Oxidation of 5-hydroxy-2'-deoxyuridine into isodialuric acid, dialuric acid, and hydantoin products

Oxidation products of cytosine, including 5-hydroxycytosine and 5-hydroxyuracil, are highly susceptible to subsequent oxidation. Here, the oxidation products of 5-hydroxy-2'-deoxyuridine have been studied by NMR and MS analyses. The initial products were diastereomers of isodialuric acid nucleoside. These products subsequently decomposed into corresponding dialuric acid derivatives at neutral pH. The position of the carbonyl and hydroxyl groups, at C5 and C6 for isodialuric acid and at C6 and C5 for dialuric acid derivatives, respectively, was determined by 1H- and 13C NMR analyses. In addition, these analyses revealed that the carbonyl groups of both isodaluric and dialuric acid derivatives exist in their fully hydrated form in aqueous solution. Finally, the dialuric acid derivatives were observed to undergo subsequent decomposition into the corresponding 5-hydroxyhydantoin derivatives. Studies of a trinucleotide containing 5-hydroxyuracil suggest that the reactions described herein for the monomer can be extrapolated to DNA.     

熊果酸衍生物的合成及抗肿瘤血管生成活性

对熊果酸C28位与C3位进行结构修饰得到了24个衍生物, 并利用 1H NMR, 13C NMR, MS及HR-MS对这些化合物进行了结构表征. 进一步通过MTT法, 以内皮细胞HUVEC为主要模型, 研究了24个衍生物抗肿瘤血管生成的活性, 同时以A549, Bel-7402及MCF-7细胞为模型研究了上述衍生物对肿瘤细胞的抑制活性. 研究结果表明, 与熊果酸相比, 化合物5, 9, 12e和14e对HUVEC细胞有较好的选择性, 化合物12a和13h比熊果酸的抗肿瘤血管生成活性略高, 因此通过适当改变熊果酸C28位的结构可以提高其对内皮细胞HUVEC的选择性, 增强抗肿瘤血管生成活性. 本文结果表明, 熊果酸及其衍生物是潜在的具有抗肿瘤血管生成作用的先导化合物, 通过有效的结构优化可能得到新型的抗肿瘤血管生成的化合物.     

Synthesis of 5-(dimethylsilyl)pentylalkylferrocene-grafted HTPB (alkylFc-HTPB) via platinum-catalyzed hydrosilylation

In this work, at first alkylferrocene derivatives were synthesized according to procedure described in the literature. (5-Chloropentanoyl)ferrocene derivatives were prepared by Friedel–Crafts acylation of ferrocene and alkylferrocene derivatives with 5-chloropentanoyl chloride in dichloromethane, and AlCl₃ was used as catalyst. The corresponding 5-chloropentylferrocene derivatives were synthesized from reduction of these products by NaBH₄ in diglyme at 0 °C. Finally (5-alkylferrocenylpentyl)dimethylsilane was synthesized from reaction of 5-chloropentylferrocene derivatives with magnesium in THF and reaction of corresponding Grignard reagents with chlorodimethylsilane in 82–87% yields. ¹H and ¹³C NMR, FT-IR spectroscopy supported the predicted structure of the product. Nine samples of alkylferrocene-grafted hydroxyl-terminated polybutadiene (alkylFc-HTPB) derivatives, containing different percent of iron, were synthesized by hydrosilylation reaction of [5-(alkylferrocenyl)pentyl]dimethylsilane with hydroxy-terminated polybutadiene (HTPB), in the presence of catalytic amount of the hexachloroplatinic acid (Speier’s catalyst). FT-IR spectroscopy was utilized to follow the progress of the reaction, by monitoring the loss of the Si–H absorption at 2110 cm^?1, and the reaction was completed in 24 h. Some properties of resulting prepolymer like viscosity, glass transition temperature and iron percentage as important parameters in production of composite propellants were investigated. For example, the viscosity increased with increasing iron content because of the greater extent of ferrocene grafting in the polymer.     

