Theoretical mechanistic study of the reaction of the methylidyne radical with methylacetylene

A detailed doublet potential energy surface for the reaction of CH with CH₃CCH is investigated at the B3LYP/6-311G(d,p) and G3B3 (single-point) levels. Various possible reaction pathways are probed. It is shown that the reaction is initiated by the addition of CH to the terminal C atom of CH₃CCH, forming CH₃CCHCH 1 (1a,1b). Starting from 1 (1a,1b), the most feasible pathway is the ring closure of 1a to CH₃–cCCHCH 2 followed by dissociation to P ₃ (CH₃–cCCCH+H), or a 2,3 H shift in 1a to form CH₃CHCCH 3 followed by C–H bond cleavage to form P ₅ (CH₂CHCCH+H), or a 1,2 H-shift in 1 (1a, 1b) to form CH₃CCCH₂ 4 followed by C–H bond fission to form P ₆ (CH₂CCCH₂+H). Much less competitively, 1 (1a,1b) can undergo 3,4 H shift to form CH₂CHCHCH 5. Subsequently, 5 can undergo either C–H bond cleavage to form P ₅ (CH₂CHCCH+H) or C–C bond cleavage to generate P ₇ (C₂H₂+C₂H₃). Our calculated results may represent the first mechanistic study of the CH + CH₃CCH reaction, and may thus lead to a deeper understanding of the title reaction.     

Phosphoralaninate Pronucleotides of Pyrimidine Methylenecyclopropane Analogues of Nucleosides: Synthesis and Antiviral Activity

The Z- and E-thymine and cytosine pronucleotides 3d, 4d, 3e, and 4e of methylenecyclopropane nucleosides analogues were synthesized, evaluated for their antiviral activity against human cytomegalovirus (HCMV), herpes simplex virus 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human immunodeficiency virus type 1 (HSV-1), and hepatitis B virus (HBV) and their potency was compared with the parent compounds 1d, 2d, 1e, and 2e. Prodrugs 3d and 4d were obtained by phosphorylation of parent analogues 1d or 2d with reagent 8. A similar phosphorylation of N⁴-benzoylcytosine methylenecyclopropanes 9a and 9b gave intermediates 11a and 11b. Deprotection with hydrazine in pyridine–acetic acid gave pronucleotides 3e and 4e. The Z-cytosine analogue 3e was active against HCMV and EBV. The cytosine E-isomer 4e was moderately effective against EBV.     

Synthesis of the Fluoromethyl Derivatives of Carbocyclic Oxetanocin A

Abstract

Treatment of the 2,3-di-O-benzoate 1 with sodium boronhydride mainly afforded the 3-O-benzoate 2 accompanied with isomers 3a,b and fully deprotected product 4. Compound 2 was converted to 5, from which 8 was obtained. The 1-cyclobutanols 8 and 5 were successfully condensed with 6-chloropurine by Mitsunobu reaction to give 9 and 11, respectively. After partial deprotection, the cyclobutyl nucleosides 10 and 15 were subjected to fluorination using DAST to afford the fluoromethyl analogs 12 and 16 from which target compounds 14 and 17 were obtained in good yields, respectively.

     

A Convenient Synthesis of Acyclic Adenosines with an Unsaturated Side Chain by Modification of 9-(2,3-O-Isopropylidene-D-Ribityl)Adenine

Abstract

In expectation of discovering their antiviral activity, acyclic adenosine derivatives 7, 11, 12, and 16 were designed as analogs of neplanocin A (NPA) and L-eritadenine which are strong inhibitors of S-adenosyl-L-homocysteine hydrolase. The 1′,5′-seco-analog of 4′-deoxymethyl-NPA (DHCA) 7 was synthesized by dideoxygenation of 9-(2,3-O-isopropylidene-D-ribityl)adenine (2). Acyclic DHCA analogs 11 and 16 were obtained by Wittig reaction of the aldehyde 3 with Ph₃P=CHCO₂Et and Ph₃P=CHCN, respectively. Hydrolysis of the ester 11 afforded a vinylog of L-eritadenine 12. The synthesized acyclic nucleosides 7, 10, and 11 were evaluated for antiviral activity, however, none of them showed any significant antiviral activity.     

