Role of the Bay- and L-Regions in the Metabolic Activation and Carcinogenicity of Picene and Dibenz[ a,h ]anthracene

Early carcinogenicity tests found no evidence of activity for picene but found considerable initiating and carcinogenic activity for DBA. More recent investigation suggests that both pentacyclics are complete carcinogens when administered as single s.c. injections in NMRI mice, despite findings that picene acts as neither an initiating nor promoting agent. To investigate this contradiction, the complete carcinogenicity of both isomers was compared by s.c. injection in female Sprague-Dawley rats. The results demonstrated that 1 w mol of DBA administered three times weekly for 20 doses, induced sarcomas in all test animals by 33 weeks (100%). Similar treatment with picene did not induce sarcoma in any test animals by 37 weeks (0%). These present results agree with the earlier studies. It follows then that the metabolic activation and carcinogenicity of DBA and picene are dependent on the presence of an L-region, but are independent of the presence of a bay-region.     

5-Methoxy, 7-methylbenz[a]anthracene: Crystal Structure of a Planar Weak Carcinogen

Abstract

The crystal and molecular structure of 5-methoxy,7-methylbenz[a]anthracene has been determined by X-ray diffraction at room temperature to an R-index of 0.062 over 936 reflections. The molecule, the first methoxy-substituted methylbenz[a]anthracene to be analysed, is highly planar, with the carbon and oxygen atoms of substituents lying within 0.04 Å of the mean plane of the polycyclic skeleton. Carbon–oxygen bond lengths in the methoxy group are unequal at 1.372(7) and 1.426(9) Å and the C_aromatic–O bond makes dissimilar angles of 113.5(7) and 124.3(7)° at C(5). The shortest C–C bonds are C(5)–C(6) = 1.351(9) at the substituted K-region, C(8)–C(9) = 1.352(9), C(10)–C(11) = 1.362(9) Å, and C(3)–C(4) = 1.361(10) Å. In the unsubstituted bay region, the long beach bond C(13)–C(18) = 1.454(9) Å is flanked by beach bond angles C(12)–C(18)–C(13) = 121.2(6) and C(18)–C(13)–C(1) = 123.1(6)°.     

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.     

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.     

Synthesis and characterization of 9,10-[di-p-(7-diethylamino- coumarin-3-yl) thiopheneyl]anthracene as fluorescent material

A novel N-coumarin derivative, namely 9,10-[di-p-(7-diethylamino-coumarin-3-yl) thiopheneyl]anthracene ((CTh)₂A), containing anthracene as the core and 3-thiophene N-coumarin as the substituent was synthesized, and its structure was confirmed by ¹H NMR and IR spectroscopies. The optical, electrochemical and thermal properties were investigated. Thermogravimetric analysis and PL spectra reveal the high thermal and good photoluminescence characteristics. The coumarin derivative exhibits blue photoluminescence with high fluorescence quantum yield in solution (up to 40%). The results show that the derivative would serve as promising organic light-emitting diode luminescent material.     

DNA Polymerase Action on Oligonucleotide Templates from Human Ha-ras Protooncogene Containing N6-Deoxyadenosine Adducts Derived from Trans Addition of (+)- and (-)-anti-Benzo[c]phenanthrene-3,4-dihydrodiol 1,2-epoxides at Codon 61

In the present work we have used a DNA polymerase assay to investigate the primer extension with T7 DNA polymerase (Sequenase 2.0) and the Klenow fragment of Escherichia coli DNA polymerase I (exo ^? KF) on chemically synthesized 21mer templates representing partial sequences of the human Ha-ras protooncogene with site-specifically positioned trans-N ⁶-dA adducts of (-)- (adduct 1) and (+)-anti-benzo[c]phenanthrene 3,4-dihydrodiol 1,2-epoxides (adduct 2) at codon 61 (CA?G; A? indicates the adducted position). With Sequenase 2.0 a complete block of primer extension opposite both adduct 1 and 2 was noted using a 10mer primer reaching the (n-1)-position of the adduct. A detailed analysis revealed that Sequenase 2.0 exclusively allowed the misincorporation of dAMP opposite both adducts. In contrast, exo ^? KF allowed a significant full-length extension of the primer beyond adduct 2, whereas this process occured only to a very minor extent for adduct 1. Correspondingly, a more intensive block of the polymerization reaction opposite adduct 1 was seen. Analysis of the arrest bands revealed that dAMP was preferentially incorporated opposite to adduct 1; also incorporation of dGMP was observed, but to a minor extent. Similarly, dAMP was also incorporated opposite to adduct 2 along with dTMP, the latter indicating a correct base pairing. Additional experiments with exo ^? KF using different 11mer primers containing each of the four nucleotides opposite the adduct suggest that the primer extension beyond adduct 2 observed with the 10mer primer is an error-free process.     

