Benzimidazo[1,2-c]quinazoline dimers as potential antitumor agents

The 6-substituted benzimidazo[1,2-c]quinazoline 1 is a lead structure from our DNA intercalator program and is cytotoxic to the human colon cancer tumor line HT-29 with an inhibitory concentration 50, IC₅₀ of 4.00 μM. In order to try and improve the limited cytotoxicity of this class of compound we prepared a series consisting of two benzimidazo[1,2-c]quinazoline moieties linked by a polyalkylamino bridge, of different length and substitution. The compound with the -NH-(CH₂)₃-N(CH₃)-(CH₂)₃-NH-bridge had an inhibitory concentration 50, IC₅₀ of 0.5 μM. When tested in vivo, however, no clear anti-tumor activity was produced in the human breast cancer tumor line MX-1 or the human melanoma tumor line LOX, human tumor xenografts models.     

A Facile One Stage Synthesis of Oxazolines Under Microwave Irradiation

A rapid, high yielding procedure for the synthesis of 2-substituted oxazolines has been achieved under microwave irradiation from alkyl and aryl nitriles and β-amino alcohols using a mild Lewis acid catalyst.     

超声波促进离子液体中Biginelli一锅法合成苯并咪唑并[2,1-b]喹啉-6-酮

在超声波辐射下, 芳香醛、1,3-环己二酮和2-氨基苯并咪唑3组分在离子液体([bmim]Br)介质中经Biginelli反应“一锅煮”合成了一系列新型苯并咪唑并[2,1-b]喹啉-6-酮衍生物. 2-氨基苯并咪唑的使用是对经典的Biginelli反应的发展, 并且该方法具有反应条件温和、产率较高(65%～86%)及环境友好等优点. 产物经IR, ¹H NMR和元素分析确证了结构.     

Synthesis of Structurally Related Purines: Benzimidazo[1,2-a]pyridines, Benzimidazo-[1,2-c]pyrimidines, and Pyrazolo-[1,5-a]pyrimidines

Summary.  Reactions of sodium salts of 3-hydroxymethylene-2-alkanones with 2-cyanomethylbenzimidazole afforded benzimidazo[1,2-a]pyridines. Analogues reactions with 2-aminobenzimidazole and 5-aminopyrazoles afforded benzimidazo[1,2-c]pyrimidines and pyrazolo[1,5-a]pyrimidines. Received December 12, 1999. Accepted (revised) February 12, 2000     

Facile One-Pot,Multicomponent Synthesis of Pyridines Under Microwave Irradiation

A series of 2-amino-6-(2-oxo-2H-chromen-3-yl)-4-pyridine-3-carbo-nitriles were synthesized by the one-pot, multicomponent reaction of 3-acetyl-coumarin, aromatic aldehydes, malononitrile, and ammonium acetate in acetic acid under microwave irradiation. The reactions were completed in 10–13 min with 61–86% yields, were environmental benign, and had easy workup. Their structures were confirmed by ¹H NMR, IR, and MS spectra and elemental analysis.     

Synthesis and Monoamine Oxidase Inhibitory Activity of 3-Substituted 5H-Indeno[1,2-c]pyridazines

The one-pot synthesis of nine 5H-indeno[1,2-c]pyridazines is described. These compounds are shown to be potent, reversible inhibitors of monoamine oxidase B (MAO-B) with little or no effect on monoamine oxidase A (MAO-A). Qualitative structure-activity relations indicate that the MAO-B inhibitory activity is strongly influenced by electronic and bulk properties of substitutents.     

A Novel Synthesis of Imidazo[1,2-c]pyrimidines

A new method for the preparation of imidazo[1,2-c]pyrimidines is described.     

