新型吡咯并三嗪酮类PARP-1抑制剂的设计、合成及生物活性

分别以5-溴-2-氟苯甲腈(1a)和3-溴苯甲腈(1b)为原料,经Sonogashira偶联,脱三甲基硅基保护基,三分子偶联及水解等5步反应制得中间体2-氟-5-［(4-氧代-3,4-二氢吡咯［1,2-d］［1,2,4］三嗪-1-基)甲基］苯甲酸（6a)和3-[(4-氧代-3,4-二氢吡咯［1,2-d］［1,2,4］三嗪-1-基)甲基］苯甲酸（6b）。环烷基甲酸经酰氯化,缩合和脱Boc保护基3步反应制得环烷基哌嗪-1-基甲酮(7a~7c)。 6a与NCS（1 eq.）反应制得5-［(6-氯-4氧代-3,4二氢吡咯［1,2-d］［1,2,4］三嗪-1-基)甲基］-2氟 苯甲酸(6c); 6a与NCS(2 eq.)反应制得5-［(6,7-二氯-4氧代-3,4二氢吡咯［1,2-d］［1,2,4］三嗪-1-基)甲基］-2氟-苯甲酸(6d)。 6a~6d, 6a~6c分别与7a~7c和1-（2-嘧啶基）哌嗪在TBTU（缩合剂）,DIPEA（碱）的作用下合成了13个新型吡咯并三嗪酮类PARP-1抑制剂(8a~8m),其结构经¹HNMR和MS(ESI)表征。采用Alarm blue法研究了8a~8m对肿瘤细胞MDA-MB-436的抑制活性(IC₅₀)。结果表明：8f, 8g, 8i和8j对MDA-MB-436有较强的抑制活性（IC₅₀=30.5~69.3 nmol·L^-1）。     

Oxidative azacyclization of 1-monosubstituted thioureas in reaction with [bis(acyloxy)iodo]arenes to form 1,2,4-thiadiazole derivatives

For the first time, derivatives of 1,2,4-thiadiazoles have been obtained by the reaction of [bis(acyloxy)iodo]arenes with 1-monosubstituted thioureas. 1-Acetylthiourea is subject to intermolecular azacyclization to form 3,5-bis-(acetylamino)-1,2,4-thiadiazole in reaction with [bis(acyloxy)iodo]benzene. 1-Phenylthiourea forms 3,5-bis-(phenylamino)-1,2,4-thiadiazole in a single-stage reaction with (diacetoxyiodo)benzene. The reaction of 1-phenylthiourea with [bis(trifluoroacetoxy)iodo]benzene leads to the formation of 5-imino-4-phenyl-3-phenylamino-4H-1,2,4-thiadiazoline.     

Fine-tuning of metallaborane geometries: chemistry of iridaboranes derived from the reaction of

From reaction of [(Cp*Ir)2HxCl(4-x)] (x=1, 0) and LiBH4, arachno-[[Cp*IrH2]B3H7](1) is produced in moderate yield concurrently with [Cp*IrH4]. In contrast, reaction of [(Cp*Ir)2H2Cl2] with LiBH4 results in arachno-[[Cp*IrH]2(mu-H)B2H5] (3) in high yield at room temperature but a mixture of 1 and [[Cp*IrH]2(mu-H)BH4] (2) at 0 degrees C. BH3 x THF converts 1 to arachno-[(Cp*IrHB4H9] (4) and 2 to 3 with 1 as a minor product. Further, reaction of 3 with excess of BH3 x THF results in formation of nido-[[Cp*Ir]2-(mu-H)B4H7] (6) formed by loss of H2 from the intermediate arachno-[[Cp*IrH]2B4H8] (5). Reaction of 1 with [Co2(CO)8] permits the isolation of two metallaboranes, arachno-[[Cp*Ir(CO)]-B3H7] (7) and nido-[1-[Cp*Ir]-2,3-Co2-(CO)4(mu-CO)B3H7] (8). Treatment of 4 with [Co2(CO)8] gives only one single mixed-metal metallaborane nido-[1-[Cp*Ir]-2-Co(CO)3B4H7 (9) in high yield. Finally, pyrolysis of 8 results in loss of hydrogen and formation of pileo-[1-[Cp*Ir]-2,3-Co2(CO)5B3H5] (10) with a BH-capped square-pyramidal structure. With kinetic control rational synthesis of a variety metallaboranes has been achieved by varying the number of chlorides in the monocyclopentadienylmetal halide dimer, reaction temperature, types of monoborane, and metal fragment sources.     

