A comparative study of the thermal stability of oligodeoxyribonucleotides containing 5-substituted 2'-deoxyuridines

Two series of modified oligonucleotides based on the self-complementary dodecamer d(CGCTAATTAGCG) were synthesized. The first contained the -C identical withCCH2R linker at C5 of deoxyuridine at position 4 (T*) of d(CGCT*AATTAGCG) and the second contained the -SR linker. The goal of the study was to evaluate and compare these two types of side chains for suitability as tethers for linking reporter groups to oligonucleotides. Our primary concern was how these tethers would effect duplex stability. The modified nucleosides were synthesized by palladium-mediated coupling reactions between the substituted alkyne and 5'-(4, 4'-dimethoxytrityl)-5-iodo-2'-deoxyuridine and between a disulfide and 5-chloromercurio-2'-deoxyuridine. The C5 deoxyuridine side chains evaluated included C identical with CCH3, C identical with CCH2NHC(O)CH3, C identical with CCH2N(CH3)2, C identical with CCH2N-HC(O)C5H4N, C identical with CCH2NHC(O)C10H15, SCH3, SC6H5 and SCH2CH2NHC(O)CH3. The nucleosides containing these substituents were incorporated into oligo-deoxyribonucleotides by standard phosphoramidite methodology. Melting studies demonstrated that the sequence containing the C identical with CCH3side chain had the highest T m value (59.1 degrees C) in comparison with the control sequence (T m = 55.2 degrees C) and that any additional substituent on C3 of the propynyl group lowered the T m value relative to propynyl. Nevertheless, even the most destabilizing substituent, adamantylcarbamoyl, yielded an oligodeoxyribonucleotide that dissociated with a T m of 54 degrees C, which is only 1.2 degrees C less than the control sequence. In contrast, the thioether substituents led to lower T m values, ranging from as low as 45.1 degrees C for SPh up to 52.2 degrees C for SMe. Replacing the methyl of the SMe substituent with a CH2CH2NHC(O)CH3 tether led to no further reduction in melting temperature. The T m value of the CH2CH2NHC(O)CH3-containing oligonucleotide was less than the natural sequence by 1.6 degrees C/substituent. This is sufficiently small that it is anticipated that the C5 thioether linkage may be as useful as the acetylenic linkage for tethering reporter groups to oligonucleotides. More importantly, the thioether linkage provides a means to position functional groups to interact specifically with opposing complementary (target) sequences.     

Synthesis of 5-substituted quinazolinone derivatives and their inhibitory activity in vitro

Quinazolinone derivatives I and their methyl esters were synthesized and evaluated as nonclassical lipophilic inhibitors of thymidylate synthase. Compounds Ib and Ic containing OH and CO2H as R substituents, respectively, were most effective, indicating that hydrogen bonding may contribute to the increased inhibitory activity. These compounds further showed high cytotoxic activity against tumor cells in culture.     

Synthesis of 1- and 2-substituted indazoles as anthelmintic agents

Selective synthesis of 1- and 2-acyl-, alkoxycarbonyl-, and carbamoylindazoles are described. Spectroscopic data which were the basis for structural assignments are presented. These compounds, particularly methyl 2H-indazole-2-carboxylate and N-heptyl-N-methyl-2H-indazole-2-carboxamide, lack the spectrum of anthelmintic activity of the benzimidazole and benzotriazole anthelmintics to which they are structurally related.     

Some 6-aza-5-substituted-2'-deoxyuridines show potent and selective inhibition of herpes simplex virus type 1 thymidine kinase

The synthesis and X-ray crystal structures of a series of 5-substituted-6-aza-2'-deoxyuridines is reported. These nucleoside analogues inhibit the phosphorylation of thymidine by HSV-1 TK but have no effect on the corresponding human enzyme. Detailed examination of one analogue proves it to be a competitive inhibitor of thymidine with a Ki of 0.34 microM and is a very poor substrate. The analogues are not substrates for the enzyme and also do not inhibit the degradation of thymidine by thymidine phosphorylase. Molecular modelling showed that the inhibitors fit well in the active site of HSV-1 TK, provided the conformation of the sugar moiety is the same for thymidine in the complex.     

