An Abbreviated Synthesis of 7,12-Dimethylbenz[ a ]anthracene and Benzo[ c ]chrysene Metabolites Using the Suzuki Reaction

Efficient syntheses of important metabolites of 7,12-dimethylbenz[ a ]anthracene (DMBA) and benzo[ c ]chrysene (B[ c ]C), via Suzuki coupling reaction are described. This approach provides an excellent method for the preparation of 3-methoxy-DMBA 5 , 10-methoxy-B[ c ]C 14 and 2-methoxy B[ c ]C 20 , and hence for the corresponding dihydrodiols 6 , 15 , and 21 . Following a similar Suzuki reaction, DMBA-6(5 H )-one 8 was also synthesized in high yield.     

New SYNTHETIC METHOD OF 13H-DIBENZO[A,DE]ANTHRACENE-13-ONE

The polycyclic aromatic ketone, 13H-dibenzo[a,de]anthracene-13-one (5,6-BBz) is useful as a starting material for synthesis of undecacyclic aromatic compounds by means of condensation. To synthesize 5,6-BBz, glycerol condensation of benzo[a]anthraquinone was conducted. The condensation, however, gave two structural isomers besides 5,6-BBz and the isolation was very difficult; separation of the crude products by column chromatography or high-vacuum sublimation was unsuccessful because of their similarity in structure and vapor pressure. Only a little 5,6-BBz was obtained by repeated recrystallization, but the amount was insufficient for condensation. Thus, we developed a new synthetic method which affords 5,6-BBz selectively. 9-(o-Chlorobenzoyl)anthracene was synthesized by the Friedel-Crafts' reaction of anthracene with o-chlorobenzoyl chloride and aluminum chloride anhydride. In order to suppress the production of 9,10-di(o-chlorobenzoyl) anthracene, the reaction was performed at low temperature. The crude products obtained were purified by column chromatography on activated alumina and then recrystallized with benzene, which yielded yellow crystals of 9-(o-chlorobenzoyl)anthracene. The structure of 9-(o-chlorobenzoyl)anthracene was determined by X-ray diffraction analysis for the first time. Cyclo-dehydrohalogenation of 9-(o-chlorobenzoyl) anthracene gave 5,6-BBz selectively, the amount of which was sufficient for synthesizing undecacyclic aromatic hydrocarbons.     

Effect of Methyl Substitution on Molecular Shapes and Dimensions of Phenanthrenes and Benz[a]anthracenes

For polynuclear aromatic hydrocarbons (PAH) such as the benz[a]anthracenes (BA), carcinogenic activity is appreciably influenced by the numbers and positions of methyl and other substituents and hence by the molecular shapes. The planarities and dimensions, as determined by X-ray single-crystal structure analyses, of methyl-substituted BA and related PAH, including methyl phenanthrenes (MP) which also contain the carcinogenically important bay and K regions, are compared.

BA molecules with substituents well removed from the bay region, including those substituted at 5 or 6 (the K region), are nearly, but not quite, planar, with a mutual inclination of several degrees between A and C rings on each side of the bay region. With one or both bay positions 1 and 12 methyl-substituted, distortion is much greater (A/C up to 29° in 1,12-dimethyl BA). For phenanthrenes, the presence of the two methyl substituents in the bay, as in 2,4,5,7-tetra MP, can lead to A/C of 28° compared with the very small (2°) mutual inclination in 9,10-di MP. In the bay regions of all the PAH studied, the beach C–C bond is typically as long as 1.45–1.46 Å and the beach C–C–C bond angles are enlarged to 122–123°.     

Syntheses of Dibenzo[h,rst]Pentaphene and Naphtho[1,2,3,4-rst]Pentaphen

Abstract

Syntheses of the fused heptacyclic polyarenes dibenzo[h,rst]pentaphene (1), naphthol[1,2,3,4-rst]pentaphene (2), and the pentacyclic polyarene 8H-naphth[1,2,3-de]anthracene (8), of interest in carcinogenesis research, are described.     

