Two-component,one-pot synthesis of pyrimido[1,2-b] [1,2,4,5]tetrazines

Derivatives containing the cyclohepta4′,5′thieno[2′,3′:4,5]pyrimido[1,2-b][1,2,4,5]-tetrazin-6-one system were prepared from the reaction of 3-amino-2-thioxo-1,2,3,5,6,7,8,9-octahydro-4H-cyclohepta[4,5]thieno[2,3-d]pyrimidin-4-one (5) or its 2-methylthio derivative 6 with hydrazonoyl chlorides 9. The mechanism of the studied reactions has been discussed and the biological activity of the isolated products has been evaluated.     

2-巯基-5-甲氧基咪唑并[4,5-b]吡啶的合成及表征

以2,6-二氯吡啶为原料,用甲醇/氢氧化钠体系进行甲氧基取代,用硝酸钾/浓硫酸进行硝化反应,再用氨水氨解,制得2-氨基-3-硝基-6-甲氧基吡啶(Ⅲ),最后用氯化亚锡于75℃反应4h还原Ⅲ,再用二硫化碳环化合成2-巯基-5-甲氧基咪唑并[4,5-b]吡啶,总收率为43.6%。产物结构用IR、1HNMR和MS作了表征。     

8-氨基苯并[4,5]呋喃并[3,2-d]嘧啶类衍生物的合成与结构表征

以5-硝基水杨醛为原料,经过氰基化、醚化、两次成环、氯代等反应合成11个新型的8-位氨基取代苯并[4,5]呋喃并[3,2-d]嘧啶类化合物,利用1HNMR、13CNMR、IR和MS对其结构进行了表征,并对该反应条件进行了探索,得出最优的反应条件。     

The synthesis of fused and pendant pyrazole heterocyclic compounds from 5-amino-3-methyl-1-phenylpyrazole and their evaluation as fluorescent brightening agents

5-Amino-3-methyl-1-phenylpyrazole ( 1 ) has been condensed with EMME ( 2 a) and EMCA ( 2 b) and the resulting ethyl 5-aminoacrylates ( 3 a–b) cyclized to pyrazolo[3,4,-b]pyridines ( 4 a–b). 3-Methyl-1-phenylpyrazol-5-yl diazonium salt ( 7 ), prepared from ( 1 ) was coupled with tobias acid ( 8 ) and 2-methoxy-6-aminoquinoxaline ( 9 ) to get the corresponding O-aminoarylazo and heterylazo dyes ( 10 ) which were oxidatively cyclized to 2-N-(3-methyl-1-N-phenylpyrazol-5-yl)-1,2,3-triazolo[4,5-a] naphthalene and [4,5-f] quinoxaline derivative ( 11 ). The spectral properties of the compounds ( 4 a–b, 5 , 6 , 11 a–b) were studied.     

Synthesis,antimicrobial, anti-inflammatory and antioxidant activity of novel Spiro (imidazo[4′,5′:4,5′]benzo[1,2-e][1, 4] thiazepine)-9,3′-indolines

An efficient synthesis of novel spiro(imidazo[4′,5′:4,5′]benzo[1,2-e][1, 4]thiazepine)-9,3′-indolines has been accomplished from 5-amino-2-mercapto benzimidazole, istains and mercapto acetic acid. Compounds 6 were characterized by IR, ¹H NMR, ¹³C NMR and mass spectral data. The title compounds 6a–6e were evaluated for their antimicrobial, anti-inflammatory and antioxidant activity. Compounds 6a–6e exhibited significant antimicrobial activity, and as potent anti-inflammatory and antioxidant activities as that shown by standard drugs.     

6-甲基-2-苯基咪唑[2,1-b]并-1,3,4-噻二唑-5-N'-取代苯基亚甲基碳酰肼的设计与合成

根据已有的具有抗肿瘤活性的咪唑[2,1-b]并-1,3,4-噻二唑类化合物的结构及其构效关系,以2-氨基-5-苯基-1,3,4-噻二唑和溴代乙酰乙酸乙酯为原料设计并合成了8个6-甲基-2-苯基咪唑[2,1-b]并-1,3,4-噻二唑-5-碳酰肼的腙类衍生物.通过1HNMR、LC-MS、IR等方法对其结构进行了确证.     