N,N′-乙撑双[N(乙磺酸钠)-十二酰胺]的合成与性能评价

以乙二胺、2-氯乙基磺酸钠、月桂酸等为原料合成了N,N′-乙撑双[N(乙磺酸钠)-十二酰胺](简记为DTM-12)。以IR和1HNMR对其结构进行了初步表征。该目标产物水溶液的CMC(0.5 mmol/L)分别是十二烷基硫酸钠和十二烷基磺酸钠的1/16和1/20,γCMC(29.7 mN/m)低8~9 mN/m。DTM-12分别与十二烷基三甲基溴化铵(DTAB)和辛基酚聚乙氧基醚9-10EO(Triton X-100)组成的复配体系在摩尔比为3∶7时,CMC达到0.106和0.049 mmol/L,γCMC达到25.4和31.7 mN/m,优于十二烷基磺酸钠组成的复配体系。DTM-12还具有良好的起泡性和稳泡性。     

Synthesis of Stereoisomeric N 6-Deoxyadenosine Adducts of syn- and anti- Dihydrodiol Epoxides of Benzo[a]pyrene and Their Incorporation into 18-mer DNA Sequences from Human Ha-ras Protooncogene

Oligonucleotide sequences synthesized with specifically positioned and structurally defined adducts of dihydrodiol epoxides (DE) of polycyclic aromatic hydrocarbons like benzo[a]pyrene (B[a]P) are useful tools to study in detail the solution structure of corresponding duplexes by NMR techniques as well as the interaction of a single adduct with DNA polymerases. Here we report the successful incorporation of trans-N ⁶-dA-B[a]PDE adducts derived from the syn- and anti-diastereomers of B[a]PDE into 18-mer oligonucleotides representing partial human Ha-ras sequences surrounding codon 61 (CAG). The key step in our approach is a nucleophilic displacement reaction of a deoxyinosine derivative activated at the 6-position by a sulfonate group with a racemic aminotriol providing a regio- and stereospecific synthesis of the N ⁶-dA adducts. The aminotriol precursors are prepared by direct aminolysis of the DE's or by a stereoselective opening of the oxirane ring with sodium azide followed by reduction. The fully protected diastereomeric trans-N ⁶-dA-B[a]PDE adducts were separated by preparative HPLC and subsequently transformed into the corresponding phosphoramidites. The synthesis of four 18-mers was performed on a DNA synthesizer incorporating in each sequence [d(5′-GGC·CA*G·GAG·GAG·TAC·AGC-3′)] a single dA adduct (A*) at Codon 61 using standard phosphoramidite chemistry. After extensive purification of the 18-mers by reverse phase HPLC and analysis by PAGE, the presence of the trans-N⁶ -dA-B[a]PDE adducts in the oligonucleotides was confirmed by fluorescence spectroscopy.     

A Metabolic Activation Mechanism of 7 H -Dibenzo[ c,g ]carbazole Via o -Quinone. Part 1: Synthesis of 7 H -Dibenzo[ c,g ]carbazole-3,4-dione and Reactions with Nucleophiles

7 H -Dibenzo[ c,g ]carbazole (DBC) is a potent carcinogen present in the environment. The metabolic activation pathway of DBC has not been completely understood. The formation of the DBC- o -quinone was proposed and the novel DBC-3,4-dione was chemically synthesized from 4-OH- or 3-OH-DBC, using the Fremy's salt at room temperature. The DBC-3,4-dione was found to react readily with model nucleophile, 2-mercaptoethanol, to afford 1-(2'-hydroxyethylthio)-DBC-3,4-dione through 1,4-Michael addition. An adduct of DBC-3,4-dione with adenine was obtained; adducts formed with other DNA bases and nucleosides were partially characterized and are under further analysis. Under the same conditions, DBC-3,4-dione with guanine did not yield an adduct. These results are encouraging for further studies on DNA binding of DBC through 3,4-dione in vitro and in vivo.     