Synthesis of 2-Hydroxybenzo[a]pyrene,a Tumorigenic Phenol Derivative of Benzo[a]pyrene

An efficient synthesis of 2-hydroxybenzo[a]pyrene (1a) from 4,5,9,10-tetrahydropyrene via 2-methoxy-4,5,9,10-tetrahydropyrene (2e) is described. Friedel–Crafts acetylation of tetrahydropyrene affords the 2-acetyl derivative which is transformed to the 2-methoxy derivative 2e via Baeyer–Villager oxidation, hydrolysis, and treatment with dimethyl sulfate. Friedel–Crafts succinoylation of 2e with succinic anhydride and AlCl₃ takes place regiospecifically in the 7-position. The product is transformed to 1a via Clemmensen reduction, HF cyclization, Wolff–Kishner reduction, catalytic dehydrogenation, and demethylation with HBr.     

Comparison of N-Heterocyclic Aromatics Dibenzo[c,g]Carbazole and Dibenz[a,j]Acridine : Metabolism,DNA Binding and Mutation

N-Heterocyclic aromatics, such as carbazole and acridine derivatives, are environmental carcinogenic pollutants. Examples of these compounds are 7H-dibenzo[c,g]carbazole (DBC) and dibenz[a,j]acridine (DBA). The ionization potential (IP) for DBC is lower than for DBA. DBC is metabolized in lung and liver by way of phenols or directly through radical cations. DBC-induced liver and lung tumors have mutations in the 61^st codon of ras. DBA is metabolized in skin by way of a diol-epoxide of DBA. DBA-induced skin tumors have mutations in 12^th, 13^th and 61^st codons of ras. In summary, the metabolic activation of DBC proceeds through different adduction pattern pathways than does DBA and leads to different ras mutational spectra.     

Synthesis and Structure Determination of the Adducts of Dibenzo[a,l]pyrene Diol Epoxides and Deoxyadenosine or Deoxyguanosine

Abstract

(±)?Syn?dibenzo[a,l]pyrene diol epoxide (DB[a,l]PDE) and (±)?anti?DB[a,l]PDE were reacted with deoxyadenosine (dA) or deoxyguanosine (dG) in dimethylformamide at 100 °C for 30 min. The crude products were purified by reverse phase HPLC under gradient and isocratic conditions. The structure of each adduct was assigned by 1D and 2D NMR spectra and by fast atom bombardment mass spectrometry. Five adducts were isolated from the reaction of (±)?syn?DB[a,l]PDE and dA: syn?DB[a,l]PDE?N⁶dA?1, syn?DB[a,l]PDE?N⁶dA?2, syn?DB[a,l]PDE?N⁶dA?3, syn?DB[a,l]PDE?N⁶dA?4 and syn?DB[a,l]PDE?N7Ade. Four adducts were isolated from the reaction of (±)?anti?DB[a,l]PDE and dA: anti?DB[a,l]PDE?N⁶dA?1, anti?DB[a,l]PDE?N⁶dA?2, anti?DB[a,l]PDE?N⁶dA?3 and anti?DB[a,l]PDE?N⁶dA?4. Two adducts were isolated from the reaction of (±)?syn?DB[a,l]PDE and dG: (±)?11,12,13?trihydroxy?tetrahydroDB[a,l]P?14?N²dG and (±)?11,12,13?trihydroxy?tetrahydroDB[a,l]P?14?N7Gua. Two adducts were isolated from the reaction of (±)?anti?DB[a,l]PDE and dG: (±)?11,12,13?trihydroxy?tetrahydroDB[a,l]P?14?N²dG and (±)?11,12,13?trihydroxy?tetrahydroDB[a,l]P?14?N7Gua.     