Effect of the Route of Administration on the Induction of Cytogenetic Damage and DNA Adducts in Peripheral Blood Lymphocytes of Rats and Mice by Polycyclic Aromatic Hydrocarbons

Experiments were designed to investigate how the route of exposure to polycyclic aromatic hydrocarbons (PAHs) in mice and rats affects the induction of cytogenetic end points and DNA adduction. Both mice and rats were exposed to 100 mg/kg of benz[ a ]anthracene (B[ a ]A), benzo[ b ]fluoranthene (B[ b ]F), benzo[ a ]pyrene (B[ a ]P), or chrysene (Chr) by gavage or by intraperitoneal injection (i.p.). Peripheral blood was removed by cardiac puncture 7 days after PAH administration. Blood samples were analyzed in parallel for sister chromatid exchange (SCE) frequency, the frequency of micronuclei in cytochalasin B-induced binucleate cells (MN bn ), and DNA adduction using 32P-postlabeling. The i.p. route of exposure produced both the highest levels of cytogenetic damage and DNA adducts for each PAH. The mouse was more sensitive than the rat to PAH exposure as measured by SCE induction and the total amount of DNA adducts/ w g DNA.     

Synthesis of 2 and 6-triazolylthiazolo[4,5-b]quinoxaline derivatives and their application as fluorescent disperse dyes

Synthesis of 2-triazolylthiazolo[4,5-b]quinoxaline derivatives was achieved by diazotisation of 2-aminothiazolo[4,5-b]quinoxaline and its 6-nitro derivative using orthophosphoric acid and sodium nitrite with a trace of nitric acid, coupling with suitable aromatic amines and subsequent cyclisation of the resulting ortho amino azo compounds. Diazotisation of 2,6-diaminothiazolo[4,5-b]quinoxaline with concentrated hydrochloric acid and sodium nitrite and subsequent coupling and cyclisation resulted in the 6-triazolylthiazolo[4,5-b]quinoxaline derivatives. These compounds were applied on polyester as fluorescent disperse dyes.     

Identification of Stereochemical Configurations of Cyclopenta[ cd ]pyrene DNA Adducts in Strain A/J Mouse Lung and C3H10T1/2CL8 Cells

Four major and several minor DNA adducts were resolved by 32 P-postlabeling analysis of DNA from strain A/J mouse lung and C3H10T1/2CL8 (C3H10T1/2) mouse embryo fibroblasts treated with cyclopenta[ cd ]pyrene (CPP). The identical pattern of adducts was seen in vivo and in vitro. Cochromatography of synthetic resolved diastereomers of cis - and trans - N 2 -CPP-deoxyguanosine-3'-phosphates with the in vivo adducts obtained from strain A/J mouse lung and in vitro adducts obtained from C3H10T1/2 cells allowed identification of the predominant DNA adduct as cis -(3 R ,4 S )- N 2 -CPP-deoxyguanosine. The second most abundant adduct formed in vivo and in vitro was identified as trans -(3 S ,4 S )- N 2 -CPP-deoxyguanosine.     

2-巯基-5-甲氧基咪唑并［4,5-b］吡啶的合成工艺

对新型质子泵抑制剂泰妥拉唑的关键中间体2-巯基-5-甲氧基咪唑并[4,5-b]吡啶的合成工艺进行了研究，以2,6-二氯吡啶为原料，先硝化得到2,6-二氯-3-硝基吡啶，然后经胺化得2-氨基-3-硝基-6-氯吡啶，再与甲醇钠反应得2-氨基-3-硝基-6-甲氧基吡啶，用铁粉还原得2,3-二氨基-6-甲氧基吡啶，最后与二硫化碳环化制得标题化合物。各步反应的最佳反应条件(反应温度，反应时间，摩尔收率)分别为，硝化： 110℃, 8 h, 79.3％; 胺化：室温, 10 h, 87.6％; 甲氧基化：65℃, 30min, 98.7％; 还原：回流, 3hrs; 环化：回流, 4hrs, 71.3％(还原及环化两步)。 标题化合物熔点与文献报道一致，并通过1H NMR进一步确证结构。     

噻吩并[2,3-d]嘧啶衍生物的研究现状

2,4-二氨基噻吩并[2,3-d]嘧啶类衍生物和2-氨基-4-氧代噻吩并[2,3-d]嘧啶类衍生物是一些重要生物活性化合物的母体结构,对这两类化合物进行了归纳,并对其合成方法逐一进行了简要阐述.     