Synthesis and Biological Activity of Some Unsaturated 6-Azauracil Acyclonucleosides

A useful route is described for obtaining Z and E unsaturated alkylating agents 3 and 4. Coupling 6-azauracils 5 and 6 with unsaturated alkylating agent followed by the deprotection with H⁺ resin gave acyclonucleosides 11–14 in good overall yields. Unsaturated acyclonucleosides phosphonates 19 and 20 were prepared using potassium carbonate as base and 4-bromobut-2-enyl diethyl phosphonate 16 as the alkylating agent. The introduction of a propargyl group at the N-3 position of acyclonucleosides 7, 8, 17, 18, 19, and 20 was achieved using potassium carbonate in DMF.     

Synthesis of octyl S-glycosides of tri- to pentasaccharide fragments related to the GPI anchor of Trypanosoma brucei

The three oligosaccharide octyl-S-glycosides Man-α1,6-Man-α1,4-GlcNH₂-α1,S-Octyl (19), Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH₂-α1,S-Octyl (27) and Man-α1,2-Man-α1,6-(Gal-α1,3)Man-α1,4-GlcNH₂-α1,S-Octyl (37), related to the GPI anchor of Trypanosoma brucei were prepared by a stepwise and block-wise approach from octyl 2-azido-2-deoxy-3,6-di-O-benzyl-1-thio-α-d-glucopyranoside (8) and octyl 2-O-benzoyl-4,6-O-(1,1,3,3-tetraisopropyl-1,3-disiloxane-1,3-diyl)-1-thio-α-d-mannopyransoside (9). Glucosamine derivative 8 was obtained from 1,3,4,6-tetra-O-acetyl-2-azido-2-desoxy-β-d-glucopyranose (1) in five steps. Mannoside 9 was converted into the corresponding imidate 12 and coupled with 8 to give disaccharide octyl-S-glycoside 13 which was further mannosylated to afford trisaccharide 19 upon deprotection. Likewise, mannoside 9 was galactosylated, converted into the corresponding imidate and coupled with 8 to give trisaccharide 25. Mannosylation of the latter afforded tetrasaccharide 27 upon deprotection. Condensation of 25 with disaccharide imidate 35 gave, upon deprotection of the intermediates, the corresponding pentasaccharide octyl-S-glycoside 37. Saccharides 19, 27 and 37 are suitable substrates for studying the enzymatic glycosylation pattern of the GPI anchor of T. brucei.     

Studies on the Later Stage of the Biosynthesis of Pleuromutilin

Mutilin (4) and deoxy analogues 2 and 3 are biosynthetic precursors of pleuromutilin (1) in the later stage of biosynthesis. Precursors 2 and 3 are required for studies on the oxygenation steps in biosynthesis, and were synthesized from readily available 1 via 4 by deoxygenation of the hydroxy groups. Feeding experiments with the ²H-labeled precursors confirmed their microbial conversion into 1.     

Study of reactivity of cyanoacetohydrazonoethyl-N-ethyl-N-methyl benzenesulfonamide: preparation of novel anticancer and antimicrobial active heterocyclic benzenesulfonamide derivatives and their molecular docking against dihydrofolate reductase

Abstract

This article describes the synthesis of some novel heterocyclic sulfonamides having biologically active thiophene 3, 4, 5, 6, coumarin 8, benzocoumarin 9, thiazole 7, piperidine 10, pyrrolidine 11, pyrazole 14 and pyridine 12, 13. Starting with 4-(1-(2-(2-cyanoacetyl)hydrazono)ethyl)-N-ethyl-N-methylbenzenesulfonamide (2), which was prepared from condensation of acetophenone derivative 1 with 2-cyanoacetohydrazide. The structures of the newly synthesized compounds were confirmed by elemental analysis, IR, ¹H NMR, ¹³C NMR, ¹⁹F NMR and MS spectral data. All the newly synthesized heterocyclic sulfonamides were evaluated as in-vitro anti-breast cancer cell line (MCF7) and as in-vitro antimicrobial agents. Compounds 8, 5 and 11 were more active than MTX reference drug and compounds 12, 7, 4, 14, 5 and 8 were highly potent against Klebsiella pneumonia. Molecular operating environment performed virtual screening using molecular docking studies of the synthesized compounds. The results indicated that some prepared compounds are suitable inhibitor against dihydrofolate reductase (DHFR) enzyme (PDBSD:4DFR) with further modification.     

