共查询到20条相似文献,搜索用时 31 毫秒
1.
Raghavendra NM Jyothsna A Venkateswara Rao A Subrahmanyam CV 《Bioorganic & medicinal chemistry letters》2012,22(2):820-823
The existing NSAIDs having number of toxicities emphasises the need for discovery of new non-toxic anti-inflammatory agents. In this Letter, we present the simple two step chemical synthesis, in vivo pharmacological screening and docking study of few N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs. Different amino benzothiazoles were chloroacetylated and further reacted with substituted piperazines in presence of a base to get N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs (A1-C4). These compounds were evaluated for anti-inflammatory activity by carragenan induced paw oedema method. Promising compounds were screened for toxicity by evaluating the ulcerogenic potential. Molecular docking experiments were carried out against COX-2 enzyme using Surflex-Dock GeomX programme of Sybyl software on Dell T-1500 workstation to confirm the mechanism of action of active compounds among the series. In silico study reveal the binding interactions of N-(benzo[d]thiazol-2-yl)-2-(piperazin-1-yl)acetamide analogs with COX-2 protein and is in agreement with the in vivo anti-inflammatory activity. 相似文献
2.
Mingzhang Gao Min Wang Qi-Huang Zheng 《Bioorganic & medicinal chemistry letters》2018,28(13):2234-2238
The reference standards methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate (5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-methoxybenzamide (5c), and their corresponding desmethylated precursors 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoic acid (6a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-hydroxybenzamide (6b), were synthesized from 5-amino-2,2-difluoro-1,3-benzodioxole and 3-substituted benzoic acids in 5 and 6 steps with 33% and 11%, 30% and 7% overall chemical yield, respectively. Carbon-11-labeled casein kinase 1 (CK1) inhibitors, [11C]methyl 3-((2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)carbamoyl)benzoate ([11C]5a) and N-(2,2-difluoro-5H-[1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]imidazol-6-yl)-3-[11C]methoxybenzamide ([11C]5c), were prepared from their O-desmethylated precursor 6a or 6b with [11C]CH3OTf through O-[11C]methylation and isolated by HPLC combined with SPE in 40–45% radiochemical yield, based on [11C]CO2 and decay corrected to end of bombardment (EOB). The radiochemical purity was >99%, and the molar activity (MA) at EOB was 370–740?GBq/μmol with a total synthesis time of ~40-min from EOB. 相似文献
3.
Tatsumi R Seio K Fujio M Katayama J Horikawa T Hashimoto K Tanaka H 《Bioorganic & medicinal chemistry letters》2004,14(14):3781-3784
A series of 3-substituted 1-azabicyclo[2.2.2]octanes was discovered as the alpha7 nicotinic acetylcholine (alpha7) receptor agonists. It was found that (+)-3-[2-(benzo[b]thiophen-2-yl)-2-oxoethyl]-1-azabicyclo[2.2.2]octane (+)-15b has potent agonistic activity for the alpha7 receptor. 相似文献
4.
B Avila A Roth H Streets DS Dwyer MJ Kurth 《Bioorganic & medicinal chemistry letters》2012,22(18):5976-5978
A number of (1H-1,2,3-triazol-1-yl)benzo[d]thiazoles were synthesized utilizing a versatile Cu-catalyzed azide-alkyne click reaction (CuAAC) on tautomeric benzo[4,5]thiazolo[3,2-d]tetrazole (1) and 2-azidobenzo[d]thiazole (2) starting materials. Moreover, one of the resulting products of this investigation, triazolbenzo[d]thiazole 22, was found to possess significant neuroprotective activity in human neuroblastoma (SH-SY5Y) cells. 相似文献
5.
Ochiai K Takita S Eiraku T Kojima A Iwase K Kishi T Fukuchi K Yasue T Adams DR Allcock RW Jiang Z Kohno Y 《Bioorganic & medicinal chemistry》2012,20(5):1644-1658
(-)-6-(7-Methoxy-2-trifluoromethylpyrazolo[1,5-a]pyridin-4-yl)-5-methyl-4,5-dihydro-3-(2H)-pyridazinone (KCA-1490) is a dual PDE3/4 inhibitor that exhibits potent combined bronchodilatory and anti-inflammatory activity. A survey of potential bicyclic heteroaromatic replacement subunits for the pyrazolo[1,5-a]pyridine core of KCA-1490 has identified the 4-methoxy-2-(trifluoromethyl)benzo[d]thiazol-7-yl and 8-methoxy-2-(trifluoromethyl)quinolin-5-yl analogues as dual PDE3/4-inhibitory compounds that potently suppress histamine-induced bronchoconstriction and exhibit anti-inflammatory activity in vivo. 相似文献
6.