Comprehensive Comparisons between 1-Phenyl-3-methyl-5-pyrazolones, 1-(4-Methoxyphenyl)-3-methyl-5-pyrazolones and 1-(2-Naphthyl)-3-methyl-5-pyrazolones as Labeling Reagents Used in LC-DAD-ESI-MS-MS Analysis of Neutral Aldoses and Uronic Acids

Comprehensive comparisons between three 1-aryl-3-methyl-5-pyrazolone (AMP) labeling reagents were carried out for the analysis of reductive monosaccharides using reversed phase high performance liquid chromatography diode array detection coupled to electrospray ionization mass spectrometry. AMP derivatives included 1-phenyl-3-methyl-5-pyrazolone (PMP), 1-(4-methoxyphenyl)-3-methyl-5-pyrazolone (PMPMP) and 1-(2-naphthyl)-3-methyl-5-pyrazolone (NMP). The separation of AMP-monosaccharides was found to be pH-dependent under reversed phase conditions and acceptable separations were obtained at pH < 4.5. The elution orders of AMP-aldoses were rationalized by geometric factors involved in the presence of hydroxyl groups at C2 and C3 positions of the saccharide moiety. When PMP or PMPMP were used as labeling agents Glucose and galactose were completely separated, while arabinose and xylose were observed to co-elute. The use of NMP revealed that arabinose and xylose could be separated while glucose and galactose were co-eluted. MS-MS data of AMP-monosaccharides gave characteristic fragment ions resulting from cleavage between the C2–C3 bond (m/z 373 for PMP derivatives, m/z 433 for PMPMP derivatives, and m/z 473 for NMP derivatives). Bond breakage between C1–C2 (m/z 359 for PMP derivatives, m/z 419 for PMPMP derivatives, and m/z 459 for NMP derivatives) of the saccharide moiety was also found to be characteristic for AMP-saccharides. Application to the analysis of hydrolyzed rape pollen polysaccharides revealed the presence of four unexpected monosaccharides, namely ribose, erythrose, threose and glyceraldehyde.     

含噻二唑官能基的对叔丁基硫桥杯[4]芳烃衍生物的合成及结构

以对叔丁基硫桥杯[4]芳烃(1)为原料, 在碳酸钾存在下与碘甲烷反应, 生成1,3-二取代桥杯[4]芳烃(2), 其分别与1,2-二溴乙烷, 1,3-二溴丙烷在碳酸钾的存在下进行烷基化反应, 生成硫桥杯[4]芳烃衍生物3和4. 在氢氧化钠存在下,其与过量的含不同官能团的2-巯基-1,3,4-噻二唑反应, 生成下缘含1,3,4-噻二唑基的硫桥杯[4]芳烃衍生物5a, 5b, 6a和6b, 并通过了¹H NMR, ¹³C NMR, IR, MS和元素分析的确证. 同时, X射线分析确定了硫桥杯[4]芳烃3和5a的晶体结构.     

挂式-四氢双环戊二烯热裂解产物分布研究

研究了常压下, 温度为450～650 ℃, 停留时间为15.44～4.03 s条件下的JP-10 (挂式-四氢双环戊二烯)热裂解产物分布. 在相对较长的停留时间下, JP-10热裂解转化率对温度很敏感. 热裂解主要产物为甲烷、乙烯、丙烯、丁烯、丁二烯、环戊二烯、苯、甲苯、苯乙烯、环戊烯的乙烯基取代物及C5, C6异构体(戊二烯、环戊烯的甲基取代物、环己烯、己二烯和环戊二烯甲基取代物), 其中, C1～C4、环戊二烯、苯、甲苯、乙烯基取代环戊烯为初始产物.     

Co2(CO)8-mediated endo mode cyclization of epoxy-alcohol: synthesis of 2-ethynyl-3-hydroxy-2-methyltetrahydropyran and 2-ethynyl-3-hydroxy-3-methyltetrahydropyran derivatives

Successive treatment of 4,5-epoxy-5-methyl-7-trimethylsilyl-6-heptyne-1-ol with Co2(CO)8 at 0 degrees C and a catalytic amount of BF3 x OEt2 at -78 degrees C gave the tetrahydropyran derivatives with the cobalt-complexed moiety. Similarly 4,5-epoxy-4-methyl-7-trimethylsilyl-6-heptyne-1-ol underwent ring closure under the above conditions to provide the corresponding tetrahydropyran derivatives. The preferential endo mode cyclization over the exo one was observed in these experiments.     