超分子化合物(C12N2H9)2(C12N2H8)[SW12O40]的合成与结构表征

利用水热法合成了超分子化合物（C12N2H9）2（C12N2H8）[SW12O40],通过元素分析和X射线单晶衍射确定了其晶体结构,该晶体为正交晶系,P2（1）2（1）2（1）空间群,晶胞参数为a=12．0168（3）A^。,b=21．0534（6）A^。,c=22．5820（6）A^。,V=5713．1（3）A^。^3,α=β=γ=90°,Z=4,Dc=3．977mg·m^-3,并通过IR和XRD进行了结构表征,采用热重分析研究了晶体的热稳定性。该化合物由邻菲罗林和Keggin结构[SW12O40]^2-阴离子组成,以氢键自组装成超分子结构化合物。     

Production and Immunochemical Characterization of a High-Affinity Monoclonal Antibody Specific for 7-(Benzo[a]pyren-6-yl)guanine (Bp-6-N7GUA), a Depurinating DNA Adduct of Benzo[a]pyrene

Molecular dosimetry of depurinating DNA adducts of benzo[a]pyrene (BP) offers a promising new approach to determining risk of PAH-induced cancer. Depurinating adducts are the predominant form of BP-induced DNA damage, are excreted in urine and, importantly, are linked to cancer initiation. We have produced a monoclonal antibody (MAb) with high specific affinity for BP-6-N7Gua, a major depurinating DNA adduct of BP, and have developed a sensitive and specific competitive enzyme-linked immunosorbent assay (ELISA). The I_50S (quantity producing 50% inhibition of MAb binding in the ELISA) of selected BP adducts and metabolites were determined. The results indicated 1) a high degree of discrimination between BP-6-N7Gua (I₅₀=750 fmol) and BP (I₅₀=900,000 fmol), 2) high affinity of the MAb for BP-6-N7Ade (I₅₀=1,500 fmol), another major depurinating DNA adduct, and 3) specific structural requirements for MAb-adduct binding. In addition, the competitive ELISA provided an accurate determination of BP-6-N7Gua added to normal human urine, at a sensitivity of 200 fmol.     

B12H12［N(C2H5)4］2对NEPE推进剂燃烧性能的影响

研究了硼氢化合物 B1 2 H1 2 [N(C2 H5 ) 4] 2 对 NEPE推进剂燃烧性能的影响 ,采用 DSC分析了 B1 2 H1 2 [N(C2 H5 ) 4] 2 与 NEPE推进剂主要组分硝酸酯的相容性以及对推进剂固化反应的催化作用和对高氯酸铵、硝胺常压热分解的催化作用 ,并利用恒压静态燃速仪测试了推进剂在 4～ 1 1 MPa的燃烧速度和燃速压力指数     

Effect of Absolute Configuration on the Optical and NMR Properties of Oligonucleotides Containing Benzo[a]Pyrene Adducts at N 6 of Deoxyadenosine

For oligonucleotide duplexes derived from trans opening of benzo[a]pyrene diol epoxides (BaP DEs) by the exocyclic N⁶-amino group of deoxyadenosine (dA), the hydrocarbon is intercalated toward the 5′-end of the modified strand when the configuration at the site of attachment of the base to the hydrocarbon (C-10) is R, and toward the 3′-end when this configuration is S. In oligonucleotide 11-mer duplexes modified by BaP DE-1 (benzylic 7-OH and epoxide oxygen cis) and DE-2 (7-OH and epoxide oxygen trans), as well as 7,8,9,10-tetrahydro BaP 9,10-epoxide, 10R adducts had consistently higher (5–9d°C) T_m values than the corresponding 10S adducts. Dodecamer duplexes from the HPRT gene with trans opened 10S (but not those with 10R) BaP DE-2 adducts at either of two adjacent dA residues exhibited blue shifts at ～350 nm at temperatures well below the T_m. We propose that these blue shifts result from a conformation in which the hydrocarbon is not stacked with the DNA bases.     

