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1.
A novel one-pot three-component condensation reaction of an aldehyde, β-ketoester and 2-aminobenzimidazole or 2-aminobenzothiazole in 1,1,3,3-N,N,N′,N′-tetramethylguanidinium trifluoroacetate as an ionic liquid is described. During the course of this reaction 4H-pyrimido[2,1-b]benzimidazoles or 4H-pyrimido[2,1-b]benzothiazoles are formed in high yields at 100 °C. The ionic liquid can be recovered conveniently and reused efficiently.  相似文献   

2.
Early work from our laboratory has shown that the mutagenicity of heterocyclic amines in Salmonella can be inhibited by hemin and chlorophyllins. We have speculated that the inhibition is a result of complex formation between heterocyclic amines and the pigments, and the speculation has been given a line of experimental evidence. We have now found that ferric-chlorophyllin (Fe-chlorophyllin) can modify the mutagenicity of 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2(NHOH)), a metabolically activated form of 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2). The mutagenicity of Trp-P-2(NHOH)) in Salmonella typhimurium TA 98 (without S9) was strongly inhibited by an addition of an equimolar Fe-chlorophyllin in the pre-incubation mixture. Fe-chlorophyllin also inhibited the mutagenicity of 2-hydroxyamino-6-methyldipyrido[1,2-a:3′,2′-d] imidazole (Glu-P-1(NHOH)). A rapid change in the UV spectrum of a mixture of Trp-P-2(NHOH) and Fe-chlorophyllin was observed. Analysis by high performance liquid chromatography showed that Trp-P-2(NHOH) was converted into 3-nitroso-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2(NO)), the mutagenic potency of which is a quarter of that of Trp-P-2(NHOH). Furthermore, the mutagenicity of Trp-P-2(NO), in turn, was inhibited by Fe-chlorophyllin. We conclude that the suppression of the mutagenicity of Trp-P-2(NHOH) is ascribable to the oxidative function of Fe-chlorophyllin, coupled with its ability to form complex formation with the planar surface of the heterocyclic amine molecules.  相似文献   

3.
A new approach to ligand design for the sequestration of metal-oxo cations has been called stereognostic coordination chemistry, in that the ligand incorporates a traditional Lewis base coordination to the metal center and a hydrogen bond donor to interact with the oxo group. This paper reports the synthesis of ligands that are more rigid and sterically predisposed to bind the targeted UO22+ cation. These are the tripod ligands tris-N,N′,N′′-[2-(2-carboxy-phenoxy)ethyl]-1,4,7-triazacyclononane bis-hydrochloride (ETAC · 2HCl) and tris-N,N′,N′′-[2-(2-carboxy-4-decyl-phenoxy)ethyl]-1,4,7-triazacyclononane tris-hydrochloride (DETAC · 3HCl), which chelate uranyl with a tris-carboxylate coordination sphere and provide a hydrogen bond donor through a protonated amine on the triazacyclononane macrocycle to interact with one uranyl oxo atom. Structural models predict that upon uranyl binding the hydrogen bond donor must point directly towards the oxo atom, enforcing a stereognostic interaction. Both ETAC and DETAC chelate the uranyl ion; DETAC is a powerful extractant and will quantitatively extract uranyl into an organic phase at pH 1.9 and above. The extraction coefficient is estimated to be 1014 in neutral aqueous conditions. Vibrational spectra of 18O labeled UO22+ have been used to probe the stereognostic coordination to uranyl utilizing hydrogen bonding.  相似文献   

4.
Three different synthetic routes have been explored for the synthesis of the mono-N-substituted phosphinoamine N-ethyl,N′bis[2(diphenylphosphino)phenyl]propane-1,3-diamine: (a) selective alkylation of N,N′bis[2(diphenylphosphino)phenyl]propane-1,3-diamine; (b) linkage of the different fragments of N-ethyl,N′bis[2(diphenylphosphino)phenyl]propane-1,3-diamine; (c) selective acylation of N,N′bis[2(diphenylphosphino)phenyl]propane-1,3-diamine followed by acetyl reduction. While approaches (a) and (b) were unsuccessful, N-ethyl,N′bis[2(diphenylphosphino)phenyl]propane-1,3-diamine was obtained by route (c) via separation of the mono- and di-alkylated P2N2-species obtained from reduction, through complexation of Ni(NO3)26H2O followed by demetallation reaction with KCN. Additional related phosphinoamine chelates and phosphonium adducts were synthesized and characterized by conventional physico–chemical techniques.  相似文献   

