Quantitation of mutagenic/carcinogenic heterocyclic aromatic amines in food products.

A method for screening genotoxic heterocyclic aromatic amines in cooked foods using solid-phase extraction and high-performance liquid chromatography with ultraviolet and fluorescence detection is described. Solid-phase extraction includes basic extraction on diatomaceous earth (Extrelut) and subsequent purification on propylsulphonic acid silica gel. This convenient procedure separates the analytes into a polar group and an apolar group. We have identified the following components in the two groups. The polar group contains aminoimidazoazaarenes i.e. 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline, 2-amino-3,4,8-trimethylimidazo[4,5-f]quinoxaline, 2-amino-3-methylimidazo[4,5-f]quinoline, 2-amino-3,4-dimethylimidazo[4,5-f]quinoline, 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine, and glutamic acid pyrolysates, i.e. 2-amino-6-methyldipyrido[1,2-a:3',2'-d]imidazole and 2-aminodipyrido[1,2-a:3',2'-d]-imidazole. The apolar group consists of five carbolines: 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole, 3-amino-1-methyl-5H-pyrido[4,3-b]indole, 2-amino-9H-pyrido[2,3-b]indole, 9H-pyrido[3,4-b]indole and 1-methyl-9H-pyrido[3,4-b]indole. The extraction efficiencies range from 45 to 90%, and the detection limits are in the low nanogram per gram range. The method was applied to the analysis of heterocyclic aromatic amines in pan-fried, oven-cooked and barbecued salmon.     

11H-Pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinoléines (aza-7 ellipticines) substituées sur leur position 6

6-Dialkylaminoalkylamino substituted 11H-pyrido[3',2':4,5]pyrrolo[2,3-g]isoquinolines (7-aza ellipti-cines) were obtained by a six step synthesis starting from 2-chloro-3-nitro pyridine and 6-amino-5-methyl (and 5,8-dimethyl) isoquinoline-1-2H-ones already described. A brief survey of biological results shows that derivatives of this new heterocyclic ring system are less interesting than their 5H-pyrido(3',4':4,5]pyrrolo[2,3-g]isoquinolines (9-aza ellipticines) and pyrido[4,3-b]carbazoles (ellipticines) analogues.     

Reaction of 2-bromomethylazoles and TosMIC: A domino process to azolopyrimidines. Synthesis of core tricycle of the variolins alkaloids

A new reaction of N-protected 2-bromomethylazoles and tosylmethyl isocyanide (TosMIC) leading to the preparation of azolopyrimidines is described. This domino sequence was used to synthesize the pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine core of alkaloids variolins from 4-methoxy-2-methylpyrrolo[2,3-b]pyrimidine in two steps.     

Heterocyclic quinones. XVI. Pharmacomodulation in the series of 11H-indolo[3,2-c]quinolinediones: synthesis, cytotoxicity and antitumor activity of 3-substituted 11H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline-1,4-diones

With the aim of obtaining new antitumor drugs more active than previously described 11H-indolo[3,2-c]quinoline-1,4-diones and 7,8,9,10-tetrahydro-11H-indolo[3,2-c]quinoline-1,4-diones, the synthesis and activities of a series of 3-substituted 11H-pyrido[3',4':4,5]pyrrolo[3,2-c]quinoline-1,4-diones and of 7,8,9,10-tetrahydro-11H-pyrido-[3',4':4,5]pyrrolo[3,2-c] quinoline-1,4-diones were studied. Some quinones were more cytotoxic in vitro towards L1210 leukemia cells but were not active in vivo towards murine P388 leukemia.     

Reaction of bromomethylazoles and tosylmethyl isocyanide. A novel heterocyclization method for the synthesis of the core of marine alkaloids variolins and related azolopyrimidines

A novel and efficient synthesis of the pyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine system, the heterocyclic core of the variolin family of marine alkaloids, is described. The route involves the reaction of 3-bromo-2-(bromomethyl)pyrrolo[2,3-b]pyridine and tosylmethyl isocyanide (TosMIC) under phase-transfer conditions. This unprecedented reaction was also used to synthesize a series of new methoxycarbonyl azolopyrimidines by reaction of TosMIC with bromomethylindoles, bromomethylbenzimidazole, and bromomethylpyrazole. Hydrolysis and decarboxylation of 5-bromo-7-methoxycarbonylpyrido[3',2':4,5]pyrrolo[1,2-c]pyrimidine obtained by this heterocyclization process and installation of the pyrimidine moiety in the C5 position open an alternative approach to complete a total synthesis of variolin B.     