Effect of Caloric Restriction on the Metabolism of Benzo[a]pyrene (BaP) and the Formation of BaP-DNA Adducts in Male Fischer 344 Rats

Abstract

The effect of caloric restriction (CR) on activities of xenobiotic metabolizing enzymes results in alterations in the metabolic activation of chemical carcinogens, with a resultant impact on DNA-carcinogen adduct formation. Using benzo[a]pyrene (BaP) as a model carcinogen, we have studied the effect of CR on the metabolic activation of BaP, in terms of both BaP metabolism and BaP-DNA adduct formation. Male Fischer 344 rats fed CR diets (60% of the food consumption of ad libitum?fed rats) showed higher activities of BaP metabolizing enzymes resulting in increases of BaP metabolism in vitro and BaP-DNA adduct formation in vivo. The results of the study of the effect of CR on the in vitro metabolism of BaP showed that CR increased the total BaP metabolism, as well as BaP-t-9, 10-diol and BaP-t-4, 5-diol formation. However, BaP-t-7, 8-diol, a proximate carcinogenic metabolite of BaP, was decreased by liver microsomes from CR-rats. Our results indicate that the effect of CR on metabolic activation of a chemical carcinogen was dependent upon the selected xenobiotic metabolizing enzymes whose activity may be significantly altered by CR.     

[Ru(bpy)_2dppz]~(2+)的合成及其与DNA的相互作用研究

首先通过两步反应合成了"光开关"分子,[Ru(bpy)2dppz]2+(简称Ru-dppz; bpy=2,2'-联吡啶,dppz=二吡啶[3, 2-a; 2', 3'-c]吩嗪),并分别用紫外-可见吸收光谱法、核磁共振和质谱表征其结构。再利用荧光法考察了Ru-dppz与双链DNA(dsDNA)的相互作用。结果表明:随着Ru-dppz与dsDNA的结合,Ru-dppz荧光强度增加。根据荧光滴定实验结果,计算所得Ru-dppz与dsDNA的结合常数为1.5×107L/mol,结合比为0.14。     

First discrete six-coordinate [Hg(N,N,S-pytsc)2] complex with a uninegative pyridine-2-carbaldehyde thiosemicarbazonate

First discrete example of six-coordinate mercury (II) complex, Hg(η³-N⁴,N³,S-pytsc)₂1, with tridentate pyridine-2-carbaldehyde thiosemicarbazonate (pystc⁻) anion having distorted trigonal prismatic geometry is described.     

无机-有机杂化硼酸盐晶体[C_6N_4H_20]_(0.5)[B_5O_6(OH)_4]的合成与表征

介绍了在低温水浴中采用溶剂蒸发法合成硼酸盐晶体[C6N4H20]0.5[B5O6(OH)4]的实验。分别采用X射线粉末衍射仪、热重分析仪和红外分析仪对样品进行了表征,通过对不同大型仪器的使用,能够使学生掌握仪器操作的方法、提高谱图解析的能力。该实验为最新的科学研究成果,知识点新颖,同时将无机合成实验与大型仪器表征有机的结合在一起,不仅能够提高学生的科研能力,还能培养学生的创新思维。     

The Interaction of Sheep Genomic DNA with a Cobalt(II) Complex Containing p-Nitrobenzoate and N,N′-Diethylnicotinamide Ligands

The synthesized cobalt(II) complex, CoPNBDENA and the binding of this complex with sheep genomic DNA were investigated by UV–Visible absorption and viscosity techniques. Also the interaction of sheep genomic DNA with the complex was studied using the agarose gel electrophoresis method. The results indicated that the complex interacted with DNA. The nature of the binding seemed to be mainly an electrostatic interaction between DNA and the cobalt(II) complex. Other binding modes such as hydrogen bonds may also exist in this system. In this study, after the interaction of DNA–CoPNBDENA, it was observed that the migration of the DNA band became slow as the amount of cobalt(II) complex was increased. This clearly demonstrates that the CoPNBDENA complex neutralizes the negative charges of DNA.     

三维开放框架结构的无机-有机杂化材料[Cu4(SiW12O40)（pyz）4]的合成与晶体结构

以α-Keggin型硅钨酸、碳酸铜和2-乙基-3-甲基吡嗪(pyz)为原料,通过水热方法合成了标题化合物。采用元素分析、红外光谱和单晶X-射线衍射法表征了该化合物的结构。晶体结构分析表明,该化合物属于正交晶系,Pna21空间群,晶胞参数a=2.238 38(4)nm,b=1.386 87(3)nm,c=2.151 07(3)nm,α=β=γ=90°,V=6.677 7(2)nm3,Z=4,F(000)=6 408,Dc=3.598 g/cm3。该化合物中一价铜离子首先被pyz配体连接成波浪型的一维链状结构,而(SiW12O40)4-阴离子作为三齿配体进一步连接这些链形成一个三维的框架结构。