Synthesis and Properties of Substituted Isoxazolo[3',4':4,5]thieno[2,3-b]pyridines

We synthesized derivatives of a novel heterocyclic system, isoxazolo[3',4':4,5]thieno[2,3-b]pyridine by sequential conversions in three steps: isomerization of 2-(2-R-ethylthio-2-oxo)-3-pyridyl cyanides obtained by alkylation from substituted 3-cyano-2(1H)-pyridinethiones by -halomethyl ketones in alkaline medium, to form 3-aminothieno[2,3-b]pyridines; diazotization of the amino group followed by nucleophilic substitution of the diazonium group by an azido group, bypassing the step of isolating the diazonium salts; and thermolysis of the azides formed.     

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.     

4-Anilinopyrimido[4',5':4,5]selenolo(2,3-b)quinoline and 4-piperazino pyrimido[4',5':4,5]selenolo(2,3-b)quinoline: new DNA intercalating chromophores with antiproliferative activity

We have used circular dichroism, hydrodynamic methods, absorbance, and fluorescence titration to study the interaction of 4-anilinopyrimido[4',5':4,5] selenolo (2,3-b)quinoline (APSQ) and 4-piperazinopyrimido[4',5':4,5] selenolo(2,3-b)quinoline (PPSQ) with DNA. The association constants of APSQ and PPSQ were of the order of 10(4)M(-1). The fluorescence properties at ionic strength 0.01M are best fit by the neighbor exclusion model, with K=0.58-9.2 x 10(4)M(-1) and an exclusion parameter of 0.9-6.4 bp. Binding to the GC-rich DNA of Micrococcus lysodeikticus was stronger than the binding to calf thymus DNA, suggest that drug binds preferentially to G+C pairs at low r. CD spectra indicate that stacking of these compounds with DNA induces a strong helicity in the usually disordered structure of this double strand. Viscosity experiments show with sonicated calf thymus DNA with PPSQ an twice increase in slope (m) as that with APSQ. PPSQ increases the T(m) for calf thymus DNA melting by approximately 10 degrees C as binding approaches saturation, with biphasic melting. The cytotoxicities of these compounds on leukemia HL-60, K-562, B16F10 melanoma and Colo-205 are quite similar and inhibition (IC(50)) was in the range of 0.39-9.80 microM. The anticancer efficacy against B16F10 melanoma has provided evidence of major anticancer activity for PPSQ. Single or multiple intraperitonial (i.p.) doses of drug proved high level activity against the subcutaneous (s.c.) grafted B16 melanoma, significantly increase in life span (ILS 139% and 170%). The aim of this study was to analyze the physiochemical properties of these compounds in an attempt to understand its superior biological activity.     

Facile synthesis of some novel pyrido[3',2':4,5]thieno[2,3-b][1,4]thiazine-8-carboxylic acids

Model tetrahydropyrido[3',2':4,5]thieno[2,3-b][1,4]thiazines 9a-c were synthesized via reductive lactamization, using sodium dithionite, of the respective 2-[(carboxyalkyl)thio]-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acids 7a-c. The latter derivatives were made via interaction of 2-chloro-7-cyclopropyl-3-nitro-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylic acid (6) with each of alpha-mercaptoacetic, alpha-mercaptopropionic, and alpha-mercaptosuccinic acids and triethylamine in aqueous acetone at room temperature. The structures of 7a-7c and 9a-9c are supported by microanalytical and spectral (IR, MS, NMR) data. Compounds 9a and 9c showed potent inhibitory activity against the IGROV1 (Ovarian Cancer) cell line.     

4,5-二氢咪唑并[1,2-b]-1',2',4'-三唑-4-酮衍生物的合成与杀菌活性

应用芳基异氰酸酯与烯基膦亚胺1的氮杂Wittig反应,得到的碳二亚胺2,再与水合肼作用得到氨基咪唑啉酮衍生物4.而后用4与芳基异氰酸酯(或酰氯)、三苯基膦、六氯乙烷和三乙胺"一锅"反应,得到4,5-二氢咪唑并[1,2-b]-1',2',4'-三唑-4-酮衍生物6或7.探讨了所合成新型稠杂环化合物的生物活性,结果表明部分化合物表现出良好的杀菌活性.如7c在50mg/L浓度时,对棉花枯萎菌、稻瘟菌、黄瓜灰霉菌和油菜菌核菌的抑制率均达100%.     

Condensed Thienopyrimidines. 14. Synthesis of 10H-Thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines

Reaction of a substituted 2-aminothienothiopyran with methyl(phenyl) isothiocyanate, intramolecular cyclization of the obtained N'-methyl(phenyl) thioureido derivatives, and work up of the cyclization products with hydrazine hydrate gave 2-hydrazinodihydrothiopyranothienopyrimidines. Treatment of the latter with pyruvic acid gave the novel 10H-thiopyrano[4',3':4',5']thieno[2',3':4,5]pyrimido[2,3-c]-1,2,4-triazines.     