Green Synthesis of Some Calix[4]Resorcinarene Under Microwave Irradiation

A green synthetic procedure for the preparation of some calix[4]resorcinarenes using a household microwave oven has been carried out. This method represents a very rapid heating alternative to the conventional method that involves very long time of reactions (from 20-24 h in conventional heating to 5-8 min in microwave irradiation). C-4-hydroxy–3-methoxycalix[4]resorcinarene (CHMPCR), C-4-methoxyphenylcalix[4]resorcinarene (CMPCR) and C-2–phenylethenilcalix[4]resorcinarene (CPECR) was achieved by placed of resorcinol, an aldehyde, HCl and ethanol inside a household microwave oven. The product was recrystallized by methanol and analyzed by spectral analysis (FTIR, H-NMR and MS). Optimization of reaction was carried out in variation of microwave power, reaction times and reactant composition. The result shows that optimum condition of synthesis of C-4-hydroxy-3–methoxycalix[4]resorcinarene (CHMPCR) with microwave irradiation were at microwave power 332 W, reaction time 8 min and the mole ratio of resorcinol and 4-hydroxy-3-methoxyphenylbenzaldehyde 1:1. This parameter gave product in 97.8% (53.7% after recrystallization). The CPECR synthesis using resorcinol and cynnamaldehyde (1:1) at microwave power 332 W for 5 min afforded the product in 97.3% (44.5% after recrystallization). Whereas the reaction of resorcinol and 4-methoxyphenylbenzaldehyde (1:1.2) at microwave power 264 W for 5 min gave CMPCR in 99.5% (68.6% after recrystallization).     

A Facile Synthesis of 5-Arylidene-2-imino-4-thiazolidinones Under Microwave Irradiation

A series of 5-arylidene-2-imino-4-thiazolidinone derivatives were synthesized by the cross-aldol condensation of aromatic aldehydes with 2-imino-4-thiazolidinone in sodium acetate/acetic acid under microwave irradiation. The reactions were completed in 10 min with 63–91% yields, were environmental benign, and had easy workup.     

A Facile Synthesis of Pyrido [1,2-a] Benzimidazoles

The synthesis and characterisation of some of the new pyrido [1,2-a] benzimidazoles from 1H-benzimidazole-2-acetonitrile and diethyl ethoxy methylene malonic ester.     

Synthesis of 3,5-Disubstituted-4,5-dihydroindeno[1,2-c] [1,2]diazepin-6(1H)-ones

3,5-Disubstituted 4,5-dihydroindeno[1,2-c][1,2]diazepin-6 (1H)-ones ( 3a–g ) were obtained in 29–72% yields by condensing 2-(substituted-2-acylethyl)-1,3-indandiones ( 1a–n ) with hydrazine. The NH group of the indenodiazepinones 3a–g is quite unreactive. Two methods based on the Michael reaction were used for preparing the acylethylindandiones 1a–n : one from 1,3-indandione and chalcone-type compounds and the other from 2-benzylidene-1,3-indandione and acetophenones. The latter method was found more practical and of more general application.     

Synthesis of substituted indolo[1,2-c]quinazolines

It was established that N-acetylindoxyl arylhydrazones are converted to 12-acetamidoindolo[1,2-c]quinazolines in acetic acid in the presence of acetic anhydride, evidently through a step involving the formation of arylhydrazoindole derivatives. A new method for the synthesis of 12-acetamidoindolo[1,2-c]quinazolines from N,O-diacetylindoxyls and arylhydrazines is proposed.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, pp. 832–835, June, 1979.     

Novel polycyclic heterocycles. XI. Synthesis of 11,12-dihydropyrido[2,1-b] [1,3]benzodiazepines, 6H-pyrido[1,2-c] [1,3,5]benzoxadiazepines,and 6H-Pyrido[1,2-c] [1,3,5]benzothiadiazepines