Synthesis of pyrrolo[2,3-d]pyrimidines with 3-amino-2-hydroxypropyl substituents

A novel route has been found for the synthesis of pyrimido[5',4':4,5]pyrrolo[2,1-c][1,4]oxazines. They are promising reagents for the preparation of pyrrolo[2,3-d]pyrimidine-6-carboxylic acid amides which contain a 3-amino-2-hydroxypropyl substituent in position 7 of the heterocyclic ring.     

A rapid stereocontrolled synthesis of the 3a-hydroxy-pyrrolo[2,3-b]indole skeleton, a building block for 10b-hydroxy-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-diones

A two-step selenocyclisation-oxidative deselenaton sequence was used to establish the 3a-hydroxy-pyrrolo[2,3-b]indole core; these tricycles were used as effective precursors to 10b-hydroxy-pyrazino[1',2':1,5]pyrrolo[2,3-b]indole-1,4-diones.     

Synthesis of some pyrimido[4′,5′:4,5]thieno[2,3-b]quinolines and related heterocycles

Several thieno[2,3-b]quinolines 6a-i have been synthesized. These compounds were used as key intermediates in the synthesis of oxazino[4′,5′:4,5]thieno[2,3-b]quinoline 8 , pyrimido[4′,5′:4,5]-thieno[2,3-b]quinolines 9–12 , triazino[4′,5′:4,5]thieno[2,3-b] quinolines 14 and imidazo[4′,5′:4,5]-thieno[2,3-b]quinolines 17 .     

Synthesis of heterocyclic compounds possessing the 4H-thieno[3,2-b]pyrrole moiety

A series of novel heterocyclic combinatorial libraries containing 4H-thieno[3,2-b]pyrrole, thieno[2',3':4,5]-pyrrol[1,2-d][1,2,4]triazine and thieno[2',3':4,5]pyrrolo[1,2-a]pyrazine heterocyclic moieties were obtained by parallel solution-phase synthesis. Key steps include different reactions of initial alkyl 4H-thieno[3,2-b]-pyrrole-5-carboxylates, such as alkylation with alkylating agents; transformation of the carboxylate group into different reactive functionalities, followed by reactions with electrophilic species; intramolecular cyclizations; and amide bond formation. Simple manual techniques for parallel reactions were coupled with easy purification procedures to give high-purity final products.     

New approaches to the synthesis of functionally substituted pyrido[3′,2′:4,5]thieno[3,2-b]pyridines and the structure of the products obtained

Substituted pyrido,[3',2':4,5]thieno[3,2-b]pyndines were obtained by the reaction of 3-amino-2-benzoylthieno [2,3-b]pyridines with malononitrile and the reaction of 3-cyanopyridine-2(IH)-thiones with 2-aryl-3-bromo-I,I-dicyanopropene. 2-Amino-4-(4-bromophenyl)-7, 9-dimethyl-3-cyanopyrido [3',2':4,5]thieno[3, 2-b]-pyridine was used for the synthesis of a derivative of pyrido[3",2":4', 5']thieno[2',3':5,6]pyrido[2,3-d]-pyrimidine. The structure of these compounds was confirmed by spectral data and x-ray diffraction structural analysis.Deceased.     

Condensed isoquinolines. 37.* Heterocyclization using 3-(arylamino)- and 3-(hetarylamino)isoquinolin-1(2H)-ones

The reaction of 3-NHR-isoquinolin-1(2H)-ones (R = Ar) with aromatic aldehydes in the presence of Me3SiCl or in acetic acid leads to the formation of derivatives of dibenzo[b,f][1, 8]naphthyridin-5(6H)- one and benzo[f]isoquino[3,4-b][1, 8]naphthyridine-5,9(6H,7H)-dione. The reaction for R = Het in the presence of Me3SiCl gives derivatives of 5H-pyrido[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, benzo[f]isoquinoline[3,4-b][1,8]naphthyridine-5,9[6H,7H]-dione, and derivatives of new heterocyclic systems, 5H-pyrazino[1',2':1,2]pyrimido[4,5-c]isoquinolin-5-one, 5H-[1,3]thiazolo[3',2':1,2]pyrimido- [4,5-c]isoquinolin-5-one, 5-H-benzo[f]pyrazolo[3,4-b][1,8]naphthyridin-5-one, and isoquino[3,4-b]- [1,5]naphthyridin-5(6H)-one. The effect of the structure of substituent R and nature of the substituent in the benzaldehydes on the structure of the reaction products was studied.     