Synthesis of dithieno[2,3-b:4',3'-d]siloles and their selective bromination

The efficient synthesis of novel unsymmetrical dithienosiloles, 7,7-dimethyl-4,6-di(trimethylsilyl)-dithieno[2,3-b:4',3'-d]silole (1) and 7,7-dimethyl-2,4,6-tri(trimethylsilyl)-dithieno[2,3-b:4',3'-d]silole (2) has been developed by intramolecular silole formation with 4,4'-dibromo-2,2',5,5'-tetrakis(trimethylsilyl)-[3,3']bithienyl (3) as the starting material in the presence of t-BuLi. Upon treatment with N-bromosuccinimide (NBS) under controlled conditions, dithieno[2,3-b:4',3'-d]silole was selectively brominated to produce mono-, di-, and tribrominated dithieno[2,3-b:4',3'-d]siloles in good yields. The crystal structures of the title compounds are described.     

Synthesis and Properties of Derivatives of the new Heterocyclic System Benz[4,5]imidazo[1,2-c]pyrido[3',2';4,5]thieno[2,3-e]pyrimidine

Derivatives of a new heterocyclic system - benz[4,5]imidazo[1,2-c]pyrido[3',2';4,5]thieno[2,3-e]pyrimidine have been obtained by successive reactions in three stages - alkylation of 3-cyanopyridine-2(1H)-thiones with 2-chloromethylbenzylimidazole to give 2-benzimidazolylmethylthio-3-cyanopyridines, closing the thiophene ring in the latter to form 3-amino-2-(benzimidazolyl-2)thieno[2,3-b]pyridines, and cyclization of the pyrimidine ring by acylation with carboxylic acid anhydrides or chlorides.     

Synthesis of Hexa- and Octahydropyrido[3'2':4,5]thieno[3,2-d]pyrimidines

The reaction of N-methylmorpholinium 4-(2-chlorophenyl)-5-cyano-2-oxo-1,2,3,4-tetrahydropyridine-6-thiolate with chloroacetamide in DMF in the presence of an excess of KOH gave 3-amino-2-carbamoyl-4-(2-chlorophenyl)-6-oxo-4,5,6,7-tetrahydrothieno[2,3-b]pyridine. Refluxing the latter with acyl chlorides in AcOH or heating in formic acid gave hexahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine derivatives and reaction with cyclohexanone gave a spiro-linked octahydropyrido[3',2':4,5]thieno[3,2-d]pyrimidine.     

Quaternization of 1H-imidazo[4,5-b]pyridine and 4-methyl-4H-imidazo[4,5-b]pyridine

Unsubstituted imidazo[4,5-b]pyridine adds methyl iodide to the pyridine N atom. Treatment of the resulting iodide with base forms 4-methyl-4H-imidazo[4,5-b]pyridine. This nucleophile can readily add methyl iodide to form only one salt, 1,4-dimethylimidazo[4,5-b]pyridinium iodide.L. M. Litvinenko Institute of Physical Organic Chemistry and Coal Chemistry, Ukraine Academy of Sciences, Donetsk 340114. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1232–1233, September, 1994. Original article submitted june 17, 1994.     

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.     

Antitumor activity of 4-amino and 8-methyl-4-(3diethylamino propylamino)pyrimido[4',5':4,5]thieno (2,3-b) quinolines

The interaction of 4-aminopyrimido [4',5':4,5] thieno (2,3-b) quinoline and 8-methyl-4-(3-diethylaminopropylamino) pyrimido [4',5':4,5] thieno (2,3-b) quinoline with DNA was studied by UV-Vis and fluorescence spectrophotometry as well as by hydrodynamic methods. On binding to DNA, the absorption spectra underwent bathochromic and hypochromic shifts and the fluorescence was quenched. These compounds are able to bind to DNA with an affinity of about 10(6) M(-1) for calf thymus DNA at ionic strength 0.01 M and their intercalating characteristic (lengthening of the DNA) depends upon the length of the chain. Binding to the GC-rich DNA of Micrococcus lysodeikticus was stronger than the binding to calf thymus DNA at ionic strength 0.01 M. The cytotoxicities of these compounds on leukemia HL-60, melanoma B16F10 and neuro 2a cells are quite similar and inhibition (IC50) is in the range of 0.992-3.968 microM. The anticancer efficacy against B16 melanoma, has provided evidence of major antitumor activity for 8-methyl-4-(3diethylaminopropylamino) pyrimido [4',5':4,5] thieno(2,3-b)quinoline. Single or multiple intraperitonial (i.p) doses of drug proved high level activity against the subcutaneous (s.c) grafted B16 melanoma, significantly increasing survival (p<0.001) and inhibiting tumor growth (T/C of 4%). This study offers a new intercalation functional group to DNA-targeted drug design.     

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.     

Efficient Synthesis of 3,5,6,8-Tetrahydro-4H-thiopyrano[4',3':4,5]thieno[2,3-d]pyrimidin-4-ones via an Iminophosphorane

3,5,6,8-Tetrahydro-4H-thiopyrano[4',3':4,51thieno[2,3-d]pyrimidin-4-ones(7) were synthesized via the base catalytic reactions of amines or phenols with carbodiimides(5),which were obtained from the aza-Wittig reactions of iminophosphoranes(4) with aromatic isocyanates.     