5.
We describe here an efficient synthesis of new 5-azaindolocarbazoles designed for cytotoxic and Chk1 inhibiting properties. The synthesis of ‘symmetrical’ and ‘dissymmetrical’ structures is discussed. Concerning the dissymmetrical 5-azaindolocarbazoles derivatives, with both an indole moiety and a 5-azaindole moiety, the synthesis was achieved using two very efficient key steps. The first one is a Stille reaction with a 3-trimethylstannyl-5-azaindole derivative and the second one a photochemical step leading to the proposed polycyclic structure. Various pharmacomodulations were performed to investigate the structure–activity relationships (SAR). Several substituents such as OBn, OH, and methylenedioxy groups were successfully introduced on the indole moiety of the 5-azaindolocarbazole. Compounds with or without substituents on the nitrogen atom of the maleimide were prepared, as well as derivatives with glucopyranosyl substituent on the nitrogen atom of the indole moiety. The cytotoxicity of these new compounds was evaluated on two cell lines (L1210, HT29). Several compounds showed cytotoxicity in the sub-micromolar range. Among the most cytototoxic was the 1,3-dioxolo[4,5-b]-6-(2-dimethylaminoethyl)-1H-pyrido[3′,4′:4,5]pyrrolo[3,2-i]pyrrolo[3,4-g]carbazole-5,7(6H,12H)-dione (35, IC50 = 195 nM on L1210). The compounds were also investigated for their Chk1 inhibiting activity. Compounds without any substitution on the maleimide moiety were the most potent. This is the case of compounds 45–47 with IC50 of, respectively, 72, 27, and 14 nM toward Chk1. Compound 46, which exhibits moderate cytotoxicity, appears to be a good candidate for development in a multi-drug anticancer therapy.  相似文献   

6.
1,10-Phenanthroline-5,6-dione (C12H6N2O2 (1)) reacts with V(η6-mesitylene)2 and Ti(η6-toluene)2 affording coordination compounds of general formula M(O,O′---C12H6N2O2)3 (M=Ti (2); M=V (3)) which further react with TiCl4 or TiCp2(CO)2 yielding the tetrametallic species M(O,O′---C12H6N2O2---N,N′)3(M′Ln)3 (M=V, M′Ln=TiCl4 (4); M=Ti, M′Ln=TiCp2 (5); M=V, M′Ln=TiCp2 (6)). The complex salt [Fe(N,N′---C12H6N2O2)3][PF6]2 (7) has been obtained from iron(II) chloride tetrahydrate and 1 in the presence of NH4PF6. The reaction of 7 with TiCp2(CO)2 affords the tetrametallic derivative [Fe(N,N′---C12H6N2O2---O,O′)3(TiCp2)3][PF6]2 (8). TiCl2(THF)2 reacts with MCp2(O,O′---C12H6N2O2) to give MCp2(O,O′---C12H6N2O2---N,N′)TiCl2 (M=Ti (9); M=V (10)). By reaction of TiCp2(O,O′---C12H6N2O2---N,N′)TiCl2 (9) with C12H6N2O2, the bimetallic derivative TiCp2(O,O′---C12H6N2O2---N,N′)TiCl2(O,O′---C12H6N2O2) (11) has been prepared, which readily adds to TiCl4, to give the trimetallic titanium derivative TiCp2(O,O′---C12H6N2O2---N,N′)TiCl2(O,O′---C12H6N2O2---N,N′)TiCl4 (12). VCp2(O,O′---C12H6N2O2---N,N′)TiCl2 (10) reacts with the tris-chelate iron(II) cation 7 affording the heptametallic cationic complex [Fe(N,N′---C12H6N2O2---O,O′)TiCl2(N,N′---C12H6N2O2---O,O′)VCp2]3 +2 isolated as the hexafluorophosphate 13.  相似文献   

7.
Various sulfidic anions and the oxidizing cations [Ru(NH3)6]3+ and N,N′-dimethyl-4,4′-bipyridinium2+ (paraquat2+) form ion pairs in aqueous solutions which display outer-sphere charge-transfer (CT) absorptions. The CT energies are used to establish a series of sulfidic anions with increasing CT donor strength: SCN2O3 2−4 3−3S3−2 −2S2 −4 2−.  相似文献   

8.
3-[3-(Piperidinomethyl)phenoxy]alkyl, N-cyano-N′-[ω-[3-(1-piperidinylmethyl)phenoxy]alkyl]guanidine and 2-(5-methyl-4-imidazolyl)methyl thioethyl derivatives containing fluorescent functionalities were synthesized and the histamine H2 receptor affinity was evaluated using the H2 antagonist [125I]-aminopotentidine. The compounds exhibited weak to potent H2 receptor affinity with pKi values ranging from <4 to 8.85. The highest H2 receptor affinity was observed for N-cyano-N′-[ω-[3-(1-piperidinylmethyl)phenoxy]alkyl]guanidines substituted with methylanthranilate (13), cyanoindolizine (6) and cyanoisoindole (11) moieties via an ethyl or propyl linker.  相似文献   