Novel Regioselective Formation of S- and N-Hydroxyl-Alkyls of 5-(3-Chlorobenzo[b]Thien-2-yl)-3-Mercapto-4H-1,2,4-Triazole and A Facile Synthesis of Triazolo-Thiazoles and Thiazolo-Triazoles. Role of Catalyst and Microwave

Regioselective alkylation of 5-(3-chlorobenzo[b]thien-2-yl)-4H-1,2,4-triazole (1) with hydroxy alkylating agents 2, 3, 13, and the 2,3-O-isopropylidene-1-O-(p-tolylsulfonyl)-glycerol (10) afforded the corresponding S-alkylated derivatives 6, 7, 11, and 14 under both conventional and microwave irradiation conditions; bentonite as a solid support gave better results, with no change in regioselectivity. A facile intramolecular dehydrative ring closure of 6, 7, 11, and 14 using K₂CO₃ in DMF afforded the corresponding fused triazolo-thiazines and thiazolo-triazole 17–19. The isopropylidenes and acetyl derivatives of the products were prepared.     

Synthesis of blockwise alkylated (1→4) linked trisaccharides as surfactants: influence of configuration of anomeric position on their surface activities

New carbohydrate-based surfactants consisting of hydrophilic cellobiosyl and hydrophobic glucosyl residues, methyl β-d-glucopyranosyl-(1→4)-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-methyl-α-d-glucopyranoside 1 (GβGαMα, G: glucopyranosyl residue, α and β: α-(1→4)- and β-(1→4) glycosidic bonds, M: methyl group), 2 (G_βG_βM_α), 3 (G_βG_αM_β), 4 (G_βG_βM_β), 5 (G_βG_αE_α, E: ethyl group), 6 (G_βG_βE_α), 7 (G_βG_αE_β), 8 (G_βG_βE_β) and eight α-and β-glycoside mixtures (a mixture of 1 and 2: 1/2 = 62/38 (9), 32/68 (10); a mixture of 3 and 4: 3/4 = 69/31 (11), 32/68 (12); a mixture of 5 and 6: 5/6 = 62/38 (13), 33/67 (14); a mixture of 7 and 8: 7/8 = 59/41 (15), 29/71 (16)) were synthesized via combined methods consisting of acid-catalyzed alcoholysis of cellulose ethers and glycosylation of phenyl thio-cellobioside derivatives. Their surface activities in aqueous solution depended on their chemical structures: α- or β-(1→4) linkage between hydrophilic cellobiosyl and hydrophobic glucosyl blocks, methyl or ethyl groups of hydrophobic glucosyl block, and α- or β-linked ether group at the C-1 of hydrophobic glucosyl block. The mixing effect of α- and β-glycosides on surface activities was also investigated. As a result, ethyl β-d-glucopyranosyl-(1→4)-α-d-glucopyranosyl-(1→4)-2,3,6-tri-O-ethyl-β-d-glucopyranoside 7 (G_βG_αE_β) had the highest surface activity, and its critical micellar concentration (CMC) and γ_CMC (surface tension at CMC) values of compound 7 were 0.5 mM (ca. 0.03 wt %) and 34.5 mN/m, respectively. The surface tensions of α- and β-glycoside mixtures except for compounds 9 and 10 were almost equal to those of pure compounds. The syntheses of the mixtures of α- and β-glycosides without purification process are easier than those of pure compounds. Thus, the mixtures should be more practical compounds for industrial use as a surfactant.     

