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.

     

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.     

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.     

An Asymmetric Synthesis of 2-Substituted Piperidines through Ozonolysis of Cyclopentenes and Reductive Aminocyclization

By the action of ozone, sodium cyanoborohydride and the optically active benzylic amines 2, the 1-substituted cyclopentenes 1, 5 and 9 were converted to a diastereoisomeric mixture of 1,2-disubstituted piperidines (3, 6 and 10), respectively. Hydrogenation of these compounds and the following work-up yielded optically active 2-alkylpiperidines (4, up to 68% e.e.), pipecolic acid (7, 84%e.e.) and 2-(hydroxymethyl)piperidine (11, up to 85%e.e.). Chromatographic separation of the major isomers of 3b and 6 enabled optically pure coniine (4b) and pipecolic acid (7) to be prepared, respectively.     

Polymer-mediated cyclodehydration of alditols and ketohexoses

The polymer PEDOT⁺ (1 or 2) mediates a cyclodehydration reaction with alditols 3, 5, 7, 9, in hydrocarbon solvents, to give cyclic ethers 4, 6, 8, or 10, respectively, in high yield with a trivial isolation protocol. Polymers 1 or 2 also mediate the cyclodehydration of ketohexoses such as d-fructose, but not aldohexoses, to the important industrial intermediate 5-hydroxymethylfurfural (17), under milder conditions when compared to reactions mediated by mineral acids. A cascade reaction with ketohexoses is observed in toluene via cyclodehydration followed by Friedel–Crafts alkylation of the initially formed benzylic alcohol to give 16.     

Synthesis of an Epoxide Derivative of Thymidine as a Potential Enzyme Inhibitor

Abstract

Attempts to prepare I -[7,8-anhydro-2,5,6-trideoxy-α-L-lyxo-(and β-n-ribo)-octofuranosyl]thymine (10) by treatment of halohydrins 6–9 with sodium hydride in DMF or sodium methoxide in methanol gave mixtures of the epoxides 10 or 11 and the 3′,8′-anhydronucleoside 12. The structure of 12 was confirmed by oxidation to the cyclic ketone 14. The successful synthesis of 10 involved a Wittig reaction on the thymidine-5′-aldehyde 16 to give the unsaturated ketoacetate 18 which was reduced in two steps to the diacetate 20. The 7′-O-tosyl derivative 21 upon treatment with sodium methoxide in chloroform gave the pure epoxide 10 which was marginally toxic to L1210 cells in culture (I₅₀=25 μM) and demonstrated borderline in vivo activity (24% ILS) against P388 murine leukemia.     

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.     

Formation Mechanism of the Free Radical Product and Its Precursor by the Reaction of Dehydro-L-ascorbic Acid with Amino Acid

During the formation of radical A (2) and its precursor (tris(2-deoxy-2-L-ascorbyl)amine, 1) by the reaction of dehydroascorbic acid (DHA) with amino acid, ascorbic acid (AsA) and the reduced red pigment (3) were newly identified, in addition to scorbamic acid (SCA) and the red pigment (4), as intermediate products. The addition of AsA to the DHA-amino acid reaction, as well as to the DHA-SCA reaction, greatly increased the formation of 3 and 1. The reaction of AsA with 4 gave rapidly 3, followed by the gradual production of 1. From these results, a reaction pathway is proposed that 3 formed by the reduction of 4 with AsA is a key intermediate and its condensation with DHA followed by reduction with AsA might produce 2 and 1.     

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 of (±)-Muscone from Ethyl 6-Methyl-8-oxopentadecanedioate

(±)-Muscone (3-methylcyclopentadecanone) (8) was synthesized from ethyl 6-methyl-8-oxopentadecanedioate (1) in a 31.9% over-all yield. Ethylene ketal (2) of 1 was cyclized to the acyloin mixture (3) by the acyloin condensation. Reduction of 3 gave 9,9-ethylenedioxy-7-methylcyclopentadecane-1,2-diol (4) which afforded 1,2-ditosyloxy derivative (5). By detosylation according to the Tipson-Cohen procedure, 5 was converted to 9,9-ethylenedioxy-7-methylcyclopentadec-1-ene (6) which was hydrogenated to 8.     