Synthesis under microwave irradiation of [1,2,4]triazolo[3,4-b] [1,3,4]thiadiazoles and other diazoles bearing indole moieties and their antimicrobial evaluation

Microwave-assisted synthesis of some novel compounds, namely, 3-(2-methyl-1H-indol-3-yl)-6-aryl-[1,2,4]triazolo[3,4-b][1,3,4]thiadiazoles 5a,b was accomplished via bromination of 2-methyl-3-[4-(arylideneamino)-5-mercapto-4H-[1,2,4]triazol-3-yl]-1H-indoles 3a,b. Also, new [1,3,4]thiadiazoles 12a,b, [1,2,4]triazoles 15a,b and [1,3,4]oxadiazoles 19a,b, with indole moieties, were prepared by cyclization of 1-[(2-methyl-1H-indole)-3-carbonyl]thiosemicarbazides 8a,b under microwave irradiation using different reaction conditions. Moreover, reaction of acid hydrazide 7 with ethyl 2-(N-phenylhydrazono)-3-oxobutanoate (20) gave the respective phenylhydrazonopyrazole derivative 21 under the reaction conditions employed. The structures of the synthesized compounds were assigned based on elemental analyses and spectral data (IR, (1)H-NMR, (13)C-NMR, MS). The antifungal and antibacterial activities of the new products were also evaluated.     

新型Bluco类β-内酰胺酶分子探针的合成

以2-氰基-6-羟基苯并噻唑为原料,与溴乙醛缩二乙醇缩合制得缩醛后再水解合成中间体6-(2-羰乙基)苯并[d]噻唑-2-甲腈(2);7-苯乙酰氨基-3-氯甲基头孢菌烷酸二苯甲酯依次经碘代和Wittig反应得(Z)-3-[3-(2-氰基苯并[d]噻唑-6-氧)丙-1-烯]-8-羰基-7-(2-苯乙酰氨基)-5-噻-1-氮[4.2.0]辛-2-烯-2-甲酸二苯甲酯(5);5经脱保护、缩合和氧化反应合成了3个新的Bluco类似物,其结构经1H NMR,13C NMR和HR-MS(ESI)表征。     

Chemo- and periselectivity in the addition of [OsO2(CH2)2] to ethylene: a theoretical study

Quantum chemical calculations by using density functional theory at the B3LYP level have been carried out to elucidate the reaction course for the addition of ethylene to [OsO2(CH2)2] (1). The calculations predict that the kinetically most favorable reaction proceeds with an activation barrier of 8.1 kcal mol(-1) via [3+2] addition across the O=Os=CH2 moiety. This reaction is -42.4 kcal mol(-1) exothermic. Alternatively, the [3+2] addition to the H2C=Os=CH2 fragment of 1 leads to the most stable addition product 4 (-72.7 kcal mol(-1)), yet this process has a higher activation barrier (13.0 kcal mol(-1)). The [3+2] addition to the O=Os=O fragment yielding 2 is kinetically (27.5 kcal mol(-1)) and thermodynamically (-7.0 kcal mol(-1)) the least favorable [3+2] reaction. The formal [2+2] addition to the Os=O and Os=CH2 double bonds proceeds by initial rearrangement of 1 to the metallaoxirane 1 a. The rearrangement 1-->1 a and the following [2+2] additions have significantly higher activation barriers (>30 kcal mol(-1)) than the [3+2] reactions. Another isomer of 1 is the dioxoosmacyclopropane 1 b, which is 56.2 kcal mol(-1) lower in energy than 1. The activation barrier for the 1-->1 b isomerization is 15.7 kcal mol(-1). The calculations predict that there are no energetically favorable addition reactions of ethylene with 1 b. The isomeric form 1 c containing a peroxo group is too high in energy to be relevant for the reaction course. The accuracy of the B3LYP results is corroborated by high level post-HF CCSD(T) calculations for a subset of species.     