An analysis of hydrophobic interactions of thymidylate synthase with methotrexate: Free energy calculations involving mutant and native structures bound to methotrexate

Since the human body for many reasons can adapt and become resistant to drugs, it is important to develop and validate computer aided drug design (CADD) methods that could help predict binding affinity changes that can result from these resistant enzymes. The free energy perturbation (FEP) methodology is the most accurate means of estimating relative binding affinities between inhibitors and protein variants. In this paper, we describe the role played by hydrophobic residues lining the active site region, particularly ⁷⁹ Ile and ¹⁷⁶ Phe, in the binding of methotrexate to the Escherichia coli (E. coli) thymidylate synthase (TS) enzyme, using the thermodynamic cycle perturbation (TCP) approach. The computed binding free energy differences on the binding of methotrexate to the native and some mutant E. coli TS structures have been compared with experimental results. Computationally, four different ‘mutations’ have been simulated on the TS enzyme with methotrexate (MTX): ⁷⁹ Ile →  ⁷⁹ Val; ⁷⁹ Ile → ⁷⁹ Ala; ⁷⁹ Ile → ⁷⁹ Leu; and ¹⁷⁶ Phe →  ¹⁷⁶ Ile. The calculated results indicate that in each of these cases, the native residues ( ⁷⁹ Ile and ¹⁷⁶ Phe) interact more favorably with methotrexate than the mutant residues and these results are corroborated by experimental measurements. Binding preference to wild type residues can be rationalized in terms of their better hydrophobic contacts with the phenyl ring of methotrexate.     

Synthesis of Acyclovir and HBG Analogues Having Nicotinonitrile and Its 2-methyloxy 1,2,3-triazole

Reaction of pyridin-2(1H)-one 1 with 4-bromobutylacetate (2), (2-acetoxyethoxy)methyl bromide (3) gave the corresponding nicotinonitrile O-acyclonucleosides, 4 and 5, respectively. Deacetylation of 4 and 5 gave the corresponding deprotected acyclonucleosides 6 and 7, respectively. Treatment of pyridin-2(1H)-one 1 with 1,3-dichloropropan-2-ol (8), epichlorohydrin (10) and allyl bromide (12) gave the corresponding nicotinonitrile O-acyclonucleosides 9, 11, and 13, respectively. Furthermore, reaction of pyridin-2(1H)-one 1 with the propargyl bromide (14) gave the corresponding 2-O-propargyl derivative 15, which was reacted via [3+2] cycloaddition with 4-azidobutyl acetate (16) and [(2-acetoxyethoxy)methyl]azide (17) to give the corresponding 1,2,3-triazole derivatives 18 and 19, respectively. The structures of the new synthesized compounds were characterized by using IR, ¹H, ¹³C NMR spectra, and microanalysis. Selected members of these compounds were screened for antibacterial activity.     

Synthesis and in vitro evaluation of antiviral and cytostatic properties of novel 8-triazolyl acyclovir derivatives

Abstract

As a part of the research aimed on identification of new nucleobase derivatives with improved biological properties, a series of novel 8-substituted acyclovir derivatives were synthesized. The 8-azidoguanosine 4 and novel 8-azidoacyclovir 9 were synthesized from commercially available guanosine 1 and acyclovir 6 which were transformed into 8-bromopurine derivatives 2 and 7 and hydrazine derivatives 3 and 8, respectively. 8-Triazolylguanosine 5 and 8-triazolylacyclovir analogs 10–12 were successfully synthesized via the Cu(I) catalyzed 1,3-dipolar cycloaddition reaction of azides 4 and 9 with propargyl alcohol, 4-pentyn-1-ol and 5-hexyn-1-ol. The novel 1,4-disubstituted 1,2,3-triazolyl compounds 5, 10–12 were evaluated for antiviral activity against selected DNA and RNA viruses and cytostatic activity against normal Madine Darby canine kidney (MDCK I) cells, and seven tumor cell lines (HeLa, CaCo-2, NCI-H358, Jurkat, K562, Raji and HuT78). While tested compounds exerted no antiviral activity at nontoxic concentrations, the 8-triazolyl acyclovir derivative 10, with the shortest alkyl substituent at the C-4 of triazole ring, was found to be the most active against the CaCo-2 cell line.     