9.
3,3′-Diindolylmethane (DIM), a major condensation product of indole-3-carbinol, exhibits chemopreventive properties in animal models of cancer. Recent studies have shown that DIM stimulates interferon-gamma (IFN-γ) production and potentiates the IFN-γ signaling pathway in human breast cancer cells via a mechanism that includes increased expression of the IFN-γ receptor. The goal of this study was to test the hypothesis that DIM modulates the murine immune function. Specifically, the effects of DIM were evaluated in a panel of murine immune function tests that included splenocyte proliferation, reactive oxygen species (ROS) generation, cytokine production and resistance to viral infection. DIM was found to induce proliferation of splenocytes as well as augment mitogen- and interleukin (IL)-2-induced splenocyte proliferation. DIM also stimulated the production of ROS by murine peritoneal macrophage cultures. Oral administration of DIM, but not intraperitoneal injection, induced elevation of serum cytokines in mice, including IL-6, granulocyte colony-stimulating factor (G-CSF), IL-12 and IFN-γ. Finally, in a model of enteric virus infection, oral DIM administration to mice enhanced both clearance of reovirus from the GI tract and the subsequent mucosal IgA response. Thus, DIM is a potent stimulator of immune function. This property might contribute to the cancer inhibitory effects of this indole.  相似文献   

10.
Density functional theory (DFT) computations at the B3LYP/Lanl2DZ level were used to elucidate the oxygen atom transfer (OAT) and coupled electron proton transfer (CEPT) reaction steps involved in the biomimetic catalytic cycle performed by polymer-supported MoVIO2(NN′)2 complexes [NN′ = phenyl-(pyrrolato-2-ylmethylene)-amine] with water as oxygen source, trimethyl-phosphane as oxygen acceptor and one-electron oxidising agents. The DFT method employed has been validated against experimental data [X-ray crystal structures of a NN′ ligand and a MoVIO2(NN′)2 complex as well as kinetic data]. The rate-limiting step in the forward-OAT from [MoVIO2] to PMe3 is the attack of PMe3 at an oxo ligand with ΔG (298 K) = 64.6 kJ mol−1. Dissociation of the product OPMe3 is facile with ΔG (298 K) = 26.3 kJ mol−1 giving a mono-oxo [MoIVO] complex which fills its coordination sphere with a further PMe3 substrate with ΔG (298 K) = 39.2 kJ mol−1. One-electron oxidation to a Mo(V) phosphane complex precedes the coordination of water/hydroxide. Additionally, the comproportionation of [MoVIO2] and [MoIVO] to dinuclear oxo-bridged [OMoV–O–MoVO] species has been calculated as the thermodynamic sink in this system and the back-OAT from dmso to mono-oxo [MoIVO] to give [MoVIO2] has been shown to involve an equilibrium between stereoisomeric [MoVIO2] complexes with an activation barrier of ΔG (298 K) = 113.1 kJ mol−1.  相似文献   

11.
The heteroditopic ligand 4′-(4,7,10-trioxadec-1-yn-10-yl)-2,2′:6′,2″-terpyridine, 2, contains an N,N′,N″-donor metal-binding domain that recognizes iron(II), and a terminal alkyne site that selectively couples to platinum(II). This selectivity has been used to investigate routes to the formation of heterometallic systems. The single crystal structures of ligand 2 and the complex [Fe(2)2][PF6]2 are reported.  相似文献   