5-叔丁基水杨醛的合成与表征

无水条件下,以4-叔丁基酚为原料,在甲氧基镁作用下对多聚甲醛进行醛基化反应合成5-叔丁基水杨醛,确立了较优的反应条件:96℃下,n(镁)∶n(4-叔丁基酚):n(多聚甲醛)=1.2∶2∶7,反应时间3 h。最佳条件下,5-叔丁基水杨醛收率达73.1%。采用1HNMR、元素分析对产物进行了结构表征。     

Synthesis, structural analysis and pharmacological effects of N2-substituted 3,4-dihydrobenzo[h]quinolin-2-amines

The introduction outlines possibilities for the design of potentially pharmacologically interesting new modifications of phenylethylamine (1) and reviews already known and nearly prepared derivatives of 1 with bridged side chains. The N2-substituted 3,4-dihydrobenzo[h]quinolin-2-amines 11a-e represent bridged beta-azanaphthylethenamines or naphthyl-formamidines. Their synthesis started from 3-chloro-N-(1-naphthyl)propionamide (14) and led via dihydrobenzoquinolinone 15, thione 19 and methylthiobenzoquinoline hydroiodide 20. HI as intermediates first to the hydroiodides of 11a-e. Treatment of 11c, d. HI with sodium hydroxide yielded the free amines 11c, d. Structure, tautomerism, (Z, E)-isomerism and conformation of the prepared benzoquinolines were studied and elucidated by one and two dimensional NMR. A synopsis of the manyfold pharmacological effects, which were found in the course of the testing of 11a-e. HI, completes the paper.     

1 beta-Methyl-2-(5-substituted pyrrolidin-3-ylthio)carbapenems. 3. Synthesis and antibacterial activity of BO-2727 and its related compounds

The synthesis and biological activity of (1R,5S,6S)-2-[(3S,5S)- 5-substituted pyrrolidin-3-ylthio]- 6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylic acid in which hydroxy-substituted aminoethyl, aminopropyl, and aminobutyl groups were introduced as substituents, are described. These derivatives showed potent antibacterial activity against Gram-positive and Gram-negative bacteria including P. aeruginosa. Among them, lenapenem (BO-2727, 7b), carrying an (R)-1-hydroxy-3-(N-methylamino)propyl group, was selected as a development candidate.     

Some new 3-methoxy-5-methyl-1,4-substituted pyrazoles

A series of 3-methoxypyrazole derivatives was synthesized and tested as antifungal agents. The substituents were chosen on the base of their lipophylicity and for their presence in well-known antifungal drugs. The compounds displayed no significant activity in vitro.     

Room-Temperature Mechanochemical Synthesis of W2B5 Powders

The mechanochemical synthesis of W₂B₅ powders was successfully carried out at room temperature. WO_2.72, B₂O₃ and Mg powder blends were mixed to form batches according to the metallothermic reduction of WO_2.72 and B₂O₃ with Mg, which were subsequently mechanically alloyed (MA) using a Spex mill at different durations to constitute W₂B₅ + MgO as final products. Following mechanochemical synthesis, MgO was removed from the system by leaching the powders with HCl. Microstructural and morphological characterizations of boride powders were carried out via scanning electron microscopy (SEM) and X-ray diffraction (XRD) analyses. Moreover, atomic absorption spectroscopy (AAS) and differential scanning calorimetry (DSC) experiments were carried out to monitor the purity of the powders at different stages of the process. After mechanical alloying of the powder batches comprising 50 pct stoichiometrically excess amount of B₂O₃ for 30 hours and leaching with a 7 M HCl solution, pure W₂B₅ powders with an average particle size of 226 nm and an average grain size of 55.3 nm were successfully synthesized.     

Structure-activity relationship of new 2-substituted penem antibiotics

The antibacterial activities of three new penems with 4-hydroxyprolinamide, 1-prolinamide and N-methyl-N-2-propionamide substituents, respectively, in position 2 and of their stereoisomers were examined against Staphylococcus aureus, Enterococcus faecalis, Enterococcus faecium, Escherichia coli and Pseudomonas aeruginosa. All substitutes conferred a broad antibacterial spectrum on the penem moiety. Changes in stereoisomerism selectively improved the activity against E. coli, S. aureus or enterococci. The structure-activity relationships of each compound were discussed in relation to minimum inhibitory concentrations, penicillin-binding protein (PBP) affinity and outer membrane permeability coefficient in E. coli. In this microorganism, PBP 2 was the target for all compounds. Changes in stereoisomerism influenced the affinity for PBPs 1A/B and 2. All antibiotics easily permeated the outer membrane of E. coli and, within each group of compounds, the penetration rate correlated with the antibacterial activity.     