Synthesis of 4(pyrazol-3-yl)[1,2,4]triazolo[4,3-a]quinoxalines and tetrazolo analog

The transformation of 2-chloro-3-[5-(acetoxymethyl)-1-phenylpyrazol-3-yl]quinoxaline 3 to 1-aryl-4-[5-(hydroxymethyl-1-phenylpyrazol-3-yl][1,2,4]triazolo[4,3-a]quinoxalines 4a-c has been achieved upon treatment with aroylhydrazines in boiling butanol. Compounds 4a-c were smoothly acetylated by acetic anhydride to give their acetyl derivatives 5a-c in good yield. 4-[5-(Acetoxymethyl)-1-phenylpyrazol-3-yl]-1-methyl[1,2,4]triazolo[4,3-a]quinoxaline was prepared by ring closure of 2-hydrazino-3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]quinoxaline 6 by the action of acetic anhydride. The reaction of 6 with acetylacetone afforded 3-[5-(hydroxymethyl)-1-phenylpyrazol-3-yl]-2-(3,5-dimethylpyrazol-1-yl)quinoxaline 8 . In addition, the reaction of 3 with sodium azide in boiling N, N-dimethylformamide yielded the fused tetrazolo[1,5-a]quinoxaline 9 .     

(E)-1-alkyl-4-

(E)-1-Alkyl-4-[2-(alkylsulfonyl)-1-ethenyl]pyridinium salts were synthesized in two steps. These sulfones were stable at pH 7.3 and underwent a nucleophilic vinylic substitution (S(N)V) with mercaptans, including thiouracile, to give the corresponding 4-(thiovinyl)-pyridinium salts. The X-ray diffraction structure of (E)-1-methyl-4-[2-(ethylsulfanyl)-1-ethenyl]pyridinium iodide indicated conjugation of the sulfur with the pyridinium ring. (Z)-1-Methyl-4-[2-(methylsulfanyl)-1-ethenyl]pyridinium iodide, prepared from the corresponding thioether by reaction with methyl iodide in diethyl ether, underwent isomerization to the E isomer in a first-order reaction in deuterated [D6]DMSO with an activation energy of 14 kcalmol(-1). At pH 7, the (E)-1-methyl-4-[2-(methylsulfonyl)-1-ethenyl]pyridinium iodide (19) reacted specifically with thiols. The reaction of this sulfone with glutathione in a TES buffer at pH 7 was a second-order reaction (k = 4,100 M(-1)s(-1) at 30 degrees C) and gave the corresponding substitution product with an intense long wavelength absorption band (lambdamax=360 nm, epsilon = 27,500 M(-1)cm(-1)). The modification of different enzymes of known structure with 19 showed the high selectivity of this reagent towards thiol groups and its usefulness in the quantitative determination of free thiol groups in proteins.     

Gold-catalyzed cyclization of (ortho-alkynylphenylthio)silanes: intramolecular capture of the vinyl-Au intermediate by the silicon electrophile

The gold-catalyzed cyclization of (ortho-alkynylphenylthio)silanes 1 produced the corresponding 3-silylbenzo[b]thiophenes 2 in good to excellent yields. For example, the reaction of [2-(1-pentynyl)phenylthio]triisopropylsilane 1a, [2-(p-anisylethynyl)phenylthio]triisopropylsilane 1e, and [2-(phenylethynyl)phenylthio]triisopropylsilane 1g in the presence of 2 mol % of AuCl in toluene at 45 degrees C gave 2a, 2e, and 2g in 98, 99, and 97% yields, respectively. This reaction proceeds through intramolecular capture of the vinyl-Au intermediate by the silicon electrophile, so-called silyldemetalation.     