Synthesis of 7,8,9,10-tetrahydropyrido[3′,4′:4,5]pyrrolo[2,3-c]quinolines

A series of structurally novel 7,8,9,10-tetrahydropyrido[3′,4′:4,5]pyrrolo[2,3-c,]quinolines, 4a-c , were synthesized via a facile Fischer indole cyclization from the appropriately substituted hydrazinoquinolines 2a-c . Acetamides 4a,c were hydrolyzed to 5a,b and further converted to tertiary amines 6a-c . Potent antihypertensive activity has been observed with a number of the title compounds as well as the intermediate 3a .     

Synthesis of diversely functionalized hexahydropyrrolo[2,3-b]indoles using domino reactions, olefination, isomerization and Claisen rearrangement followed by reductive cyclization

Hexahydropyrrolo[2,3-b]indoles 6 were synthesized in five steps from indolin-3-one 8 by a general and efficient method, in which elements of molecular diversity were readily added onto the 3a-position of the pyrrolo[2,3-b]indole ring system. Horner-Wadsworth-Emmons reaction of 2-allyloxyindolin-3-ones 7, derived from indolin-3-one 8 and a variety of allylic alcohols, smoothly proceeded with successive Claisen rearrangement to give the corresponding 3-allyl-3-cyanomethylindolin-2-ones 15. Indolin-2-ones 15 were converted into pyrrolo[2,3-b]indoles 6 using partial hydrolysis followed by reductive cyclization with LiAlH(4). Synthesis of N-methylated pyrrolo[2,3-b]indole derivatives 23 and 26 is also described.     

Investigation of nitrogen- and sulfur-containing heterocycles. 44. New heterocyclic systems. Derivatives of imidazolidino-[3,2-f]pyrido[2,3-b]-and imidazolidino[3,2-f]pyrimido[4,5-b]-1,4-thiazines. Synthesis and structure

New representatives of heterocyclic systems, imidazolidino[3,2-f]-pyrido-[2,3-b]- and imidazolidino[3,2-f]pyrimido[4,5-b]-1,4-thiazines, have been obtained. Intermediate compounds of 5N-oxalamides-6-hydroxy-7H-pyrido[2,3-b]-1,4-thiazine have been isolated and characterized. Amides of N-(pyridyl-3)- and N-(pyrimidyl-5)-oxaminic acids have been obtained.For communication 43, see [1].Translated from Khimiya Geterotsiklicheskikh Soedininii, No. 7, pp. 992–997, July, 1986.     

Thermolysis of benzannulated enyne-carbodiimides. Application in the synthesis of pyrido[1',2':1,2]pyrimido[4,5-b]indoles and related heteroaromatic compounds

Several derivatives of the pyrido[1',2':1,2]pyrimido[4,5-b]indoles 4 and the pyrazino[1',2':1,2]pyrimido[4,5-b]indoles 14 were synthesized by treatment of the benzannulated enyne-isocyanates 8 with the iminophosphoranes 9 and 13, respectively, for the aza-Wittig reaction followed by thermolysis. The reaction presumably proceeds through an initial formation of the corresponding benzannulated enyne-carbodiimides, such as 10, followed by a formal intramolecular hetero Diels-Alder reaction. Surprisingly, when the iminophosphorane 17 was used for condensation with 8, the expected pyrimido[1',6':1,2]pyrimido[4,5-b]indoles 16 were not obtained. Instead, the isomeric pyrimido[6',1':2,3]pyrimido[4,5-b]indoles 21 were isolated. Presumably, an alternative reaction pathway involving an initial [2 + 2] cycloaddition reaction to form 19 followed by ring opening could lead to 20 and, after an intramolecular radical-radical coupling, 21. Treatment of the urea derivatives 24 with dibromotriphenylphosphorane also produced in situ the benzannulated enyne-carbodiimides 25, which on thermolysis gave the isoquinolino[2',1':1,2]pyrimido[4,5-b]indoles 26. Methylation of 4a, 14a, and 26a with methyl iodide occurred exclusively at the site of the indolo nitrogen. The planar geometry of those novel heteroaromatic compounds, resembling many DNA-binding agents, makes them potential candidates as DNA intercalators.     