1-[2-氨基-1-（对甲氧基）乙基]环己醇的合成工艺改进

改进了抗抑郁药文拉法新的中间体1-[2-氨基-1-（对甲氧基）乙基]环己醇的合成工艺，以对甲氧基苯乙腈和环已酮为原料，硼氢化钾和三氯化铝作为还原催化剂，经缩合和加氢还原反应，总收率78．2％。反应条件温和，成本较低，适合工业化生产。     

Evaluation of PAH: DNA Adduct Formation in Rats Fed Coal Tar-Contaminated Diets

Previous studies have demonstrated that mouse lung is a target organ for the tumorigenic and genotoxic effects of coal tar. The present study evaluated PAH:DNA adduct formation in lung, liver, forestomach, and mammary gland of female CD rats fed various types of coal tar-contaminated diets. Coal tar-contaminated soil, an organic extract of contaminated soil, neat coal tar, and diets containing only B[ a ]P were evaluated. Ingestion of coal tar diets resulted in detectable levels of DNA adducts in lung and forestomach tissue. These adducts were primarily derived from benzo[ c ]fluorene and B[ a ]P. The adduct derived from benzo[ c ]fluorene was the most predominant. No adducts were detected in liver and mammary gland under the conditions employed in this study. The formation of a benzo[ c ]fluorene-derived DNA adduct in rat lung following coal tar exposure is consistent with previous studies performed with mice.     

Synthesis of Thiazolo(4,5-b)-quinoxalines and related compounds

The reaction of 2,3,7-trichloroquinoxaline ( 1 ) or 2,3-dichloro-7-bromoquinoxaline ( 2 ) with thiourea in DMSO gave 6,6′-dichloro- or 6,6′-dibromodiquinoxalino[2,3-b:2′:3′-e]1,4-dithiien ( 3 or 4 ). However, 1 or 2 reacts with thiourea in ethanol to give ( 3 or 4 ) beside 7-chloro- or 7-bromo-2-imino-2,3-dihydrothiazolo[4,5-b] quinoxaline ( 5 or 6 ) respectively. Interaction of 1 or 2 with acetone thiosemicarbazone gave 7-chloro- or 7-bromo-3-amino-2-imino-2,3-dihydro-thiazolo[4,5-b] quinoxaline hydrochloride ( 13 or 14 ) respectively. Cyclization of 7-chloro- or 7-bromo-3-amino-2-imino-2,3-dihydrothiazolo[4,5-b]quinoxaline ( 15 or 16 ) on treatment with aromatic acid chlorides or isothiocyanates succeeded to give 19—21 or 28 and 29 .     

Synthesis of Dihydrodiol Metabolites of Naphtho[8,1,2- GHI ]Chrysene and Dibenzo[ C,MNO ]Chrysene

Syntheses of naphtho[8,1,2- ghi ]chrysene (naphtho[1,2- e ]pyrene, N[ e ]P) 1 , dibenzo[ c,mno ]chrysene (naphtho[1,2- a ]pyrene, N[ a ]P) 2 and their dihydrodiol metabolites are described. The hydrocarbons N[ e ]P 1 and N[ a ]P 2 and their fjord region dihydrodiols 12 and 19 were synthesized using a Suzuki cross-coupling reaction followed by the appropriate manipulation of the functional groups. The K-region cis dihydrodiols of N[ e ]P-4,5-diol 20 , N[ a ]P-4,5-diol 23 , N[ a ]P-7,8-diol 24 were obtained by OsO 4 oxidation. The cis diols thus obtained were first converted to the corresponding quinones with pyridinium chlorochromate and, finally, to the desired trans dihydrodiols 22 , 27 , and 28 by NaBH 4 reduction. The mixture of trans N[ a ]P-4,5- and 7,8-dihydrodiols was separated by high-performance liquid chromatography.     