Samarium(II) iodide mediated radical/polar crossover reactions of cyclobutenes. An efficient approach to the BCD ring system of the penitrems

[reaction: see text] Radical/polar crossover reactions of derivatives of 1-(2-cyclobutenyl)-2-(2-iodoaryl)ethanones with acetone promoted by samarium diiodide and HMPA provide 1-(1-hydroxy-1-methylethyl)-2,2a,4,8b-tetrahydro-1H-cyclobuta[a]naphthalen-3-one derivatives in about 50% isolated yield. This reaction shows promise for construction of the BCD ring fragment of the penitrems.     

[Z]-1-[2-(三芳基锡基)乙烯基]环辛醇的合成和性质

本文用三苯基氢化锡、三对甲苯基氢化锡作为锡氢化试剂与1-乙炔基环辛醇进行反应, 合成了两个有机锡化合物: [Z]-1-[2-(三苯基锡基)乙烯基]环辛醇(1)和[Z]-1-[2-(三对甲苯基锡基)乙烯基]环辛醇(2), 并测定了1的晶体结构。1和2分别与ICl, Br2, I~2反应, 得到六个有机锡一卤化物和三个有机锡二卤化物(3-11)。有机锡二卤化物6和一卤化物5与KOH乙醇溶液反应, 分别得到相应的锡氧化物和锡氢氧化物(12, 13)。有机锡二卤化物8分别与含氮双齿配体[2,2'-联吡啶(Bipy),5-硝基-1,10-邻菲罗啉(Nphen),8-羟基喹啉(Oxin)]反应, 得到三个相应的配合物(14-16)。十六个新化合物通过元素分析、锡含量测定、IR、^1H NMR测定对其结构进行了表征, 同时提出了1和2的生成反应历程。     

Synthesis of 1,2-diazepino[3,4-b]quinoxalines and pyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxalines via a 1,3-dipolar cycloaddition reaction

The reaction of 6-chloro-2-(1-methylhydrazino)quinoxaline 4-oxide 8 with furfural, 3-methyl-2-thiophene-carbaldehyde, 2-pyrrolecarbaldehyde, 4-pyridinecarbaldehyde and pyridoxal hydrochloride gave 6-chloro-2-[2-(2-furylmethylene)-1-methylhydrazino]quinoxaline 4-oxide 5a , 6-chloro-2-[1-methyl-2-(3-methyl-2-thienyl-methylene)hydrazino]quinoxaline 4-oxide 5b , 6-chloro-2-[1-methyl-2-(2-pyrrolylmethylene)hydrazino]quinoxa-line 4-oxide 5c , 6-chloro-2-[1-methyl-2-(4-pyridylmethylene)hydrazino]quinoxaline 4-oxide 5d and 6-chloro-2-[2-(3-hydroxy-5-hydroxymethyl-2-methyl-4-pyridylmethylene)-1-methylhydrazino]quinoxalme 4-oxide 5e , respectively. The reaction of compound 5a or 5b with 2-chloroacrylonitrile afforded 8-chloro-3-(2-furyl)-4-hydroxy-1-methyl-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6a or 8-chloro-4-hydroxy-1-methyl-3-(3-methyl-2-thienyl)-2,3-dihydro-1H-1,2-diazepino[3,4-b]quinoxaline-5-carbonitrile 6b , respectively, while the reaction of compound 5e with 2-chloroacrylonitrile furnished 11-chloro-7,13-dihydro-4-hydroxy-methyl-5,14-methano-1,7-dimethyl-16-oxopyrido[3′,4′:9,8][1,5,6]oxadiazonino[3,4-b]quinoxaline 7.     

