Synthesis and biological activity of α-alkylacrolein dimers and their derivatives

Dimers of methacrolein and α-ethylacrolein have been obtained and undergo a Cannizzaro reaction to the corresponding pyran alcohols and sodium salts of pyran acids. Their bacteriostatic, bactericidal, and fungicidal properties have been studied. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1639–1644, November, 2008.     

Synthesis of 4′-substituted 2′-deoxy-4′-thiocytidines and its evaluation for antineoplastic and antiviral activities

4′-Azido- (7), 4′-C-fluoromethyl- (8) 4′-C-ethynyl- (9) and 4′-C-cyano- (10) 2′-deoxy-4′-thiocytidines have been synthesized. In this study, it was found that the isolated yield of 4′-thiouracil nucleoside 13 in a Lewis acid-promoted Vorbrüggen-type glycosidation utilizing 12 was better than that of the electrophilic glycosidation reaction between silylated uracil and 11. This improved result prompted us to perform the glycosidation utilizing 36 and 43 for the synthesis of 37 and 44. Introduction of the azido group was carried out by nucleophilic substitution in the 4′-benzoyloxy derivative 22a. On the other hand, 9 and 10 were synthesized by way of the chemical manipulation of the hydroxymethyl group at the 4′-position of 46.Evaluation of the antineoplastic activity of 2 and 7–10 against human B-cell (CCRF-SB) and T-cell leukemia (Molt-4) cell lines revealed that 4′-azido- (7) and 4′-C-fluoromethyl- (8) derivatives exhibited cytotoxic activity whereas no cytotoxicity was observed in the 4′-C-ethynyl- (9) and 4′-C-cyano- (10) derivatives as well as the parent compound 2. Compound 7 was also found to possess promising antiviral activity against VZV and HSV-1 without any cytotoxity against HEL host cells. It is noteworthy that 7 exhibited potent inhibitory activities against the thymidine kinase-deficient (TK^?) mutant of VZV and HSV-1.     

Synthesis of 2-O-ethyl analogues of 3′-azido- and 3′-fluoro-2′,3′-dideoxyuridines and evaluation of their biological activity against HIV

Summary 2-O-Ethyluracil and 2-O-ethylthymine were silylated with 1,1,1,3,3,3-hexamethyldisilazane and condensed in the presence ofTMS triflate with 2,3-dideoxy-3-fluoro-D-erythro-pentofuranoside, 3-azido-2,3-dideoxy-D-erythro-pentofuranoside, and 2,3-dideoxy-3-phthalimido--D-erythro-pentofuranose derivatives to give the corresponding 2-O-ethyl nucleosides. Deprotection with saturated methanolic ammonia afforded the 2,3-dideoxy-3-fluoro-2-O-ethyluridines, whereas 3-azido-2,3-dideoxy-3-O-ethyluridine was obtained by deprotection with tetrabutylammonium fluoride in tetrahydrofuran. 3-Amino-2,3-dideoxy-3-O-ethyluridine could be obtained only by treatment of the corresponding 3-azido nucleoside with triphenylphosphine in pyridine. 3-Deoxy-2-O-ethyl-3-fluorothymidine (6b) showed moderate activity against HIV-1.

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Synthese von 2-O-Ethyl-Analogen von 3-Azido- und 3-Fluor-23-dideoxyuridinen und Bestimmung ihrer biologischen Aktivität gegenüber HIV

Zusammenfassung 2-O-Ethyluracil und 2-O-Ethylthymin wurden mit 1,1,1,3,3,3-Hexamethyldisilazan silyliert und in Gegenwart vonTMS-triflat mit 2,3-Dideoxy-3-fluoro-D-erythro-pentofuranosid, 3-Azido-2,3-dideoxy-D-erythro-pentofuranosid und 2,3-Dideoxy-3-phthalimido--D-erythro-pentofuranosederivaten zu den entsprechenden 2-O-Ethyl-Nucleosiden umgesetzt. Entfernung der Schutzgruppe mit gesättigter methanolischer Ammoniaklösung lieferte 2,3-Dideoxy-3-fluor-2-O-ethyluridin; 3-Azido-2,3-dideoxy-3-O-ethyl-uridin wurde durch Entschützung mit Tetrabutylammoniumfluorid in Tetrahydrofuran erhalten. 3-Amino-2,3-dideoxy-3-O-ethyl-uridin konnte nur durch Behandeln des entsprechenden 3-Azido-Nucleosids mit Triphenylphosphin in Pyridin hergestellt werden. 3-Deoxy-2-O-ethyl-3-fluor-thymidin (6b) zeigt geringe Aktivität gegenüber HIV-1.

