linked peptides using uridylylated amino acid building blocks

The uridylylated amino acid building blocks 2-cyanoethyl-(N^α-9-fluorenylmethoxy-carbonyl-tyrosin-4-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate and 2-chlorophenyl-(N^α-fluorenyl-methoxycarbonyl-serin-3-yl)-(2′,3′-di-O-acetyluridin-5′-yl) phosphate have been used successfully in an on-line SPPS of the VPgpU from the polio, coxsackie and cowpea mosaic virus.     

Chemistry of N-functionalized spirodihydroquinolines. Unusual access to the 3-methyl-4-(2-oxo-pyrrolidinyl-1)spiro[indane-1,1′-cyclohexanes] from 1-(3-cyanopropyl)-3,4-dihydrospiro[quinoline-2,1′-cyclohexanes]

The transformation of N-substituted 3,4-dihydrospiro[quinoline-2,1′-cyclohexanes] 2 and 3 has been examined in strong acid media, at elevated temperature. It was demonstrated that the N-(γ-cyanopropyl) spirodihydroquinolines 2 in the presence of concentrated sulfuric acid or PPA underwent hydrolysis affording the γ-aminoacids 3. The spirodihydroquinoline ring rearrangement readily produces 4-(2-oxopyrrolidinyl-1)spiro[indane-1,1′-cyclohexanes] 5 in good yields. The structures of all synthesized compounds were established by means of homonuclear and inverse-detected 2D NMR experiments.     

Reactivity of 3H-1,2,4-dithiazole-3-thiones and 3H-1,2-dithiole-3-thiones as sulfurizing agents for oligonucleotide synthesis

The reactivity of 5-amino-3H-1,2,4-dithiazole-3-thiones substituted at their amino group and 5-amino-3H-1,2-dithiole-3-thiones substituted at their amino group and C4 toward compounds containing P(III) atoms has been studied. N,N-Disubstituted-N′-(3-thioxo-3H-1,2,4-dithiazol-5-yl)methanimidamides were selected as novel efficient sulfur transfer reagents suitable for DNA and RNA synthesis.     

Simple construction of fused and spiro nitrogen/sulfur containing heterocycles by addition of thioamides or thioureas on cycloalkenyl-diazenes: examples of click chemistry

New 1-cycloalkenyl-1-diazenes have been obtained in good yields from cyclic β-ketoesters and hydrazine derivatives. They furnished new cycloalkyl[d][1,3]thiazolines with thioamides or new spirocycloalkyl-thiazolinones with thioureas. Moreover they gave, with imidazolidine-2-thione and tetrahydropyrimidine-2-thione, new and interesting spiro[cycloalkyl-1,2′-imidazo[2,1-b][1,3]thiazole] or spiro[cycloalkyl-1,2′-[1,3]thiazolo[3,2-a]pyrimidine] derivatives, respectively. Cycloalkyl[d][1,3]thiazolines were useful for the further preparation of unknown thia-triaza-tricyclo derivatives. Novel hexahydro-1,3-benzothiazoles have been achieved by reaction of N,N′-dialkylthioureas on N-1-phenyl-2-(1-cyclohexenyl)-1-diazene-1-carboxyamide. The acidic hydrolysis of spirocycloalkyl-thiazolinones produced 2-imino-5-(ω-carboxyalkyl)-4-thiazolidinones.     

A convenient and efficient method for the synthesis of mono- and N,N-disubstituted thioureas

A convenient method for the synthesis of mono- and N,N-disubstituted thioureas by the debenzoylation of N-substituted- and N,N-disubstituted-N′-benzoylthioureas with hydrazine hydrate under solvent-free conditions has been developed. N-Substituted-N′-benzoylthioureas and hydrazine hydrate were mixed, and stirred at room temperature without a solvent to give the corresponding N-substituted thioureas in high yields.     

Synthesis, structure, and isomerism of N-2,4-dinitrophenylbenzotriazoles

Both isomers of N-(2′,4′-dinitrophenyl)benzotriazole, the 1(3)- and the 2-substituted, have been characterized and their reciprocal isomerism was studied. Cross-experiments in the presence of 5(6)-nitro-1H-benzotriazole proved that the isomerization of 2-(2′,4′-dinitrophenyl)-2H-benzotriazole into the 1-isomer occurs by an intermolecular mechanism. The reported reaction of 5(6)-nitro-1H-benzotriazole with 1-chloro-2,4-dinitrobenzene has been reexamined discovering that there is an error in the proportions of N-substituted isomers. A possible explanation for the observed isomerizations was proposed. Identification of all compounds by multinuclear magnetic resonance, including solid-state studies, has been achieved.     

Synthesis and pharmacological properties of 3-(2-methyl-furan-3-yl)-4-substituted-Δ<Superscript>2</Superscript>-1,2,4-triazoline-5-thiones

By the reaction of 2-methyl-furan-3-carboxylic acid hydrazide with isothiocyanates, 1-[(2-methyl-furan-3-yl)carbonyl]-4-substituted thiosemicarbazides 1 were obtained. Further cyclization with 2% NaOH led to the formation of 3-(2-methyl-furan-3-yl)-4-substituted-Δ²-1,2,4-triazoline-5-thiones 2. The pharmacological effects of 2 on the central nervous system in mice were investigated. Strong antinociceptive properties of the investigated derivatives were observed in a wide range of doses.      