Synthesis and rearrangements of aminosubstituted ferra- and ruthenatricarbaboranes

A room-temperature reaction between the [7-tBuNH-nido-7,8,9-C3B8H10]- anion (1a) and [Cp*RuCl]4 leads to the ruthenatricarbollide [1-Cp*-12-tBuNH-1,2,4,12-RuC3B8H10] (2) (yield 85%). Analogously, the room-temperature photochemical reaction of 1a with [CpFe(C6H6)]PF6 gives the previously reported iron complex [1-Cp-12-tBuNH-1,2,4,12-FeC3B8H10] (3) (yield 82%). Both reactions are associated with extensive polyhedral rearrangement, which occurs under very mild conditions and brings the carbon atoms to positions of maximum separation within the framework. Compounds 2 and 3 were also surprisingly obtained via complexation of the isomeric [8-tBuNH-nido-7,8,9-C3B8H10]- (1b) anion. Complex 2 rearranges further to [1-Cp*-10-tBuNH-1,2,4,10-RuC3B8H10] (4) upon refluxing in xylene (145 degrees C). Density functional theory calculations at the B3LYP/SDD level were used to estimate relative stabilities of these metallacarborane isomers. Compounds 2 and 4, along with the 11-vertex closo compounds [1-Cp*-1,2,3,10-RuC3B7H10] (5) and [1-Cp*-10-tBuNH-1,2,3,10-RuC3B7H9] (6), were also isolated from the reaction between [Cp*RuCl2]2 and 1a in boiling xylene. The structure of 2 was established by an X-ray diffraction study, and the constitution of all compounds was determined unambiguously by multinuclear NMR spectroscopy, mass spectrometry, and elemental analyses.     

Catalytic asymmetric synthesis of allylic aryl ethers

[reaction: see text] The reaction of trichloroacetimidate derivatives of (Z)-2-alken-1-ols with phenol nucleophiles in the presence of the palladium(II) catalyst [COP-OAc]2 provides 3-aryloxy-1-alkenes in high yields and high enantiomeric purity (typically 63-90% yield and 90-97% ee). The reaction is exemplified by 20 examples. The method employs 1 mol % of the commercially available catalysts (S)- or (R)-[COPOAc]2, produces the branched isomer with unprecedented regioselectivity, and is compatible with the presence of base-labile functionality in either reactant.     

Synthesis of some new pyrimidine selanyl derivatives

The targeted synthesis of 2-(methylsulfanyl)-6-(furan-2-yl)-4(3H)-selenoxo -pyrimidine-5-carbonitrile failed due to the formation 1-methyl-2-methylsulfanyl-6-oxo -4-(furan-2-yl)-1,6-dihydropyrimidine-5-carbonitrile. A new series of 5,6,7,8-tetrahydro-1-benzo thieno[2,3-d]pyrimidine-4-yl substituted selanyl derivatives were prepared by the reaction of sodium diselenide with 4-chloro-5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine followed by the reaction with chloroacetic acid derivatives such as ethyl chloroacetate, chloroacetamide or chloroacetonitrile. Hydrazinolysis of ethyl (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidine- 4-ylselanyl)acetate with hydrazine hydrate gave the corresponding hydrazino derivative. The latter reacted with ethyl acetoacetate, acetylacetone, diethyl malonate, ethoxymethylenemalononitrile or ethyl 2-cyano-3-ethoxyacetate to afford 5-methyl-2-[2-(5,6,7,8-tetrahydro-1-benzothieno [2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazol-3-one, 1-(3,5-dimethylpyrazol-1-yl)-2- (5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)ethanone, 1-[2-(5,6,7,8-tetrahydro -1-benzothieno[2,3-d]pyrimidine-4-ylselanyl)acetyl]-2,4-dihydropyrazolidine-3,5-dione and 5-Amino-1-[2-(5,6,7,8-tetrahydro-1-benzothieno[2,3-d]pyrimidin-4-ylselanyl)acetyl]-1H-pyrazol -4-yl substituted carbonitrile or ethyl carboxylate, respectively. The structure of the novel compounds was confirmed by spectroscopic tools (IR, ¹H NMR ¹³C NMR and mass spectra) and elemental analysis.     