An unusually facile dehydrobromination, involving the ortho-bromine atom and the = NH proton of a 2-imino-1-(phenethyl)-, 2-imino-1-(phenoxymethyl)-, or 2-imino-1-(phenylthiomethyl)-pyridine ( 2a-e ) has led to the synthesis of three novel bridgehead nitrogen tricyclic systems: 11,12-dihydropyrido[2,1-b] [1,3]benzodiazepines ( 3a,b ), 6H-pyrido[1,2-c] [1,3,5]benzoxadiazepines ( 3c,d ) and 6H-pyrido[1,2-c][1,3,5]benzothiadiazepines ( 3e ). As anticipated, these cyclizations required a base, e.g., potassium carbonate, and a catalyst, e.g., copper bronze. What was unusual, was that these reactions occurred in methanol or n-propanol, under reflux, either under anhydrous conditions, or in the presence of large amounts of water. The pmr spectra of these compounds are discussed.     

Formation of Heptaleno[1,2-c]furans and Heptaleno[1,2-c]furanones

The dehydrogenation reaction of the heptalene-4,5-dimethanols 4a and 4d , which do not undergo the double-bond-shift (DBS) process at ambient temperature, with basic MnO₂ in CH₂Cl₂ at room temperature, leads to the formation of the corresponding heptaleno[1,2-c]furans 6a and 6d , respectively, as well as to the corresponding heptaleno[1,2-c]furan-3-ones 7a and 7d , respectively (cf. Scheme 2 and 8). The formation of both product types necessarily involves a DBS process (cf. Scheme 7). The dehydrogenation reaction of the DBS isomer of 4a , i.e., 5a , with MnO₂ in CH₂Cl₂ at room temperature results, in addition to 6a and 7a , in the formation of the heptaleno[1,2-c]-furan-1-one 8a and, in small amounts, of the heptalene-4,5-dicarbaldehyde 9a (cf. Scheme 3). The benzo[a]heptalene-6,7-dimethanol 4c with a fixed position of the C?C bonds of the heptalene skeleton, on dehydrogenation with MnO₂ in CH₂Cl₂, gives only the corresponding furanone 11b (Scheme 4). By [²H₂]-labelling of the methanol function at C(7), it could be shown that the furanone formation takes place at the stage of the corresponding lactol [3-²H₂]- 15b (cf. Scheme 6). Heptalene-1,2-dimethanols 4c and 4e , which are, at room temperature, in thermal equilibrium with their corresponding DBS forms 5c and 5e , respectively, are dehydrogenated by MnO₂ in CH₂Cl₂ to give the corresponding heptaleno[1,2-c]furans 6c and 6e as well as the heptaleno[1,2-c]furan-3-ones 7c and 7e and, again, in small amounts, the heptaleno[1,2-c]furan-1-ones 8c and 8e , respectively (cf. Scheme 8). Therefore, it seems that the heptalene-1,2-dimethanols are responsible for the formation of the furan-1-ones (cf. Scheme 7). The methylenation of the furan-3-ones 7a and 7e with Tebbe's reagent leads to the formation of the 3-methyl-substituted heptaleno[1,2-c]furans 23a and 23e , respectively (cf. Scheme 9). The heptaleno[1,2-c]furans 6a, 6d , and 23a can be resolved into their antipodes on a Chiralcel OD column. The (P)-configuration is assigned to the heptaleno[1,2-c]furans showing a negative Cotton effect at ca. 320 nm in the CD spectrum in hexane (cf. Figs. 3–5 as well as Table 7). The (P)-configuration of (–)- 6a is correlated with the established (P)-configuration of the dimethanol (–)- 5a via dehydrogenation with MnO₂. The degree of twisting of the heptalene skeleton of 6 and 23 is determined by the Me-substitution pattern (cf. Table 9). The larger the heptalene gauche torsion angles are, the more hypsochromically shifted is the heptalene absorption band above 300 nm (cf. Table 7 and 8, as well as Figs. 6–9).     

Synthesis and Structure of Di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes

Di-N-arylpyrrolo[1,2-c;5,6-c]cyclooctanes were synthesized for the first time by the cyclization of N,N-dipropynylarylamines in a superbasic medium.     