Structure elucidation,complete NMR assignment and PM5 theoretical studies of new hydroxy‐aminoalkyl‐α,β‐unsaturated derivatives of the macrolide antibiotic josamycin

Four new hydroxy‐aminoalkyl derivatives of α,β‐unsaturated macrolide‐josamycin (2–5) have been synthesised and their structures have been studied by means of ¹H and ¹³C NMR and FT‐IR methods. Complete assignment of resonances in the ¹H and ¹³C NMR spectra has been made on the basis of ¹H? ¹³C HSQC, ¹H? ¹³C HMBC, ¹H? ¹H COSY, ¹H? ¹H NOESY 2D experiments. Spectroscopic data indicated that for the derivatives 3 and 4 some equilibrium between two different structures exists in contrast to derivatives 2 and 5. The lowest‐energy structures of the new derivatives of josamycin have been calculated and visualised by PM5 method at semi‐empirical level of theory, taking into account the NMR and FT‐IR data. The most significant differences between the structures of josamycin and its newly synthesised derivatives' were found in the conformation of the macrolide aglycone part and in the mutual orientation of the 4‐O‐isovalerylmycarosylmycaminose moiety relative to the aglycone part. PM5 semi‐empirical calculations indicated that the structures of the new macrolide derivatives are stabilised by rather weak intramolecular hydrogen bonds in agreement with spectroscopic data. Antimicrobial properties of the new derivatives 2–5 as well as those having an acetate group at C‐3 (6 and 7) were determined and compared to that of the parent macrolide antibiotic josamycin (1). Copyright © 2010 John Wiley & Sons, Ltd.     

From imidates to vinyl-1,2,4-triazoles: Synthesis,mechanistic aspects and first issues of their reactivity

The reaction of variously substituted acylimidates with hydrazine derivatives represents an efficient and easy to set synthetic entry towards 5-vinyl-1,2,4-triazole derivatives. The construction of the triazole ring allows the installation of variety of substituent combination at the N(1), C(3) and C(5) positions of the five-membered heterocycle in good to high yields. The method reveals selective towards 5-vinyl-1,2,4-triazoles avoiding the potential formation of seven- and five-membered side-products as supported by theoretical calculations and NMR experiments. First lines of Pd-catalyzed arylation of the vinyl fragment towards 5-styryl-1,2,4-triazoles and Cu-catalyzed arylation at the N(1) site are finally described.     

Synthesis and Structures of Polyphenylphenanthrenes

1,2,3,4,5,6,7,8-Octaphenylphenanthrene ( 4 ) and decaphenylphenanthrene ( 5 ) were prepared by very short syntheses (two or three steps) from tetraphenylfuran and polybrominated benzene derivatives. The X-ray structures of compounds 4 and 5 show them to be quite crowded, with the phenanthrene cores twisted by about 40° due to the clash of the C4 and C5 phenyl groups. Compound 4 was resolved by chromatography on a chiral support, and its free energy of activation for racemization was determined to be 24.6 kcal mol⁻¹ at 40 °C. Computational studies indicate that compound 5 has a racemization barrier approximately 6 kcal mol⁻¹ lower than 4 , and thus 5 would not be configurationally stable at room temperature.     

含噻二唑基的对叔丁基杯[4]芳烃衍生物的合成及表征

以对叔丁基杯[4]芳烃(1)为原料, 分别与1,2-二溴乙烷、1,3-二溴丙烷在碳酸钾的存在下进行选择性烷基化反应, 生成杯[4]芳烃衍生物2和3. 在氢氧化钠存在下, 化合物2和3与过量的含不同官能团的2-巯基噻二唑反应, 生成下缘含噻二唑基的杯芳烃衍生物4a～4c, 5a～5c, 其结构经¹H NMR, ¹³C NMR, IR, MS和元素分析确证.     