Acid-Catalyzed Transformations of 2-(Phenylethynyl)isoborneol

2-(Phenylethynyl)isoborneol was synthesized by treatment of camphor with lithium phenylacetylide. Skeletal rearrangements of the title compound under the Ritter reaction conditions afforded a mixture of N-(4-phenylethynyl- and 4-benzoylmethyl-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)acetamides at a ratio of 8:3. The reaction of 2-(phenylethynyl)isoborneol with formic acid involved mainly Meyer-Schuster rearrangement instead of the expected Rupe rearrangement, and the major product was 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)-1-phenylethanone. The minor product (∼6%) was 1-(2-hydroxy-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)-2-phenylethanone. The Ritter reaction of 2-(1,7,7-trimethylbicyclo[2.2.1]hept-2-ylidene)-1-phenylethanone selectively yielded N-(4-benzoylmethyl-1,7,7-trimethylbicyclo[2.2.1]hept-2-yl)acetamide.__________Translated from Zhurnal Organicheskoi Khimii, Vol. 41, No. 6, 2005, pp. 853–858.Original Russian Text Copyright © 2005 by Koval’skaya, Kozlov, Dikusar.     

Synthesis and conformational study of the first triply bridged calix[6]azatubes

[reaction: see text] The first C(3)(v)- and D(3)(h)-symmetrical triply bridged calix[6]azatubes were prepared in good yields from the known 1,3,5-tris-methylated calix[6]arene through an efficient [1 + 1] macrocyclization reaction. A remarkably regioselective hexa ipso-nitration reaction led to a calix[6]azatube substituted at the wide rim in alternate position by tBu and nitro groups. A (1)H NMR study showed that, whereas the parent bis-calix[6]arenes self-include their methoxy groups, thereby closing their inner tube, the nitro-substituted calix[6]azatube undergoes a conformational change with the expulsion of the methoxy groups, hence presenting a three-dimensional structure open for host-guest applications.     

5-[2-(对苯偶氮苯氧基)丁氧基]苯基-10,15,20-三[(对甲氧基苯基)]卟啉及其金属配合物的合成

以5-[2-(4-溴丁氧基)苯基]-10,15,20-三(对甲氧基苯基)卟啉和对羟基偶氮苯为原料,经取代反应合成新化合物5-[2-(对苯偶氮苯氧基)丁氧基]苯基-10,15,20-三[(对甲氧基苯基)]卟啉(2),2经配位反应合成了金属铜,锌配合物(2a)和(2b),其结构经UV-Vis,1H NMR,IR和元素分析表征。     

Iodine-mediated cascade cyclization of enediynes to iodinated benzo[a]carbazoles

Treatment of N,N-dimethyl 2-[2-(2-ethynylphenyl)ethynyl]anilines (1) with 1.2 equiv of iodine in CH(2)Cl(2) gave benzo[a]carbazoles (2) in good yields. Mechanistic studies showed this reaction must go through the haloindole (3) followed by iodonium ion catalyzed atom-transfer cyclization reaction to give the benzo[a]carbazoles.     

[CuCl3CPZ(O)H]络合物的合成及电化学行为的研究

盐酸氯丙嗪目前在精神病治疗中作为首选药物之一，在临床上应用于精神分裂症、狂躁症、焦虑症及更年期精神病等症．该药物吩唾咪环比较容易被氧化；1982年Geary等[1]合成了该药物的钯络合物，并对其进行了X-今线结构分析．Kawazura等[2,3]研究了该药物与体内微量元素之间的相互作用；Holbrok山研究表明用盐酸氯丙埃后脑内铜的浓度上升．而服用后药物先与蛋白质结合，与金属离子反应的可能性较小；为此本文制备了该药物的主要代谢产物之一的CPZ（0）HCI，并与体内微量元素铜（11）络合得到KUQa＊Pz问仰，对该络合物进行了元素分析和电…