The Role of Cytochrome P450 1B1 in Dibenzo[ a,l ]pyrene-induced Carcinogenesis

In human cells, the most carcinogenic polycyclic aromatic hydrocarbon dibenzo[ a,l ]pyrene (DB[ a,l ]P) forms high levels of DNA adducts through formation of the ( m )- anti -(11 R ,12 S )-diol (13 S ,14 R )-epoxide (DB[ a,l ]PDE) and its metabolic precursor, the ( m )-(11 R ,12 R )-diol. Generation of these adducts results from the catalytic activity of cytochrome P450 (P450) 1A1 and 1B1. Additional adducts such as (+)- syn -DB[ a,l ]PDE-DNA or more polar DNA adducts were detected only after increasing exposure doses of the parent compound or in cells that express P450 1A1. At low concentrations (·;100 nM) exclusively ( m )- anti -DB[ a,l ]PDE-DNA adducts were formed by P450 1B1, which is constitutively expressed in many mammalian tissues. Measurement of DNA binding and mutagenicity of DB[ a,l ]P in V79 cells expressing human P450 enzymes revealed a higher activity of P450 1B1 compared to 1A1 at low concentrations. Treatment of P450 1B1 knockout mice and DNA binding studies with fibroblasts isolated from these animals provided further evidence for the central role of P450 1B1-catalyzed formation of ( m )- anti -DB[ a,l ]PDE-DNA adducts in DB[ a,l ]P-induced carcinogenesis.     

Synthesis of some new fused thiopyrano[2,3-d]thiazoles and their derivatives

A series of some new fused thiopyrano[2,3-d]thiazole derivatives have been synthesized by a stereo-selective hetero-Diels-Alder reaction of 5-(2,4-dihydroxy-benzylidene)-4-thioxo-thiazolidine derivatives 3a,b with acrylonitrile, ethyl acrylate, N-phenylmale-imide, ω-nitrostyrene and N-phenyl-1, 3, 4-triazole-2,5-dione. 5-Amino-9-hydroxy-dihydro-benzopyrano[3′,4′:4,5]thiopyrano[2,3-d]thiazol-6-one derivatives 14a,b have been synthesized by Michael addition of 3a,b with malononitrile. Structures and conceivable mechanisms are discussed.     

Regioselective synthesis of new 5-methyl-5H-pyrimido[4′,5′:4,5][1,3]thiazino [3,2-a]perimidines

A convenient and efficient regioselective synthesis of new pyrimido[4′,5′:4,5] [1,3]thiazino[3,2-a]perimidines is described through intermolecular heterocyclization of 2,4-dichloro-5-(chloromethyl)-6-methylpyrimidine and 1H-perimidine-2(3H)-thione in short reaction times under mild conditions.     

EFFICIENT NEW SYNTHESES OF POLYCYCLIC AROMATIC HYDROCARBON ORTHO-QUINONES AND THEIR 2′-DEOXYRIBONUCLEOSIDE ADDUCTS

Three mechanisms have been proposed to explain the carcinogenic activities of polycyclic aromatic hydrocarbons (PAHs). On the basis of the nature of the active metabolites involved, they may be termed: the diol epoxide mechanism, the quinone mechanism, and the radical-cation mechanism. In connection with studies to evaluate the relative importance of these pathways, we required practical methods for the syntheses of the active PAH metabolites involved. We now report efficient new synthesis of the o-quinones of benzo[a]pyrene (BPQ), 7,12-dimethylbenz[a]anthracene (DMBAQ), and benz[a]anthracene (BAQ). These quinones are convenient synthetic precursors of the related o-catechols, trans-dihydrodiols, and diol epoxides, as well as the stable adducts of the o-quinones with 2-deoxyadenosine and 2′-deoxyguanosine.     

Photooxygenation of the Condensation Products of Naphthanthrone

The structure of the polycyclic aromatic hydrocarbon with the absorption maximum at 567 nm, synthesized by the condensation of naphth- anthrone (NT), was deduced to be benzo[rs]dinaphtho[2, 1, 8, 7-klmn:2, 3, 4, 5, 6-vwxyz]hexaphene (BDH) by semi-empirical molecular orbital calculation methods. The photooxygenation of BDH and benzo[op]naphtho[2, 1, 8, 7-hijk]anthra[2, 1, 9, 8-stuva]-pentacene (BNAP) due to irradiate to light with each absorption maximum was investigated by measurering the absorption spectra and applying semi-empirical molecular orbital calculation methods. BNAP is synthesized by the same reaction process together with dibenzo[de:op]dinaphtho[2, 1, 8, 7-hijk : 2′, 1′, 8′, 7′-syuv]pentacene (DDP). BNAP and BDH do not undergo photooxygenation. On the other hand, DDP undergoes photooxygenation. The empirical results were illustrated in terms of difference in heat of reaction, which were 25.5 and 30.2 kJ/mol for BDH and BNAP, respectively. Their values are considerably larger than -3.1 kJ/mol of DDP. The difference in heat of formation seems to be the reason why BDH and BNAP does not undergo photooxygenation.