Diethylhydrogensilyl-cyclic diethylsilylene derivatives in gas chromatography-mass spectrometry of prostanoids. III. F alpha-prostaglandins and thromboxane B2 derivatives

The gas chromatographic (GC) and GC-mass spectrometric properties of the diethylhydrogensilyl-cyclic diethylsilylene (DEHS-DES) derivatives of prostaglandin (PG) F1 alpha methyl ester, PGF2 alpha methyl ester, 6-keto-PGF1 alpha methyl ester-alkyloxime and thromboxane (TX) B2 methyl ester-alkyloxime and the DES derivative of 13,14-dihydro-15-keto-PGF2 alpha methyl ester-alkyloxime were studied. When the ketonic PGs and TXB2 were converted into their methyloxime derivatives, the methylene unit values of these five prostanoid derivatives were slightly greater than those of the corresponding dimethylethylsilyl ether derivatives. When the ketonic PGs were converted into their corresponding ethyloxime derivatives, baseline separation was achieved in 20 min by use of a methylsilicone cross-linked fused-silica capillary column. The mass spectra of these derivatives were characterized by the ion at m/z 157 for F alpha prostaglandins and m/z 269 for TXB2. The major fragmentations were directed by the DES group, and other fragmentations common to the prostanoid derivatives were losses of an ethyl radical at the silicon atom, C5H11 hydrocarbon fragment, diethylhydrogensilanol and C15-C20 hydrocarbon fragment. The mass fragmentations of these prostanoid derivatives are briefly discussed. GC with high-resolution selected-ion monitoring was carried out for the TXB2 derivative at a resolution of 8000 by monitoring the ion at m/z 269.1573. A 25-pg amount of this derivative showed a well shaped doublet with a signal-to-noise ratio of more than 300:1.     

Synthesis of Rhodomyrtone Analogs Modified at C7

We developed a route to rhodomyrtone analogs that feature different acyl groups at C7. Since electrophilic substitution reactions on the aryl part of the rhodomyrtone core led to C5 derivatives, the C5 position was blocked by a chlorine. Subsequent Duff type formylation followed by Grignard addition to the aldehyde group and oxidation gave various phenones. The benzyl protecting groups were removed by hydrogenation or boron tribromide. Some derivatives turned out to be quite active against multiple resistant Staphylococcus aureus strains and a rhodomyrtone resistant mutant (Rom^R). The chlorine at C5 seems to have a beneficial effect on the antibacterial activity.     

Azide-Functionalized Derivatives of the Virulence-Associated Sugar Pseudaminic Acid: Chiral Pool Synthesis and Labeling of Bacteria

Pseudaminic acid (Pse) is a significant prokaryotic monosaccharide found in important Gram-negative and Gram-positive bacteria. This unique sugar serves as a component of cell-surface-associated glycans or glycoproteins and is associated with their virulence. We report the synthesis of azidoacetamido-functionalized Pse derivatives as part of a search for Pse-derived metabolic labeling reagents. The synthesis was initiated with d -glucose (Glc), which served as a cost-effective chiral pool starting material. Key synthetic steps involve the conversion of C1 of Glc into the terminal methyl group of Pse, and inverting deoxyaminations at C3 and C5 of Glc followed by backbone elongation with a three-carbon unit using the Barbier reaction. Metabolic labeling experiments revealed that, of the four Pse derivatives, ester-protected C5 azidoacetamido-Pse successfully labeled cells of Pse-expressing Gram-positive and Gram-negative strains. No labeling was observed in cells of non-Pse-expressing strains. The ester-protected and C5 azidoacetamido-functionalized Pse is thus a useful reagent for the identification of bacteria expressing this unique virulence-associated nonulosonic acid.     

Synthesis of (10Z)- and (10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3: compounds to probe vitamin D conformation in receptor complex by 19F-NMR

To study the interaction of vitamin D with its receptor by 19F-NMR, (5Z,10Z)- and (5Z,10E)-19-fluoro-1alpha,25-dihydroxyvitamin D3 were synthesized starting from vitamin D2 via electrophilic fluorination of vitamin D-SO2 adducts as the key step. Regio- and stereoselective electrophilic fluorination at C(19) of vitamin D-SO2 adducts was achieved under the conditions using (PhSO2)2NF and bulky bases. The stereochemistry of the addition and elimination of SO2 of various vitamin D derivatives was studied in detail. SO2 causes Z-E isomerization of the 5,6-double bond of vitamin D and adds to the resulting (5E)-isomer from the sterically less hindered side opposite to the substituent at C(1). Elimination of SO2 from 19-substituted vitamin D-SO2 adducts proceeded exclusively in a suprafacial manner with respect to the diene part under either thermal or reductive conditions. Dye-sensitized photochemical isomerization of 19-fluorovitamin D derivatives was studied in detail. The rapid isomerization at the 5,6-double bond was followed by the slow isomerization at the 10,19-double bond to yield the (5E,10Z)-isomer (by nomenclature of the 1-OH derivatives) as the major product. (10Z)- and (10E)-19-Fluorovitamin Ds were also interconverted thermally probably via the corresponding previtamin D by 1,7-sigmatropic isomerization.     