Synthesis, local anaesthetic and antiarrhythmic activity of methyl N-(2-substituted aminopropanoyl)-3-cyanoanthranilates

A series of methyl N-(2-substituted aminopropanoyl)-3-cyanoanthranilates (4a-i), that are structurally-related to tocainide and lidocaine, was synthesized and was found to be active when evaluated for local anaesthetic activity using the frog-foot withdrawal reflex, the guinea pig wheal derm and the rabbit corneal reflex tests. A selected numbers of the series were preliminarily evaluated for antiarrhythmic activity using CaCl2-induced arrhythmia test. Compounds 4a, 4c and 4f at lower doses completely protected the animals against the induced arrhythmias.     

Liquid-liquid extraction of aluminium and gallium with 5-substituted 8-hydroxyquinolines

Various 5-substituted 8-hydroxyquinolines have been synthesized and their extractive properties studied for the separation of Ga and Al in strongly basic medium (3.5 M NaOH). Among the synthesized molecules, only YEN 10 and YAN 5 (with side chains C₁₀H₂₁CHC ∠ C₁₀H₂₁ and C₅H₁₁C ∠ C₁₁H respectively) extract the gallium ion. The extracted complexes are Ga (YAN 5)₃ and Ga (YEN 10)₂(OH)₂⁻Na⁺ and the conditional extraction constants are 10^7.5 and 10⁴, respectively. The constants for aluminium extraction are 10^7.7 and 10^3.5, respectively. YAN 5 is not selective for Ga versus Al. The rate of phase transfer is first order with respect to Ga and extractant concentrations. The phase transfer constants are 1.2×10⁻⁵ for YAN 5 and 1.05×10⁻⁵ for YEN 10, if the rate is expressed in mol m⁻² s⁻¹ and the concentrations in mol L⁻¹. These values are lower than for Kelex 100. The interfacial measurements show that the 5-substituted molecules are less concentrated at the interface than Kelex 100 molecules.     

2-substituted quinoline alkaloids as potential antileishmanial drugs

Ten 2-substituted quinoline alkaloids isolated from a plant used for treatment of New World cutaneous leishmaniasis have antileishmanial in vitro activities against the extracellular forms of Leishmania spp. BALB/c mice infected with Leishmania amazonensis PH8 or H-142 or Leishmania venezuelensis were treated 1 day after the parasitic infection with a quinoline alkaloid (100 mg/kg of body weight per day) or with reference drug N-methylglucamine antimonate (Glucantime) (56 mg of pentavalent antimony [Sbv] per kg per day) for 14 days. Lesion development was the criterium used to assess disease severity. Two three-carbon chain quinolines [2-n-propylquinoline and 2-(1',2'-trans-epoxypropyl)quinoline (chimanine D)] were more potent than N-methylglucamine antimonate against L. amazonensis PH8, and five quinoline alkaloids [2-(3,4-methylenedioxyphenylethyl)quinoline, cusparine, 2-(3,4-dimethoxyphenylethyl)quinoline, 2-(E)-prop-1'-enylquinoline (chimanine B), and skimmianine] were as effective as the reference drug. Single treatment near the site of infection, 14 days after infection with L. amazonensis, with 2-n-propylquinoline or chimanine B reduced the severity of lesions but less notably than N-methylglucamine antimonate. 2-n-Propylquinoline exhibited significant activity against the virulent strain L. venezuelensis. The active products did not show any apparent toxicities during the experiment. This study is, to our knowledge, the first to show the activity of 2-substituted quinoline alkaloids for experimental treatment of New World cutaneous leishmaniasis. Further investigations of these compounds might yet prove helpful for the development of new antileishmanial drugs.     

2-羟基-5-特辛基苯乙酮肟的合成及表征

以四氯乙烯为溶剂,对特辛基苯酚、乙酰氯、无水AlCl3和盐酸羟胺为主要原料,采用分步合成法合成了2-羟基-5-特辛基苯乙酮肟.考察了无水AlCl3用量、乙酰氯的用量、Fries重排温度、肟化反应盐酸羟胺用量以及缚酸剂无水碳酸钠用量对产物产率的影响,实验结果表明,当n(AlCl3)∶n(乙酰氯)∶n(对特辛基苯酚)=1.5∶2∶1,Fries重排温度为120℃,n(Na2CO3)∶n(盐酸羟胺)∶n(对特辛基苯酚)=0.5∶1∶1.产物收率64.9%.对合成产物利用核磁共振进行了结构表征.     