12.
Pentachlorophenol (PCP) and 1-nitro-2-naphthol were found to be potent inhibitors of enzymatic acetyl-CoA dependent activation, which is suggested as proceeding through direct O-acetylation, of N-hydroxyarylamines to tRNA binding by liver cytosolic enzymes from hamsters and rats. IC50 values of PCP for the activation of 2-hydroxyamino-6-methyldipyrido[1,2-a:3′,2′-d]imidazole (N-OH-Glu-P-1), 3-hydroxyamino-1-methyl-5H-pyrido[4,3-b]indole (N-OH-Trp-P-2) and N-hydroxy-2-aminofluorene (N-OH-AF) were 20, 25 and 17 μM, respectively, in hamster cytosol system. Similar inhibition was observed with rat liver cytosol (IC50 values of PCP and 1-nitro-2-naphthol were 13 and 12 μM, respectively, for the binding of N-OH-Glu-P-1). PCP is known as an inhibitor of sulfotransferase; however, another potent inhibitor of sulfotransferase, 2,6-dichloro-4-nitrophenol, did not inhibit the acetyl-CoA dependent binding. Antibiotic thiolactomycin, which inhibits bacterial O-acetyltransferase, did not affect the activation by hamster and rat cytosol, indicating the difference in property between bacterial and mammalian enzymes. The kinetic data obtained with hamster cytosol suggested the competitive inhibition of PCP with substrate, N-OH-Glu-P-1, and non-competitive inhibition with acetyl-CoA. In addition to the O-acetylation, PCP and 1-nitro-2-naphthol also inhibited N-acetylation of arylamines and N, O-acetyltransfer reaction of N-hydroxy-2-acetylaminofluorene (N-OH-AAF) by hamster cytosol. IC50 values for these two types of acetyltransfer reactions, however, were slightly higher than those observed for acetyl-CoA dependent activations of N-hydroxyarylamines.  相似文献   

13.
Novel 5-HT1 autoreceptor ligands based on the N-4-aryl-piperazinyl-N′-ethyl-5,6,7,8-tetrahydropyrido[4′, 3′:4,5]thieno[2,3-d]pyrimidin-4(3H)-one core are described. Aiming at antidepressants with a novel mode of action our objective was to identify potent antagonists showing balanced affinities and high selectivity for the 5-HT1A and 5-HT1B receptors. Strategies for the development of dual 5-HT1A and 5-HT1B antagonists based on 1 and 2 as leads and the corresponding results are discussed. Isoquinoline analogue 33 displayed high affinity and an antagonistic mode of action for the 5-HT1A and the 5-HT1B receptors and was characterized further with respect to selectivity, electrically stimulated [3H]5-HT release and in vivo efficacy.  相似文献   

14.
Isobrassinin (2-(S-methyldithiocarbamoylaminomethyl)indole (7a), a regioisomer of the cruciferous phytoalexin brassinin (1), exerted marked antiproliferative effects on the HeLa, A431 and MCF7 cell lines (>78.6% inhibition at 30 μM). For structure–activity relationships, further analogues were synthesized. The highest cytotoxic effect was displayed by 2-phenylimino-1,3-thiazino[5,6-b]indole (10) (10 μM, 76.8%—HeLa and 46.3%—MCF7). The effect of the natural phytoalexin brassinin was also determined.  相似文献   

15.
1,4-Dideoxy-1,4-imino-D-mannitol (DIM) was synthesized chemically from benzyl-alpha-D-mannopyranoside [Fleet et al (1984) J. Chem. Soc. Chem. Commun., 1240-1241], and was tested in vitro as an inhibitor of various alpha-mannosidases and in cell culture as an inhibitor of glycoprotein processing. DIM proved to be an effective inhibitor of jack bean alpha-mannosidase, with 50% inhibition requiring 25 to 50 ng/ml inhibitor. It also inhibited lysosomal alpha-mannosidase, but in this case 50% inhibition required about 1 to 2 micrograms/ml. In both cases, the inhibition was of the competitive type when p-nitrophenyl-alpha-D-mannopyranoside was used as the substrate. The inhibition was better at higher pH values, suggesting that DIM was more effective when the nitrogen in the ring was in the unprotonated form. In addition, rat liver processing mannosidase I was also inhibited by DIM as measured by the release of [3H]mannose from [3H]mannose-labeled Man9GlcNAc. Glycoprotein processing was examined in influenza virus-infected MDCK cells. Infected cells were incubated in various concentrations of DIM and labeled with [2-3H]mannose. Viral and cell pellets were digested with Pronase and glycopeptides were isolated by gel filtration on columns of Bio-Gel P-4. The glycopeptides were then treated with endoglucosaminidase H (Endo H) and rechromatographed on the Bio-Gel column in order to distinguish complex from high-mannose structures. As the DIM concentration in the medium was raised, more and more of the [3H]mannose was incorporated into high-mannose oligosaccharides, and less and less radioactivity was in the complex chains. Most of the Endo H-released oligosaccharides induced by DIM were of the Man9GlcNAc structure, as determined by gel filtration, HPLC, and digestion by alpha-mannosidase. Thus, DIM also appears to inhibit mannosidase I in cell culture. However, about 15% of the Endo H-released oligosaccharides appear to be hybrid types of oligosaccharides, suggesting that DIM may also inhibit mannosidase II.  相似文献   