5-(4-叠氮呋咱基)-[1,2,3]三唑[4,5-c]并呋咱内盐的合成、晶体结构及性能

以3,4-二氨基呋咱为原料,经重氮化-叠氮化、氧化-环化等反应合成了一种新型无氢富氮含能材料5-(4-叠氮呋咱基)-[1,2,3]三唑[4,5-c]并呋咱内盐(AFTF);采用红外光谱、核磁共振、元素分析等方法表征了目标物的结构;获得了AFTF的单晶并进行了晶体结构解析;采用DSC方法研究了AFTF的热稳定性,初步探讨了氧化-环化反应机理;采用Gaussian 09程序CBS-QB3方法计算了AFTF的固相生成热,基于晶体密度和固相生成热,利用EXPLO5爆轰软件预估了AFTF的爆轰性能。结果表明,化合物AFTF晶体为正交晶系,空间群为P 2(1)2(1)2(1),晶胞参数为:a=8.1782(17),b=8.6446(18),c=11.521(2),V=814.5(3)3,Z=4,μ=0.151 mm^-1,F(000)=440;AFTF的熔点为101.02℃,热分解温度为186.39℃;AFTF晶体密度为1.795 g/cm 3(296 K),氮含量为63.6%,理论爆速为8.982 km/s,爆压为33.5 GPa,生成热为1178.9 kJ/mol,爆热为6450.8 kJ/kg,表明AFTF是一种爆轰性能优良的无氢富氮高能量密度化合物,有望应用于高能推进剂或气体发生剂领域;低熔点特性有望使其作为熔铸炸药载体使用。     

Reaction of hydrazonoyl halides 49 1: Synthesis and antimicrobial activity of some new pyrimido[1,2-b][1,2,4,5]tetrazin-6-one,tetrazino[3,2-b]quinazolin-5-one,pyrimidino[1,2-b]1,2,4,5-tetrazin-5-one and triazolo[4,3-a]pyrimidine derivatives

Pyrimido[1,2-b][1,2,4,5]tetrazin-6-one, tetrazino[3,2-b]quinazolin-5-one, pyrimidino[1,2-b]1,2,4,5-tetrazin-5-one and triazolo[4,3-a]pyrimidine derivatives were synthesized from C-(4-methyl-2-phenyl)thiazol-5-oyl-N-phenyl-hydrazonoyl bromide and different pyrimidine-2-thiones. New compounds had their structures confirmed by elemental and spectral analysis and were screened antimicrobial activity.     

Crystal Structure of HydG from Carboxydothermus hydrogenoformans: A Trifunctional [FeFe]‐Hydrogenase Maturase

The structure of the radical S‐adenosyl‐L ‐methionine (SAM) [FeFe]‐hydrogenase maturase HydG involved in CN^?/CO synthesis is characterized by two internal tunnels connecting its tyrosine‐binding pocket with the external medium and the C‐terminal Fe₄S₄ cluster‐containing region. A comparison with a tryptophan‐bound NosL structure suggests that substrate binding causes the closing of the first tunnel and, along with mutagenesis studies, that tyrosine binds to HydG with its amino group well positioned for H‐abstraction by SAM. In this orientation the dehydroglycine (DHG) fragment caused by tyrosine Cα?Cβ bond scission can readily migrate through the second tunnel towards the C‐terminal domain where both CN^? and CO are synthesized. Our HydG structure appears to be in a relaxed state with its C‐terminal cluster CysX₂CysX₂₂Cys motif exposed to solvent. A rotation of this domain coupled to Fe₄S₄ cluster assembly would bury its putatively reactive unique Fe ion thereby allowing it to interact with DHG.     

对称四甲基六元瓜环与2-戊基苯并咪唑盐酸盐自组装包合物晶体结构

以对称四甲基六元瓜环(TMeQ[6])为主体,2-戊基苯并咪唑盐酸盐(PB)为客体,在水溶液中自组装形成主客体超分子化合物{PB@TMeQ[6]}.Cl.9(H2O),利用X-射线单晶衍射技术对化合物的晶体结构进行了表征。实验结果表明,主客体之间通过多种非共价键作用形成1∶1的主客体包合物,客体的芳环被瓜环包结于空腔内,烷基置于瓜环端口外侧,包合物结构单元之间与共用水分子通过氢键连接成一维超分子链。     

Comparative Oncogenic Activation of 7H-Dibenzo[C,G]Carbazole and Dibenz[A,J]Acridine

7H-Dibenzo[C, G]carbazole (DBC) is a potent liver, lung and skin carcinogen while dibenz[A, J]acridine (DBA) is a moderate skin carcinogen. DBC is metabolized to phenols and DBC-DNA adducts are formed through the 2-, 3-, and 4-phenols or directly through radical cations. Mutations in ras as a result of DBC, activation are found exclusively in codon 61 in liver, lung and skin. DBA is metabolized to dihydrodiols, and phenols and DBA-DNA adducts are formed through the diol-epoxides and possibly through bis-diol-epoxides. Mutations in ras, as a result of DBA activation, are found in codons 12, 13, and 61. These results indicate that although the two compounds are structurally similar, differing by one carbon in the middle ring, there are differences in their metabolism, DNA binding, mutational spectra and target-organ carcinogenesis.     