苦槛蓝叶中的黄酮类化合物

为了解苦槛蓝(Myoporum bontioides A.Gray)的化学成分,采用色谱分离技术从苦槛蓝叶片中分离得到11个黄酮类化合物。通过波谱分析,他们的结构分别鉴定为:桔皮素(1)、甜橙素(2)、5,4′-二羟基-6,7,8,3′-四甲氧基黄酮(3)、4′,5,7,8-四甲氧基黄酮(4)、去甲基川陈皮素(5)、5-羟基-6,7,3′,4′-四甲氧基黄酮(6)、3′,4′,5,6,7,8-六甲氧基黄酮(7)、二氢山柰酚(8)、木犀草素(9)、3′,4′,5,7-四羟基-3-甲氧基黄酮(10)和芹黄素(11)。除化合物9之外,其他化合物均为首次从苦槛蓝叶片中分离得到。孢子萌发法测定结果表明,化合物1,2,8和9对香蕉炭疽菌(Colletotrichum musae)具有较好的抑菌活性。这为苦槛蓝叶片中有效成分的利用提供了理论依据。     

Inhibition of soluble epoxide hydrolase activity by compounds isolated from the aerial parts of Glycosmis stenocarpa

The aim of this study is to search for soluble epoxide hydrolase (sEH) inhibitors from natural plants, bioassay-guided fractionation of lipophilic n-hexane and chloroform layers of an extract of the aerial parts of Glycosmis stenocarpa led to the isolation of 12 compounds (1–12) including murrayafoline-A (1), isomahanine (2), bisisomahanine (3), saropeptate (4), (24?S)-ergost-4-en-3,6-dione (5), stigmasta-4-en-3,6-dion (6), stigmast-4-en-3-one (7), β-sitosterol (8), 24-methylpollinastanol (9), trans-phytol (10), neosarmentol III (11) and (+)-epiloliolide (12). Their structures were elucidated on the basis of spectroscopic data. Among them, neosarmentol III (11) was isolated from nature for the first time. All the isolated compounds were evaluated for their inhibitory activity against sEH. Among isolated carbazole-type compounds, isomahanine (2) and bisisomahanine (3) were identified as a potent inhibitor of sEH, with IC₅₀ values of 22.5?±?1.7 and 7.7?±?1.2?µM, respectively. Moreover, the inhibitory action of 2 and 3 represented mixed-type enzyme inhibition.     

Morpho-histochemical characterization of salivary gland cells of males of the tick <Emphasis Type="Italic">Rhipicephalus</Emphasis><Emphasis Type="Italic">sanguineus</Emphasis> (Acari: Ixodidae) at different feeding stages: description of new cell types

This study describes the changes undergone by cells of the salivary glands of unfed and feeding (at day two and four post-attachment) Rhipicephalus sanguineus males, as well as new cell types. In unfed males, types I and II acini are observed with cells “undifferentiated”, undefined 1 and 2 (the latter, with atypical granules), a, c1 and c3; type III is composed of cells d and e; and type IV present cells g. In males at day two post-attachment, type I acini exhibit the same morphology of unfed individuals. An increase in size is observed in types II, III, and IV, as cells are filled with secretion granules. Some granules are still undergoing maturation. In type II acinus, cells a, b and c1–c8 are observed. Cells c7 and c8 are described for the first time. Cells c7 are termed as such due to the addition of polysaccharides in the composition of the secretion granules (in unfed individuals, they are termed undefined 1). Type III acini exhibit cells d and e completely filled with granules, and in type IV, cells g contain granules in several stages of maturation. In males at day four post-attachment, type I acini do not exhibit changes. Granular acini exhibit cells with fewer secretion granules, which are already mature. In type II acini, cells a, b, c1–c5 are present, type III exhibit cells d and e, and type IV contain cells g with little or no secretion. This study shows that in the salivary glands of R. sanguineus males, cells a, c1, and c3 of type II acinus, and cells d and e of type III do not exhibit changes in granular content, remaining continuously active during the entire feeding period. This indicates that during the intervals among feeding stages, gland cells reacquire the same characteristics found in unfed individuals, suggesting that they undergo reprogramming to be active in the next cycle.     