16.
Synthesis of lobucavir prodrug, L-valine, [(1S,2R,3R)-3-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methyl ester monohydrochloride (BMS 233866), requires regioselective coupling of one of the two hydroxyl groups of lobucavir (BMS 180194) with valine. Either hydroxyl group of lobucavir could be selectively aminoacylated with valine by using enzymatic reactions. N-[(Phenylmethoxy)carbonyl]-L-valine, [(1R,2R,4S)-2-(2-amino-6-oxo-1H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methyl ester (3, 82.5% yield), was obtained by selective hydrolysis of N,N′-bis[(phenylmethoxy)carbonyl]bis[L-valine], O,O′-[(1S,2R,3R)-3-(2-amino-6-oxo-1H-purin-9-yl)cyclobuta-1,2-diyl]methyl ester (1) with lipase M, and L-valine, [(1R,2R,4S)-2-(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)-4-(hydroxymethyl)cyclobutyl]methyl ester monohydrochloride (4, 87% yield) was obtained by hydrolysis of bis[L-valine], O,O′-[(1S,2R,3R)-3-(2-amino-6-oxo-1H-purin-9-yl)cyclobuta-1,2-diyl]methyl ester, dihydrochloride (2), with lipase from Candida cylindracea. The final intermediate for lobucavir prodrug, N-[(phenylmethoxy)carbonyl]-L-valine, [(1S,2R,4R)-3-(2-amino-6-oxo-1H-purin-9-yl)-2-(hydroxymethyl)cyclobutyl]methyl ester (5), could be obtained by transesterification of lobucavir using ChiroCLEC™ BL (61% yield), or more selectively by using immobilized lipase from Pseudomonas cepacia (84% yield).  相似文献   

17.
18.
The syntheses and antihypertensive activity of the thieno[3,4-b]pyran and thieno[2,3-b]pyran isosteres of the potassium channel opener (PCO) RWJ 26629 (± 2a) are reported. While the unsubstituted thiophene derivatives were active at 20 mg/kg, introduction of a strong electron withdrawing group in the 2-position of the thieno[3,2-b] series increased potency. Similar substitution on the thieno[3,4-b] series significantly lowered potency. Compounds 26 and 30 are approximately 5-fold more potent than the prototypic PCO cromakalim (± 1).  相似文献   

19.
A semi-rigid 5-hydroxytryptamine (5-HT) analogue, RU28253 [5-methoxy-3-(1′,2′,5′,6′-tetrahydropyridin-3′-yl) indole], is a potent 5-HT1 and 5-HT2 agonist. It is isomeric to RU24969 [5-methoxy-3-(1′,2′,5′,6′-tetrahydropyridin-4′-yl) indole], a conformationally restricted 5-HT homologue, which has been extensively used in the study and classification of 5-HT receptors. A series of RU28253 derivatives with diverse substituents on indole 5-position were synthesized and their dissociation constants determined at the 5-HT1 and 5-HT2 receptors.  相似文献   

20.
Indole glucosinolates, present in cruciferous vegetables have been investigated for their putative pharmacological properties. The current study was designed to analyse whether the treatment of the indole glucosinolates—indole-3-carbinol (I3C) and its metabolite 3,3′-diindolylmethane (DIM) could alter the carbohydrate metabolism in high-fat diet (HFD)-induced C57BL/6J mice. The plasma glucose, insulin, haemoglobin (Hb), glycosylated haemoglobin (HbA1c), glycogen and the activities of glycolytic enzyme (hexokinase), hepatic shunt enzyme (glucose-6-phosphate dehydrogenase), gluconeogenic enzymes (glucose-6-phosphatase and fructose-1,6-bisphosphatase) were analysed in liver and kidney of the treated and HFD mice. Histopathological examination of liver and pancreases were also carried out. The HFD mice show increased glucose, insulin and HbA1c and decreased Hb and glycogen levels. The elevated activity of glucose-6-phosphatase and fructose-1,6-bisphosphatase and subsequent decline in the activity of glucokinase and glucose-6-phosphate dehydrogenase were seen in HFD mice. Among treatment groups, the mice administered with I3C and DIM, DIM shows decreased glucose, insulin and HbA1c and increased Hb and glycogen content in liver when compared to I3C, which was comparable with the standard drug metformin. The similar result was also obtained in case of carbohydrate metabolism enzymes; treatment with DIM positively regulates carbohydrate metabolic enzymes by inducing the activity of glucokinase and glucose-6-phosphate dehydrogenase and suppressing the activity of glucose-6-phosphatase and fructose-1,6-bisphosphatase when compared to I3C, which were also supported by our histopathological observations.  相似文献   

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