Synthesis and evaluation as NOP ligands of some spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-ones and spiro[piperidine-4,5'(6'H)-[1,2,4]triazolo[1,5-c]quinazolines

Some spiro[piperidine-4,2'(1'H)-quinazolin]-4'(3'H)-ones 3 and spiro[piperidine-4,5'(6'H)-[1,2,4]triazolo[1,5-c]quinazolines] 4 were synthesized and evaluated as ligands of the nociceptin receptor. The examined compounds showed partial agonistic activity, except compounds 3, 4n that proved to be pure antagonists.     

Intercalating, cytotoxic, antitumour activity of 8-chloro and 4-morpholinopyrimido [4',5':4,5]thieno(2,3-b)quinolines

Circular dichroism, hydrodynamic methods, absorbance and fluorescence titration's were employed to study the interaction of 8-chloropyrimido[4',5':4,5]thieno(2,3-b)quinolin-4(3H)-one (chloro-PTQ) and 4-morpholinopyrimido[4',5':4,5]thieno(2,3-b)quinoline (morpholino-PTQ) with DNA. The association constant of chloro-PTQ and morpholino-PTQ were of the order of 10(5) and 10(6) M(-1). The fluorescence properties at ionic strength of 10mM are best fit by the neighbor exclusion model, with Ki of 0.3 x 10(4) M(-1) to 3.2 x 10(6) M(-1). CD spectra indicate that stacking of these compounds with DNA induces strong helicity in the usually disordered structure of the double strand. Viscosity experiments with sonicated rod like DNA fragments, produced a calculated length of 2.4A/bound of chloro/morpholino-PTQ molecule. The binding of chloro/morpholino-PTQ to DNA increased the melting temperature by about 1.5-7.0 degrees C. The cytotoxicity of these compounds on K-562, HL-60, Colo-205 and B16F10 melanoma are quite similar and IC(50) was in the range of 1.1-8muM. The anticancer efficacy against B16F10 melanoma has provided evidence of major anticancer activity for morpholino-PTQ. Single or multiple i.p. doses of compounds showed high level of activity against the subcutaneous (s.c.) grafted B16 melanoma with a significant increase in life span (161% and 272%). The aim of this study was to analyze the physicochemical properties of the chloro/morpholino-PTQ in an attempt to understand their superior biological activity. This research offers a new intercalation functional group to DNA targeted drug design.     

Derivatives of Condensed Thienopyrimidimines. 13. Synthesis and Structure of Pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidines

Methods for the synthesis of 5-substituted 10,10-dimethyl-10,11-dihydro-8H-pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidines have been developed. An X-ray crystallographic study of 5-(2-ethoxymethylhydrazino)-10,10-dimethyl-10,11-dihydro-8H-pyrano[4',3':4,5]thieno[3,2-e]-1,2,4-triazolo[2,3-c]pyrimidine has been carried out.     

Chemical and photochemical synthesis of substituted dihydro-thieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones and tetrahydro-dithieno[2,3-b:2',3'-d]thieno[2'',3''c:2'',3''c']diquinolin-6,14-dione

Some new substituted dihydrothieno[2',3':4,5]thieno[2,3-c]quinolin-6-ones 9- 12 and tetrahydrodithieno[2,3-b: 2',3'-d]thieno[2',3'-c:2',3'-c']diquinolin-6,14-dione (17) were prepared from the corresponding new anilides 5-8 and from the corresponding dianilide 15, respectively, by a multistep combination of chemical and photochemical reactions. All the prepared compounds are of particular interest because they might serve as DNA intercalators in anticancer therapy.     

Planar beta-linked oligothiophenes based on thieno[3,2-b]thiophene and dithieno[3,2-b:2',3'-d]thiophene fused units

A series of planar beta-linked oligothiophenes based on thieno[3,2-b]thiophene and dithieno[3,2-b:2',3'-d]thiophene fused units were synthesized. The optical data indicate a blue shift of the absorption maximum in comparison to the alpha-linked analogues due to cross-conjugation between fused rings. The crystal structures of 3,3'-bi(thieno[3,2-b]thiophene) and 3,3';6',3"-ter(thieno-[3,2-b]thiophene) reveal edge-to-face pi-stacked dimer motifs, whereas the crystal structure of 3,3'-bis(dithieno[3,2-b:2',3'-d]thiophene) consists of face-to-face pi-stacked molecules. [structure: see text]     

N-oxides of imidazo[4,5-b]quinoxalines and imidazo[4,5-b]pyrazines

The N-oxides and N,N-dioxides of methyl derivatives of imidazo[4,5-b]quinoxaline and imidazo[4,5-b]pyrazine were synthesized. The higher reactivity of the 2-methyl group in the N-oxides of 2-methylimidazo[4,5-b]quinoxaline as compared with the corresponding unoxidized derivatives was demonstrated.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1266–1270, September, 1972.