Method for the Synthesis of Uric Acid Derivatives

Abstract

A general procedure to obtain tetra-substituted uric acid by stepwise N-alkylation is described. 2,6-Dichloropurine (1) was condensed with 1-propanol by Mitsunobu reaction to give 9-propyl congener (2). Treatment of 2 with ammonia gave adenine derivative (4a), which was converted to the 8-oxoadenine (5b) in 3 steps. Methylation of 5b proceeded site-specifically to give 6-amino-2-chloro-7,8-dihydro-7-methyl-9-propylpurin-8-one (6) as a sole product. Compound 6 was successively treated with NaNO₂ and iodomethane to give 2-chloro-1,6,7,8-tetrahydro-1,7-dimethyl-9-propylpurin-6,8-dione (9) accompanied by the O ⁶-methyl product (8) in 75% and 6.9%, respectively. After nucleophilic substitution of 9 with NaOAc, the product (11) was reacted with iodomethane to give the uric acid (12) and the 2-methoxy product (13) in 46% and 15.5%, respectively. However, the reaction of 11 with the benzylating agents gave only O-benzyl products (14a,b).     

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.     

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.     

基本药物制度实施与乡镇卫生院补偿机制转变

目的 了解乡镇卫生院各项收支及药品补偿状况,探讨基本药物制度实施后,取消药品加成对乡镇卫生院的影响。方法 收集华东三省49家乡镇卫生院财务及药品收支数据,对定量资料进行统计分析。结果 乡镇卫生院主要的补偿渠道依然是药品收入,乡镇卫生院收入增长主要归因于增加药品收入。在财政补助收入大幅增加的情况下,乡镇卫生院对药品收入的依赖程度有所降低。结论 基本药物制度的实施对乡镇卫生院的平稳运行有影响,可采取加强财政补助、建立综合补偿机制、遏制药品价格虚高等措施保证乡镇卫生院在改革中的平稳运行。     

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,synthesis of novel pyranotriazolopyrimidines and evaluation of their anti-soybean lipoxygenase,anti-xanthine oxidase,and cytotoxic activities

The synthesis of 14-(aryl)-14H-naphto[2,1-b]pyrano[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-2-yl) acetamidoximes 2a–e has been accomplished by reaction of 2-acetonitrile derivatives 1a–e with hydroxylamine. Cyclocondensation reaction of precursors 2a–e with some elctrophilic species such as ethylorthoformate, acetic anhydride, and methyl-acetoacetate provided the new oxadiazole derivatives 3a–e, 4a–e, and 5a–e, respectively. On the other hand, the reaction of precursors 2a–e with 2-chloropropanoyl chloride afforded the new acetimidamides 6a–e which evolve under reflux of toluene to the new oxadiazoles 7a–e. The synthetic compounds were screened for their anti-xanthine oxidase, anti-soybean lipoxygenase, and cytotoxic activities. Moderate to weak xanthine oxidase and soybean lipoxygenase inhibitions were obtained but significant cytotoxic activities were noted. The most cytotoxic activities were recorded mainly (i) 5a was the most active (IC_50?=_?4.0?μM) and selective against MCF-7 and (ii) 2a was cytotoxic against the four cell lines with selectivity for MCF-7 and OVCAR-3 (IC_50?=_?17 and 12?μM, respectively) while 2e is highly selective against OVCAR-3 (IC_50?=_?10?μM).     

Stereoselective Synthesis of Some 3-Nitroglucopyranosyladenine Analogues via a Nitroolefin: Intermediate as Potential Therapeutic Agents

Abstract

Three isomers of 9-(4,6-O-benzylidene-3-deoxy-β-D-hexopyranosyl) adenines (2–4) were isolated. The manno isomer 2 could be isomerized to the gluco isomer 3. The manno (2) and galacto isomer (4) were deprotected to 5 and 7, respectively. Michael addition of some organic amines and thiolates to the nitroolefin intermediate (8) gave the corresponding 2-(substituted)-3-nitro-glucopyranosides (9a-h). Compounds 9a,c,h were deprotected to 10a,c,h. Sodium azide with 8 gave the triazolo nucleoside 11, which was deprotected to 12. 2-Deoxy-3-nitro analogue 14 was also obtained.