1-氟-二苯[a,d]环庚酮的合成

以邻苯二甲酸酐和邻氟苯乙酸为原料,经高温缩合、还原、环化得到1-氟二苯[a,d]环庚酮,总收率为33.2%。该方法操作较简便,收率较高,具有工业生产价值。     

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 Effect of 7 H -Dibenzo[ c,g ]carbazole and Benzo[ a ]pyrene Mixture on DNA Adduct Formation in Strain A/J Mouse Model: Preliminary Report

Complex mixtures consist of homocyclic and heterocyclic polycyclic aromatic compounds (PACs) represented by benzo[ a ]pyrene (B a P) and 7 H -dibenzo[ c,g ]carbazole (DBC), respectively. To exert their biological effects, PACs are metabolized into reactive intermediates, which can form DNA adducts. In this preliminary report, male A/J mice were given a single intraperitoneal injection. Groups of three animals were treated with DBC (2 or 10 mg/kg) or B a P (10 or 100 mg/kg). Mixtures of DBC:B a P were given at doses of 2:10, 2:100, 10:10, or 10:100 mg/kg. DNA adduct levels in lungs collected three days posttreatment were determined by the 32 P-postlabeling method. The results indicate that, in the lungs, exposure to mixtures containing more B a P than DBC resulted in the absence of adduct 3 (DBC) and significantly higher total adduct levels. This suggests that B a P is being preferentially metabolized, resulting in less DBC adduction.     

A novel synthesis of indeno[2',1': 5,6] pyrido[2,3- d ][1,2,4]triazolo[4,3- a ]pyrimidines

Reaction of 5-(4-chlorophenyl)-2-thioxo-2,3-dihydro-1H-indeno[2',1':5,6] pyrido[2,3-d]pyrimidine-4,6-dione with hydrazonoyl chlorides gave 1,2,4-triazolo[4,3-a]pyrimidine derivatives regioselectively in good yields. The structures of the newly synthesized compounds are established on the basis of chemical and spectroscopic evidence as well as their synthesis by alternative methods.     

7-苄氨基-9,10-二氢-1,2,4-三氮唑并[4,3-a]喹啉衍生物的合成

以6-氨基-3，4-二氢-2(1H)-喹啉酮为起始原料，经缩合、还原、硫代、环合等反应合成了5个未见报道的7-苄氨基-9，10-二氢-1，2，4-三氮唑并[4，3-a]喹啉衍生物。产物及中间产物的结构经红外光谱和核磁共振谱确证。     

3-取代-6,7-二氢-5H-吡咯[2,1-c][1,2,4]三唑-5-羧酸甲酯的合成研究

以2-吡咯烷酮-5-羧酸甲酯为原料,经甲基化、取代和环合等反应,合成了16个目标化合物,其中13个为新化合物,其结构经~1HNMR和HR-MS确证。并且研究了环合反应条件,确定了环合反应的溶剂、催化剂及用量,即以氯苯为溶剂,2 mol%的醋酸为催化剂。该合成方法环合条件温和、操作简单,具有较强的通用性。     

高效液相色谱法检测植物油中苯并[a]芘的含量

建立并验证高效液相色谱法检测植物油中苯并[a]芘的含量.将植物油样品溶于正己烷中混匀,用苯并[a]芘固相萃取柱净化,用正己烷洗脱苯并[a]芘,荧光检测器检测.苯并[a]芘在0.1～100μg/kg浓度范围内线性相关系数r2=0.9999,本方法平均回收率为96.95%～101.30%,相对标准偏差RsD为0.980%～...     

新环3-甲基-1-苯基-6-芳基偶氮-7-羟基双吡唑[5,1-c:3',4'-e]并-1,2,4-三嗪的合成

为进一步研发抑制细胞分裂周期磷酸酯酶CDC25B的抗肿瘤药物,以3-氨基-5-吡唑啉酮为原料,合成了8个新的标题化合物。通过元素分析、IR和1HNMR确证所得化合物的结构,并且确定其中有3个化合物对CDC25B具有较好的抑制活性。