Synthesis of oligonucleotides containing two putatively mutagenic DNA lesions: 5-hydroxy-2'-deoxyuridine and 5-hydroxy-2'-deoxycytidine

Spontaneous oxidative DNA damage occurs as a consequence of aerobic metabolism, lipid peroxidation, immune responses, ionizing radiation, and some chemical oxidants. These processes yield a vast array of oxidized DNA bases and sugars. The existence of significant steady-state levels of oxidized DNA bases in the genome suggests that these lesions are not completely repaired on a biologically relevant time scale and thus may contribute to mutagenesis. In particular, studies have shown that the steady-state levels of 5-hydroxy-2'-deoxycytidine (dC5-OH) and its deamination product, 5-hydroxy-2'-deoxyuridine (dU5-OH), are similar to those found for 7,8-dihydro-8-oxoguanosine, a known highly mutagenic lesion formed by oxidation of guanosine. Structural and biological properties of dC5-OH and dU5-OH have been constrained by the lack of synthetic methodology for oligonucleotides containing these modified bases. A method is described here for the solid-phase synthesis of oligonucleotides containing dC5-OH and dU5-OH. Preparation of each of the required phosphoramidites involved the selective protection of the base 5-hydroxyl group over the deoxyribose 5'- and 3'-hydroxyl groups. The base composition and the incorporation of the adducts into synthetic heptanucleotides were confirmed after purification of the modified oligonucleotides by enzymatic digestion and HPLC analysis. Mass spectrometric analysis of the oligonucleotide products by electrospray MS and GC/MS further confirmed their composition. Most significantly, deamination of the dC5-OH oligomer to a putative dU5-OH product during solid-phase DNA synthesis or oligonucleotide deprotection was not detected by any analytical technique employed.     

V_2O_5核壳结构微米球的合成及其电化学性能

中空结构的V_2O_5材料由于在锂离子嵌入和循环稳定性方面有明显优势,获得了科研人员的特别关注。然而通过简易方法来制备均匀且具有复杂内部结构的V_2O_5中空微米球仍面临挑战。本文首次利用V_2O_5、H_2C_2O_4·2H_2O、H_2O和正丁醇进行溶剂热反应,得到蛋黄结构前躯体,然后将前躯体于空气中烧结,获得均匀的多层V_2O_5核壳结构微米球。采用X射线衍射(XRD)、扫描电镜(SEM)、透射电镜(TEM)及电化学测试等手段对其进行表征和测试。V_2O_5核壳结构微米球用作锂离子电池正极材料时,在2.5~4 V电压区间、200 mA/g电流密度条件下放电比容量高达122 m Ah/g,循环200圈后容量保持率高达95.9%。该材料优异的电化学性能主要由于结合了低维和三维纳米结构。     

5—[（4—氯—2—膦酸基苯基）偶氮]—8—氨基喹啉的合成及其与钴的显色反应研究

以8-氨基喹啉为母体合成了5-［（4-氯-2-膦酸基苯基）偶氮］-8-氨基喹啉（CPPAQ）。在pH8.1的硼砂缓冲溶液中,试剂与钴形成紫色络合物,其最大吸收波长位于590nm,表观摩尔吸光系数ε=1.28×105,钴量在0～10μg／25mL范围内符合比尔定律,方法用于VB12中钴的测定,结果满意。     

Synthesis of 11-substituted androstenediones and testosterones as human decidual cell growth inhibitors

11 alpha-Hydroxytestosterone (1a), 11 beta-hydroxytestosterone (1b), 11 alpha-methoxytestosterone (1c), 11 beta-methoxytestosterone (1d), 11-ketotestosterone (1e), and delta 9(11)-testosterone (1f) were synthesized from hydrocortisone (4b) or 11-epi-hydrocortisone (4a). The six target compounds, together with 11 alpha-methoxyandrostenedione (2c), 11 beta-methoxyandrostenedione, (2d) and their lead compound, testosterone (1), were found to effectively inhibit the growth and differentiation of human decidual cells in culture. There is no observable binding of these compounds to estrogen receptor of rabbit uterus. The introduction of a polar group (e.g., hydroxyl and carbonyl) to C-11 of androstenes decreases both the relative binding affinities to progesterone receptor and the inhibitory effects on human decidual cell growth, while the methylation of 11-hydroxyl group minimizes these effects. The similar effects of a polar group at C-11 of testosterone (1) on the inhibitory effects on human decidual cell growth and the relative binding affinities to progesterone receptor of rabbit uterus may suggest that one of the mechanisms of human decidual cell growth inhibition by these compounds is the anti-progestational activity of these androgens.