Field method for determination of traces of thiols in natural waters

Derivatization with 2,2′-dithiobis(5-nitropyridine) (DTNP) was used to stabilize thiols in field samples and to determine these compounds by liquid chromatography (LC) with ultraviolet detection. Alternatively, the thiols can be regenerated from DTNP derivatives using tributylphosphine (TBP) and derivatized with o-phthalaldehyde (OPA). The DTNP derivatives were stable at pH 5 and 6 for more than 2 weeks in the reaction mixture, but the stability was considerably lower at pH values > 8. Derivatization at pH 6 was routinely done and the reaction was complete within 5 min. The derivatives can be extracted quantitatively on commercial C₁₈ cartridges, which allows several-fold sample enrichment. The cartridge-adsorbed derivatives are stable at 0–5 °C for long periods and, therefore, can be stored for LC separation at a later date. DTNP derivatives of ten low-molecular-weight thiols were separated on a C₁₈ microbore column using gradient elution and a flow-rate of 200 μl min^?1. The relative standard deviation based on repeated analyses of standards is about 5% in the range 0.5–2 nM. Without C₁₈ cartridge enrichment, the detection limits of the studied thiols are in the range 50–100 nM. These limits are further reduced by about 100-fold by using the OPA method after regeneration of thiols from the DTNP derivatives using TBP. Applications of the method to coastal sediment pore water and anoxic Black Sea water are illustrated.     

Bisphosphonate derivatives of nucleoside antimetabolites: hydrolytic stability and hydroxyapatite adsorption of 5'-beta,gamma-methylene and 5'-beta,gamma-(1-hydroxyethylidene) triphosphates of 5-fluorouridine and ara-cytidine

Kinetics of the hydrolytic reactions of four bisphosphonate derivatives of nucleoside antimetabolites, viz., 5-fluorouridine 5'-beta,gamma-(1-hydroxyethylidene) triphosphate ( 4), 5-fluorouridine 5'-beta,gamma-methylene triphosphate ( 5), ara-cytidine 5'-beta,gamma-(1-hydroxyethylidene) triphosphate ( 6), and ara-cytidine 5'-beta,gamma-methylene triphosphate ( 7), have been studied over a wide pH range (pH 1.0-8.5) at 90 degrees C. With each compound, the disappearance of the starting material was accompanied by formation of the corresponding nucleoside 5'-monophosphate, the reaction being up to 2 orders of magnitude faster with the beta,gamma-(1-hydroxyethylidene) derivatives ( 4, 6) than with their beta,gamma-methylene counterparts ( 5, 7). With compound 7, deamination of the cytosine base competed with the phosphate hydrolysis at pH 3-6. The measurements at 37 degrees C (pH 7.4) in the absence and presence of divalent alkaline earth metal ions (Mg (2+) and Ca (2+)) showed no sign of metal ion catalysis. Under these conditions, the initial product, nucleoside 5'-monophosphate, underwent rapid dephosphorylation to the corresponding nucleoside. Hydrolysis of the beta,gamma-methylene derivatives ( 5, 7) to the corresponding nucleoside 5'-monophosphates was markedly faster in mouse serum than in aqueous buffer (pH 7.4), the rate-acceleration being 5600- and 3150-fold with 5 and 7, respectively. In human serum, the accelerations were 800- and 450-fold compared to buffer. In striking contrast, the beta,gamma-(1-hydroxyethylidene) derivatives did not experience a similar decrease in hydrolytic stability. The stability in human serum was comparable to that in aqueous buffer (tau 1/2 = 17 and 33 h with 4 and 6, respectively), and on going to mouse serum, a 2- to 4-fold acceleration was observed. To elucidate the mineral-binding properties of 4- 7, their retention on a hydroxyapatite column was studied and compared to that of zoledronate ( 1a) and nucleoside mono-, di-, and triphosphates.     