Design of potent fluoro-substituted chalcones as antimicrobial agents

Owing to ever-increasing bacterial and fungal drug resistance, we attempted to develop novel antitubercular and antimicrobial agents. For this purpose, we developed some new fluorine-substituted chalcone analogs (3, 4, 9–15, and 20–23) using a structure–activity relationship approach. Target compounds were evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv and antimicrobial activity against five common pathogenic bacterial and three common fungal strains. Three derivatives (3, 9, and 10) displayed significant antitubercular activity with IC₅₀ values of ≤16,760. Compounds derived from trimethoxy substituent scaffolds with monofluoro substitution on the B ring of the chalcone structure exhibited superior inhibition activity compared to corresponding hydroxy analogs. In terms of antimicrobial activity, most compounds (3, 9, 12–14, and 23) exhibited moderate to potent activity against the bacteria, and the antifungal activities of compounds 3, 13, 15, 20, and 22 were comparable to those of reference drugs ampicillin and fluconazole.     

Synthesis and Reactions of Some Glycosylamine Derivatives of 6-Azauracil Nucleosides

Abstract

Reaction of the silylated 6-azauracil (2) with 2-acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-D-glucose (3) gave 1-(2-acetamido-3,4,6-tri-O-acetyl-2-deoxy-ß-D-glucopyranosyl)-6-azauracil (4), which gave the free nucleoside 5 on deblocking. Acetalation of 5 gave the monoacetal 6 which was oxidized into the ketone 7. Reduction of 7 gave the allo-nucleoside 9 which on hydrolysis afforded the free nucleoside 10. Alternatively, compound 10 was obtained from mesylation of 6 to give 8 followed by subsequent acetolysis and hydrolysis.     

Chemical Constituents of Cape Aloe and Their Synergistic Growth-Inhibiting Effect on Ehrlich Ascites Tumor Cells

The constituents of cape aloe were investigated after a preliminary screening of the growth-inhibiting effect on Ehrlich ascites tumor cells (EATC) of several extracts of this plant. Ten compounds were isolated from the dichloromethane (CH₂Cl₂) extract that showed the strongest activity, and their structures were elucidated as aloe-emodin (1), p-hydroxybenzaldehyde (2), p-hydroxyacetophenone (3), pyrocatechol (4), 10-oxooctadecanoic acid (5), 10-hydroxyoctadecanoic acid (6), methyl 10-hydroxyoctadecanoate (7), 7-hydroxy-2,5-dimethylchromone (8), furoaloesone (9), and 2-acetonyl-8-(2-furoylmethyl)-7-hydroxy-5-methylchromone (10) based on MS and various NMR spectroscopic techniques. Compounds 2–7 were isolated for the first time from cape aloe. Compounds 4–7 and 10 showed a significant growth-inhibiting effect, and compound 1 exhibited a remarkable synergistic effect on compounds 8–10, which was not observed with the treatment by each compound alone on EATC. These results suggest that the strong growth-inhibiting effect of the CH₂Cl₂ extract was dependent not on one compound alone, but on the synergistic effect from the combination of compound 1 and the other compounds.     

Antimicrobial constituents of peel and seeds of camu-camu (Myrciaria dubia)

Various antimicrobial constituents of camu-camu fruit were isolated. Acylphloroglucinol (compound 1) and rhodomyrtone (compound 2) were isolated from the peel of camu-camu (Myrciaria dubia) fruit, while two other acylphloroglucinols (compounds 3 and 4) were obtained from camu-camu seeds. The structures of the isolated compounds were characterized by spectrophotometric methods. Compounds 1 and 4 were confirmed to be new acylphloroglucinols with different substituents at the C7 or C9 position of 2, and were named myrciarone A and B, respectively. Compound 3 was determined to be isomyrtucommulone B. This is the first report of the isolation of 3 from a natural resource. The antimicrobial activities of compounds 1, 3, and 4 were similar to those of 2, and the minimum inhibitory concentrations were either similar to or lower than that of kanamycin. These results suggest that the peel and seeds of camu-camu fruit could be utilized for therapeutic applications.