Addition compounds of nucleophiles and 3-ethylthio-6-oxo-6H-1,2-dithiolo[4,3-c]1,2-dithiolium tetrafluoroborate. Synthesis of 3H,6H-1,2-dithiolo[4,3-c]1,2-dithiole-3-one-6-thione

Summary A smooth method of synthesizing 3H, 6H-1,2-dithiolo[4,3-c]1,2-dithiole-3,6-dithione (3), and also its partial desulfuration to yield 3H, 6H-1,2-dithiolo[4,3-c]1,2-dithiole-3-one-6-thione (4) is presented. The ethylation product5 of the monothione4 reacts with various nucleophilic reagents to form remarkably stable adducts. The adducts of5 with methanol,tert-butyl mercaptan, and with aniline could be isolated and characterized by their¹H-NMR spectra.

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Anlagerungsverbindungen von Nukleophilen an 3-Ethylthio-6-oxo-6H-1,2-dithiolo[4,3-c]1,2-dithioliumtetrafluoroborat. Synthese von 3H,6H-1,2-Dithiolo[4,3-c]1,2-dithiol-3-on-6-thion

Zusammenfassung Eine glatte Synthese für 3H,6H-1,2-Dithiolo[4,3-c]1,2-dithiol-3,6-dithion (3) und für dessen partielle Entschwefelung zu 3H,6H-1,2-Dithiolo[4,3-c]1,2-dithiol-3-on-6-thion (4) wird angegeben. Das Ethylierungsprodukt5 des Monothions4 reagiert mit unterschiedlichen Nukleophilen zu bemerkenswert stabilen Addukten. Die Addukte mit Methanol,tert.-Butylmercaptan und mit Anilin wurden isoliert und durch ihr¹H-NMR-Spektrum charakterisiert.

     

微波作用下3-取代-(1H)-嘧啶［1，2-a］喹啉-1-酮的一步合成法

5-(双甲硫基亚甲基 ) -2 ,2 -二甲基 -1 ,3 -二环己 -1 ,4-二酮 (1 ) [1] 既具有丙二酸亚异丙酯的环状结构 ,又具有乙烯基硫代缩酮的结构特征 .它是一种多功能的合成试剂 ,其最重要性质是可与多种亲核试剂发生加成反应 ,继而消除甲硫基 ,从而可以转变成一系列有用的合成中间体 (2 ) [2～ 5] .若亲核试剂具有两个亲核部位 Nu1及 Nu2 ,则 Nu1反应后 ,Nu2可进一步与丙二酸亚异丙酯的羰基进行分子内的亲核加成 ,从而形成环状化合物 (3 ) ,这一模式已在多种杂环化合物合成中获得应用[6～ 8] .Me SMe SOOMe OOMe　+ Nu1-Nu Me SNu1Nu …     

Synthesis of 9-Substituted Berberine Derivatives with Microwave Irradiation

Hyperglycemia is frequently accompanying with hyperlipidemia. To explore the potent drugs with dual-activity and dual-site effects that could reduce blood glucose and blood lipid at the same time, fibrate group with lipid-lowering effect on the 9th position of berberine(BBR) was introduced using the drug design combination principle and the multi-target collaborative treatment method. Moreover, the molecular structure of BBR was modified, and six 9-substituted derivatives of BBR were designed and synthesized, among which, five compounds have never been reported before. In addition, the molecular structures of these derivatives were identified using liquid chromatography-mass spectrometry(LC-MS), ¹H nuclear magnetic resonance(¹H NMR) and ¹³C NMR, respectively. Furthermore, the microwave irradiation experimental technique was applied in the synthesis reaction using the novel microwave synthesizer, which accelerated the reaction rate, enhanced the reaction yield, reduced the reaction by-products, and simplified the post-processing steps. In the meantime, the 9-position regioselective demethylation of BBR was explored through quantum chemical calculation during the synthesis of berberrubine. The computations were consistent with the experimental results, which contributed to deducing the mechanism of its selective methylation.