     

The insight of in vitro and in silico studies on cholinesterase inhibitors from the roots of Cimicifuga dahurica (Turcz.) Maxim.

Cholinesterases (ChEs) are enzymes that break down neurotransmitters associated with cognitive function and memory. We isolated cinnamic acids (1 and 2), indolinones (3 and 4), and cycloartane triterpenoid derivatives (5–19) from the roots of Cimicifuga dahurica (Turcz.) Maxim. by chromatography. These compounds were evaluated for their inhibitory activity toward ChEs. Compound 1 was determined to have an IC₅₀ value of 16.7?±?1.9?μM, and to act as a competitive inhibitor of acetylcholinesterase (AChE). Compounds 3, 4 and 14 were found to be noncompetitive with IC₅₀ values of 13.8?±?1.5 and 6.5?±?2.5?μM, and competitive with an IC₅₀ value of 22.6?±?0.4?μM, respectively, against butyrylcholinesterase (BuChE). Our molecular simulation suggested each key amino acid, Tyr337 of AChE and Asn228 of BuChE, which were corresponded with potential inhibitors 1, and 3 and 4, respectively. Compounds 1 and 4 were revealed to be promising compounds for inhibition of AChEs and BuChEs, respectively.     

A Practical and Stereospecific Approach to the Synthesis of 3′-Deoxy-2′,3′-didehydrothymidine (D4T)

Abstract

Starting with D-glucose, 5-t-butyldimethylsilyl-3-deoxy-D-arabinose (5) was prepared. Condensation of 5 with cyanamide followed by reaction of the resulting oxazoline 6 with methyl-2-formylpropionate furnished the anhydronucleoside 7. t-Butoxide elimination of 7 gave the target compound in moderate yields due to concomitant 1′,2′-double bond formation. However, phenylselenolate and phenylthiolate opened 7 regiospecifically to the corresponding seleno and thio compounds, 10 and 11, respectively. Oxidative elimination of 10 and the pivaloyl derivative 12 gave 5′-t-butyldimethylsilyl (8) and 5′-pivaloyl (13) D₄T in excellent yield.     

Conformational behaviours of 2-substituted cyclohexanones: a complete basis set,hybrid-DFT study and NBO interpretation

The generalised anomeric effect (GAE) and gauche effect (GE) associated with donor–acceptor delocalisations, dipole–dipole interactions and total steric exchange energies (TSEE) on the conformational properties of 2-methoxy- (1), 2-methylthio- (2), 2-methylseleno- (3), 2-fluoro- (4), 2-chloro- (5) and 2-bromocyclohexanone (6) have been studied by means of ab initio and hybrid density functional theory methods and natural bond orbital (NBO) analysis. All methods used showed that the axial conformation stability increased from 2-methoxy- (1) to 2-methylselenocyclohexanone (3) and also from 2-fluoro- (4) to 2-bromocyclohexanone (6), which is in agreement with reported NMR data. The results obtained by complete basis set 4 (CBS-4), B3LYP/6-311+G** and HF/6-311+G** levels for compounds 1, 5 and 6 are very similar, but the CBS-4 results for compound 4 are not in agreement with the reported experimental data (vapour phase). The NBO analysis showed that the GAE increases from compounds 1 to 3 and also from compounds 4 to 6. The low axial conformer populations of compounds 1 and 4 can be reasonably explained by their small GAE. GE does not have significant impact on the conformational behaviours of compounds 1–6 and GAE succeeds in accounting qualitatively for the increase in the axial preferences in both series of compounds. The results showed that the calculated Δ(TSEE_eq–ax) values decrease from compounds 4 to 6 which contradicts the suggested arguments in the literature about these compounds. On the other hand, the calculated differences between the dipole moment values of the axial and equatorial conformations, Δ(μ_eq ? μ_ax), increase from compounds 1 to 2, but decrease from compounds 2 to 3 and also decrease from compounds 4 to 6. The calculated GAE values are more significant for the explanation of the conformational preferences of compounds 1–6 than the dipole–dipole repulsion effects. The correlations between the GAE, GE, dipole–dipole interactions, Wiberg Bond Index, TSEE, donor and acceptor orbital energies and occupancies, structural parameters and conformational behaviour of compounds 1–6 have been investigated.