     

Synthesis and biological activity of new avermectin 5-O- and 4″-O-acyl derivatives

Acylation of avermectin B₁ with vicinal 1,2-dicarboxylic acid anhydrides leads only to 5-O-acyl derivatives in high yields. Avermectin 4″-O-acyl derivatives were obtained under similar conditions from avermectin B₁ 5-O-TBS-derivatives in good yields. The compounds obtained are of interest as antiparasitic agents.     

Synthesis of 4-mono- and dialkyl-2′-deoxycytidines and their insertion into an oligonucleotide

Starting with 4-thio-2′-deoxyuridine, the simple synthesis of N⁴-mono- and dialkyl-2′-deoxycytidines is described. The N⁴-methyl derivative has been incorporated into the oligonucleotide chain d(CGm⁴CGCG).     

Synthesis of 2,3′,4′-tricyanobiphenyl derivatives and tetraphenylphthalocyanines based thereon

The nitration of 2,3′,4′-tricyanobiphenyl with subsequent transformations of the obtained product provided 4-X-2,3′,4′-tricyanobiphenyls (X = NO₂, NH₂, NHCOCH₃, Br, I). The condensation of the initial biphenyl or its 4-X-derivatives (X = NO₂, NHCOCH₃, Br, I) in the presence of zinc acetate afforded the corresponding zinc complexes of tetra(4-X-2-cyanophenyl)phthalocyanines.     

New nucleoside analogues and their 5′-triphosphates: Synthesis and biological properties

Bicyclic furano-and pyrrolo[2,3-d]pyrimidine nucleosides and purine nucleosides modified at the N¹ atom and/or the 6-position have been synthesized. Among the tested nontoxic bicyclic nucleosides and N⁶-carboxyalkyladenosines, only furo[2,3-d]pyrimidine with the C₁₀H₂₁ substituent and N⁶-carboxymethyladenosine exhibit moderate anti-HCV activity in the virus replicon system and N¹-hydroxyinosine exhibits high anti-HCV activity and significant cytotoxicity. The corresponding 5′-triphosphates have been synthesized and studied as substrates/inhibitors of HCV enzymes: NS5B protein (RNA-dependent RNA polymerase) and NS3 protein (NTP-dependent RNA helicase).     

A straightforward and efficient synthesis of praziquantel enantiomers and their 4′-hydroxy derivatives

A new method for the synthesis of praziquantel enantiomers via resolution of praziquanamine with (S)-(+)-naproxen was developed. The four 4′-hydroxy derivatives were obtained through each single praziquanamine enantiomer, coupling with cis- and trans-4-(benzyloxy)cyclohexanecarboxylic acids and subsequent hydrogenolysis for the deprotection of the 4′-OH cyclohexane residue. Additionally, the in vitro cysticidal activity of the compounds was tested, finding that (R)-(−)-praziquantel is the eutomer.     

Synthesis of 4′H-spiro[adamantane-2,3′-isoquinoline] derivatives

Russian Journal of Organic Chemistry -     

Synthesis and mesomorphic properties of 2-(4′-alkoxybiphenyl-4-yl)-1H-benzimidazole derivatives

Three series of 2-(4′-alkoxybiphenyl-4-yl)-1H-benzimidazole derivatives (nM-x), which possessed 5-nitrobenzimidazole (nM-N series), benzimidazole (nM-H series) or 5-methylbenzimidazole (nM-M series) units at the end of the molecule, were synthesised and characterised by infrared, ¹H- and ¹³C-nuclear magnetic resonance spectra, electrospray ionisation-mass spectrometry and elemental analysis. Their phase transition behaviour was investigated by differential scanning calorimetry, polarising optical microscopy and X-ray diffraction. All the compounds exhibited enantiotropic smectic mesophases with wide temperature domains for a carbon number in the alkoxy chain from 6 to 16, where the mesophase ranges were 14–91°C and 17–99°C during heating and cooling processes for the nM-N compounds, 7–25°C and 8–49°C for the nM-H compounds and 48–81°C and 52–85°C for the nM-M compounds, respectively. The effect of the length of alkoxy chain on mesomorphic properties was discussed. The nM-N and nM-M exhibited a much wider mesophase range whether during heating or cooling process than the corresponding nM-H series, especially for the longer terminal chain (n > 8), which indicated that the substituent in the benzimidazole moiety was helpful in increasing the mesophase stability.     