Synthesis of C60-fused tetrahydrothiophene derivatives via nucleophilic cycloaddition of thiocyanates

Nucleophilic cycloaddition of thiocyanates 1a-e with C60 in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene afforded C60-fused 2-iminotetrahydrothiophene derivatives 2a-e and methanofullerenes 3a-d. The product distributions were highly sensitive to the substrates employed. The 2-iminotetrahydrothiophene derivatives 2a-e could be further manipulated by hydrolysis and acetylation to give 2-oxotetrahydrothiophene derivatives 4a-e and 2-acetamidotetrahydrothiophene derivatives 5a-e. A possible reaction mechanism for the formation of products 2a-e and 3a-d was proposed.     

Correlation of the physicochemical properties of symmetric 1,3-dialkoylamidopropane-based cationic lipids containing single primary and tertiary amine polar head groups with in vitro transfection activity

The physicochemical properties of a novel series of symmetric 1,3-dialkylamidopropane-based cationic amphiphiles [M. Sheikh, J. Feig, B. Gee, S. Li, M. Savva, In vitro lipofection with novel series of symmetric 1,3-dialkoylamidopropane-based cationic surfactants containing single primary and tertiary amine polar head groups, Chem. Phys. Lipids 124 (2003) 49-61] were studied by several techniques, in an effort to correlate cationic lipid structure with transfection efficacy. It was found that only the unsubstituted amine and tertiary amine dioleoyl derivatives 1,3lmp5 and 1,3lmt5, respectively, mediated in vitro transfection activity in the absence of helper lipids. This activity pattern was consistent with ethidium bromide fluorescence quenching studies, which indicated that only these two derivatives bound to and efficiently condense plasmid DNA at physiological pH. Dynamic light scattering indicated that lipoplexes made by these two cationic lipids were relatively small particles below 1 microm, in sharp contrast to lipoplexes bigger than 3 microm composed of saturated cationic derivatives. Transmission electron microscopy studies clearly indicated that cationic lipid dispersions made by saturated derivatives form multilamellar tubules at physiological pH. Calorimetric studies showed that cationic amphiphiles with saturated acyl chains longer than 12 carbons exhibit solid-to-liquid crystalline phase transitions above 37 degrees C. In agreement with the microscopy and calorimetry studies, Langmuir film balance experiments indicated that saturated derivatives with hydrophobic chains longer that 12 carbons are not well hydrated and exist at a chain-ordered state at ambient temperature. Calculation of compressibility moduli from monolayer compression isotherms at 23 degrees C suggested that monolayers made by cationic lipids bearing saturated acyl chains are less compressible relative to those of the dioleoyl derivatives 1,3lmp5 and 1,3lmt5. In conclusion, high hydration, increased fluidity and high elasticity of cationic lipid assemblies in isolation, all correlate with high in vitro transfection activity.     

Synthesis,Structures, Resolution,and Chiroptical Properties of 1,16‐Diaryl‐Substituted Benzo[5]helicene Derivatives

An efficient route to the synthesis of benzo[5]helicene derivatives functionalized on the interior side of the helix was developed, and resulted in a series of 1,16‐diaryl‐substituted benzo[5]helicene derivatives starting from easily available 7‐methoxytetralone. X‐ray crystal structures showed that the benzo[5]helicene derivatives had highly helical, twisted structures, and could all create hierarchical packing architectures with alternating P and M layers in the solid state. Moreover, seven pairs of enantiomers based on 1,16‐diaryl‐substituted benzo[5]helicene derivatives were also obtained by efficient resolution through HPLC with semipreparative chiral columns. The enantiomers all showed clear mirror‐image circular dichroism (CD) spectra and high specific optical rotations, and their absolute configurations were determined by X‐ray crystallography. Interestingly, a helical nanotubular structure was formed by the self‐assembly of one enantiomer through halogen bonding. Furthermore, the enantiomers were found to have high racemization barriers and thermostability, which might be caused by the introduction of aryl substituents at the C1(C16) position.