A general and efficient route to 3′-deoxy-3′-N-, S-, and C-substituted altropyranosyl thymines from 2′,3′-O-anhydro-mannopyranosylthymine

An efficient route to 1-(2,3-O-anhydro-4,6-O-phenylmethylene-β-d-mannopyranosyl) thymine from 1,2,4,6-tetra-O-acetyl-3-O-tosyl-β-d-glucopyranose has been devised. This newly synthesized epoxide is opened up regioselectively at the C-3′-position by N-, S-, and C-nucleophiles to afford a wide range of new 3′-deoxy-3′-substituted altropyranosyl thymines.     

Determination of the second-order H NMR parameters for the aromatic protons in 4-fluoroaniline and application to the analysis of the H NMR spectra for the aromatic protons in N-(4′-fluorophenyl)succinamic acid and in N-(4′-fluorophenyl)-3,3-difluorosuccinamic acid

Four studies of the ¹H NMR spectrum for the aromatic protons of 4-fluoroaniline between 1958 and 1974 give three very different solutions to the second-order, AA′BB′X, spectrum. A re-evaluation of the second-order spectrum was done at 300 MHz. Simultaneous simulations of the ¹H NMR spectrum and ¹⁹F NMR spectrum for 4-fluoroaniline were done using WINDNMR-Pro, and a new set of parameters for the six coupling constants was obtained from the optimized simulations. This new set of parameters was used as a basis to evaluate the AA′BB′X spectrum for the aromatic protons in N⁴-(4′-fluorophenyl)succinamic acid and in N⁴-(4′-fluorophenyl)-3,3-difluorosuccinamic acid by simultaneous simulations of the ¹H NMR spectrum and ¹⁹F NMR spectrum for each using WINDNMR-Pro. Formation of the amide bond results in small, but significant, changes in the values for the set of parameters in both molecules. These results confirm that second-order analyses as an AA′BB′X system are required for derivatives of 4-fluoroaniline, rather than first-order analyses that have been used in previous reports.     

N-(acridin-9-yl)arenesulfonamides: Synthesis,quantum chemical studies and crystal structure analysis to establish the tautomeric preferences

The potentiality of the N-(acridin-9-yl)arenesulfonamide moiety as a hybrid pharmacophore due to the distinct pharmacological activities of acridines and aryl/heteroaryl sulfonamides prompts to synthesise N-(acridin-9-yl)arenesulfonamides and study their structural properties. Various N-(acridin-9-yl)arene/heteroarenesulfonamides were obtained through the development of a new methodology adopting the Pd₂(dba)₃-catalyzed CN bond formation strategy for the reaction of 9-chloloroacridine with arene/heteroarenesulfonamides. The 1H and ¹³C NMR spectra suggest these N-(acridin-9-yl)arene/heteroarenesulfonamides to exist solely as the sulfonimide tautomer rather than anticipated sulfonamide form and was confirmed by the single crystal XRD analysis of one of the newly synthesized compounds. The quantum chemical studies rationalized this tautomeric preference revealing that the sulfonimide tautomers are more stable than the sulfonamide tautomers by ?0.67 to ?5.12?kcal/mol in the gas phase. In the solid state, the sulfonimide tautomer is stabilized by intermolecular hydrogen bond between NH?OS and π? π stacking between the acridine rings.     

Synthesis of 4′-substituted 2,2′:6′,2″-terpyridines via a Mitsunobu reaction

Treatment of 2,6-di(pyridin-2-yl)pyridin-4(1H)-one with various appropriately protected ω-substituted primary alcohols or a nucleoside (3,3′-O-diBz-dUrd) in dry THF in the presence of triphenylphosphine and diisopropylazodicarboxylate gives the corresponding 4′-substituted terpyridines in high yield.     

A new series of potentially hexadentate ligands derived from 2,2′-bipyridine

Reaction of 2,2′-bipyridine-6-carboxaldehyde with the appropriate aliphatic diamine in MeOH and subsequent reduction with NaBH₄ gives the new, potentially hexadentate, ligands N,N′-bis(2,2′-bipyridin-6-ylmethyl)ethane-1,2-diamine (bmet), N,N′-bis(2,2′-bipyridin-6-ylmethyl)propane-1,3-diamine (bmpp) and N,N′-bis(2,2′-bipyridin-6-ylmethyl)hexane-1,6-diamine (bmhx). The syntheses and characterisation of these ligands are reported; the ligands are isolated as the hydrochloride salts, with purification effected by either recrystallisation or cation exchange chromatography. [Co(bmet)](ClO₄)₃ · H₂O is obtained on reaction of bmet · 4.25HCl · 2.5H₂O with Na₃[Co(O₂CO)₃] · 3H₂O, and X-ray structural analysis shows this to have a pair of very short Co–N bonds. The synthesis and characterisation of the first coordination complex containing 6-(aminomethyl)-2,2′-bipyridine (amb) is also described.     

Novel four-component route to the synthesis of spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives

An effective route to spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives is described. This involves reaction of isatin, 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, and benzylamine derivatives or aliphatic amines in the presence of alkyl acetoacetate (1,3-dicarbonyl compounds) in dry methanol under reflux conditions. The reactive 1:1 enaminone, which is obtained from the addition of the amine to 1,3-dicarbonyl compound, adds to the α,β-unsaturated ketone, which is formed from the reaction of isatin and 1-phenyl-2-(1,1,1-triphenyl-λ⁵-phosphanylidene)-1-ethanone, to produce the alkyl 1′-benzyl-2′-methyl-2-oxo-6′-phenyl-1′H-spiro[indoline-3,4′-pyridine]-3′-carboxylate derivatives in excellent yields.