Collisionally activated dissociation of protonated 2′-deoxycytidine, 2′-deoxyuridine, and their oxidatively damaged derivatives

We examined the collisionally activated dissociation (CAD) pathways of protonated 2'-deoxycytidine (dC), 5-formyl-2'-deoxycytidine (5-FmdC), 5-hydroxy-2'-deoxycytidine (5-OHdC), 5-hydroxymethyl-2'-deoxycytidine (5-HmdC), and their corresponding stable isotope-labeled compounds to gain insights into the effects of modifications on the fragmentation pathways of the pyrimidine bases. Multi-stage MS (MSn) results showed that protonated cytosine, its 5-hydroxyl- and 5-hydroxymethyl-substituted derivatives, but not its 5-formyl-substituted analog, could undergo Dimroth-like rearrangement in the gas-phase. The elimination of HNCO was one of the major fragmentation pathways observed for the protonated ions of all dC derivatives except for 5-hydroxymethylcytosine, which underwent this loss only after a H2O molecule had been eliminated. In addition, the protonated cytosine and 5-hydroxycytosine can undergo a facile elimination of NH3 molecule. This loss, however, was not observed for protonated 5-hydroxymethylcytosine, 5-formylcytosine, and their uracil analogs. Taken together, our study demonstrated that modifications could alter markedly the CAD patterns of the protonated pyrimidine bases. The results from this study provided a basis for the identifications of other modified pyrimidine bases/nucleosides by tandem mass spectrometry.     

Acetyl- and O-alkyl- derivatives of β-mangostin from Garcinia mangostana and their anti-inflammatory activities

Pure β-mangostin (1) was isolated from the stem bark of Garcinia mangostana L. One monoacetate (2) and five O-alkylated β-mangostin derivatives (3–7) were synthesised from β-mangostin. The structures of these compounds were elucidated and determined using spectroscopic techniques such as 1D NMR and MS. The cytotoxicities and anti-inflammatory activities of these five compounds against RAW cell 264.7 were tested. The structural-activity relationship studies indicated that β-mangostin showed a significant activity against the LPS-induced RAW cell 264.7, while the acetyl- as well as the O-alkyl- β-mangostin derivatives did not give good activity. Naturally occurring β-mangostin demonstrated comparatively better anti-inflammatory activity than its synthetic counterparts.     

Synthesis and crystal structure of β-N-(5-methyl-4-oxo-5,6-dihydro-4H-1,3-thiazin-2-yl)isonicotinohydrazide

In the presence of amines under mild conditions, β-N-(methacryloylcarbamoythioyl)isonicotinohydrazide underwent intramolecular heterocyclization to give β-N-(5-methyl-4-oxo-5,6-dihydro-4H-1,3-thiazin-2-yl)isonicotinohydrazide, the spatial structure was confirmed by X-ray crystallography.     

Synthesis of 4-aminoguaiazulene and its δ-lactam derivatives

A method for nitrogen insertion into guaiazulene hydrocarbons is developed. A one-pot reaction of 7-isopropyl-1-methylazulene-4-carboxylic acid, diphenylphosphoryl azide, and an alcohol (MeOH, ^tBuOH or BnOH) affords the corresponding carbamates. Deprotection of benzyl (7-isopropyl-1-methylazulen-4-yl)carbamate under basic conditions gave 4-aminoguaiazulene, which undergoes ring annulation reactions with 1,2-dicarbonyl reagents to yield tricyclic δ-lactams.     

Synthesis of 6,8-dichloroquinolones utilizing new method and evaluation of their antibacterial activities

Several 6,8-dichloroquinolone analogues were synthesized from the key intermediate compound of 2,3,4,5-tetrachlorobenzene carbonyl chloride,which was obtained from the starting material of tetrachlorophthalic anhydride.Their in vitro antibacterial activities were evaluated.As a result of this study,compounds 21c and 21d were twofold more potent than ciprofloxacin (CPFX) and norfloxacin (NFLX) against Staphylococcus aureus-9,and with the same potent as CPFX and NFLX while against Escherichia coli-2,but were less potent than references in against Pseudomonas aeruginosa-17.