A new route to annulated oligothiophenes

[reaction: see text] A new convenient method for the construction of thiophene-annulated thieno[2,3-b]thiophenes has been proposed. The key step of the method is ring closure of 10H-bisthienodithiocin-10-one by strong bases. The syntheses of two previously unknown annulated oligothiophenes, thieno[2,3-b]thieno[3',2':4,5]thieno[3,2-d]thiophene (1a) and thieno[3,2-b]thieno[2',3':4,5]thieno[3,2-d]thiophene (1b), have been described to illustrate the success of the method.     

Reactions of Roquefortin with Alkyl Chloroformates

Reactions of roquefortin with alkyl chloroformates provide 3-(1-(alkoxycarbonyl)imidazol-4-ylmethylene]-10b-(1,1-dimethyl-2-propenyl)-5a,10b,11,11a-tetrahydro-2H-pyrazinol[1',2':1,5]pyrrolo[2,3-b]indole-1,4(3H,6H)-diones.     

Reaction of diketene with cyanothioacetamide: A convenient and regioselective method for the preparation of new 4(1H)-pyridone derivatives

The reaction of diketene with cyanothioacetamide in dry dioxane in the presence of triethylamine gives triethylammonium 3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinethiolate. The regioselective S-alkylation of this thiolate is a convenient method for the preparation of substituted 4(1H)-pyridones and also derivatives of thiazolo[3,2-a]pyridine and thieno[2,3-b]pyridine. The action of 2-amino-1,1,3-tricyanopropene on this thiolate leads to its transformation into a new heterocyclic system, namely, 5H-pyrido[2′,3′:4,5]thiopyrano[2,3-b]pyridine; treatment with iodine yields the oxidation product, namely, the corresponding bis(2-pyridyl) disulfide. The structure of isopropyl (3-cyano-6-methyl-4-oxo-1,4-dihydro-2-pyridinyl)thioacetate was confirmed by X-ray diffraction structural analysis. __________ Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 716–725, May, 2007.     

Synthesis of 1,2,4-triazolo[4,3-c]-, tetrazolo[1,5-c]-, and 1,2,4-triazino[5,6-c]pyrano[4'3':4,5]pyrrolo-[3,2-e]pyrimidine derivatives

4-Hydrazinopyrano[4',3':4,5]pyrrolo[2,3-d]pyrimidines served as precursors in the synthesis of new heterocyclic systems, namely, 1,2,4-triazolo[4,3-c]-, tetrazolo[1,5-c]-, and 1,2,4-triazino[5,6-c] pyrano[4',3':4,5]-pyrrolo[3,2-e]pyrimidines.A. L. Mndzhoyan Institute of Fine Organic Chemistry, National Academy of Sciences of the Republic of Armenia, 375014 Yerevan. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 5, pp. 700-703, May, 1995. Original article submitted January 10, 1995; revision submitted April 20, 1995.     

Synthesis and Properties of 6-Amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles

We have established that when 5-chloro-6-[cyano(2,3-dihydro-1-R-benzo[d]azol-2-yl)methyl]-2,3-pyrazinedicarbonitriles are reacted with nucleophilic reagents (aliphatic and aromatic amines, hydrogen sulfide), annelation of the five-membered ring occurs on the [b] face of the pyrazine with formation of 6-amino-7-hetaryl-5-R-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles and 6-amino-7-(1H-benzo[d]imidazol-2-yl)thieno[2,3-b]pyrazine-2,3-dicarbonitrile respectively. Further heating with excess of acylating reagent leads to formation of a novel heterocyclic system 1H-benzo[4,5]imidazo[1,2-c]pyrazino[2',3':4,5]pyrrolo[3,2-e]pyrimidine. Reaction of vicinal dinitriles with hydrazine hydrate leads to the novel system 1H-pyrrolo[2',3':5,6]pyrazino[2,3-d]pyridazine.