Tsukasa Mizuhara Shinya Oishi Hiroaki Ohno Kazuya Shimura Masao Matsuoka Nobutaka Fujii 《Bioorganic & medicinal chemistry》2012,20(21):6434-6441
3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is an antiretroviral agent with submicromolar inhibitory activity against human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. In the current study, the structure–activity relationships of accessory groups at the 3- and 9-positions of pyrimido[1,2-c][1,3]benzothiazin-6-imine were investigated for the development of more potent anti-HIV agents. Several different derivatives containing a 9-aryl group were designed and synthesized using Suzuki–Miyaura cross-coupling and Ullmann coupling reactions. Modification of the m-methoxyphenyl or benzo[d][1,3]dioxol-5-yl group resulted in improved anti-HIV activity. In addition, the 2,4-diazaspiro[5.5]undec-2-ene-fused benzo[e][1,3]thiazine derivatives were designed and tested for their anti-HIV activities. The most potent 9-(benzo[d][1,3]dioxol-5-yl) derivative was two–threefold more effective against several strains of HIV-1 and HIV-2 than the parent compound, PD 404182. 相似文献
7.
Nurmaya Effendi Kenji Mishiro Takeshi Takarada Daisuke Yamada Ryuichi Nishii Kazuhiro Shiba Seigo Kinuya Akira Odani Kazuma Ogawa 《Bioorganic & medicinal chemistry》2019,27(2):383-393
Several malignant tumors and fibrotic diseases are associated with PDGFRβ overexpression and excessive signaling, making this receptor attractive for molecular targeting and imaging approaches. A series of benzo[d]imidazole-quinoline derivatives were designed and synthesized to develop radioiodinated compounds as PDGFRβ-specific imaging probes. The structure activity relationship (SAR) evaluation of the designed compounds was performed. Among them, 2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (5a) and 4-{2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (5d) exhibited a relatively high PDGFRβ-TK inhibitory potency, whereas iodinated 5a derivative 5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]-8-(piperazin-1-yl)quinoline (8) exhibited a superior inhibitory potency as PDGFRβ inhibitor than iodinated 5d derivative 4-{5-iodo-2-[5-(2-methoxyethoxy)-1H-benzo[d]imidazol-1-yl]quinolin-8-yl}morpholine (11). Furthermore, [125I]8 and [125I]11 were synthesized and evaluated for PDGFRβ radioligand ability, both in vitro and in vivo. Cellular uptake experiments showed that [125I]8 had a higher uptake in BxPC3-luc cells as PDGFRβ-positive cells than [125I]11. Incubation of [125I]8 after pretreatment of PDGFRβ ligands significantly reduced the uptake of [125I]8. In biodistribution experiments using tumor-bearing mice, [125I]8 accumulation in the tumor 1?h postinjection was higher than that of the benzo[d]imidazol-quinoline derivative [125I]IIQP, used in our previous research. These results indicate that [125I]8 could be a promising PDGFRβ imaging agent. Although its clinical application requires further structural modifications, the results obtained in this research may be useful for the development of PDGFRβ-specific radioligands. 相似文献
8.
Zhu S Ruchelman AL Zhou N Liu AA Liu LF LaVoie EJ 《Bioorganic & medicinal chemistry》2005,13(24):6782-6794
The exceptional topoisomerase I-targeting activity and antitumor activity of 5-(2-N,N-dimethylamino)ethyl-8,9-dimethoxy-2,3-methylenedioxy-5H-dibenzo[c,h][1,6]naphthyridin-6-one (ARC-111, topovale) prompted studies on similarly substituted benzo[i]phenanthridine-12-carboxylic ester and amide derivatives. Among the benzo[i]phenanthridine-12-carboxylic esters evaluated, the 2-(N,N-dimethylamino)ethyl, 2-(N,N-dimethylamino)-1-methylethyl, and 2-(N,N-dimethylamino)-1,1-dimethylethyl esters possessed similar cytotoxicity, ranging from 30 to 55 nM in RPMI8402 and KB3-1 cells. Several of the carboxamide derivatives possess potent topoisomerase I-targeting activity and cytotoxicity. The 2-(N,N-dimethylamino)ethyl, 2-(N,N-diethylamino)ethyl, and 2-(pyrrolidin-1-yl)ethyl amides were among the more cytotoxic benzo[i]phenanthridine-12-carboxylic derivatives, with IC50 values ranging from 0.4 to 5.0 nM in RPMI8402 and KB3-1 cells. 相似文献
9.
Mazurov A Klucik J Miao L Phillips TY Seamans A Schmitt JD Hauser TA Johnson RT Miller C 《Bioorganic & medicinal chemistry letters》2005,15(8):2073-2077
A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha7 over other nAChRs (e.g., the alpha4beta2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-8l), has potent agonistic activity for the alpha7 nAChR (EC(50)=33nM, I(max)=1.0), at concentrations below those that result in desensitization. 相似文献
10.
Pan W Miao HQ Xu YJ Navarro EC Tonra JR Corcoran E Lahiji A Kussie P Kiselyov AS Wong WC Liu H 《Bioorganic & medicinal chemistry letters》2006,16(2):409-412
A novel class of 1-[4-(1H-benzoimidazol-2-yl)-phenyl]-3-[4-(1H-benzoimidazol-2-yl)-phenyl]-ureas are described as potent inhibitors of heparanase. Among them are 1,3-bis-[4-(1H-benzoimidazol-2-yl)-phenyl]-urea (7a) and 1,3-bis-[4-(5,6-dimethyl-1H-benzoimidazol-2-yl)-phenyl]-urea (7d), which displayed good heparanase inhibitory activity (IC(50) 0.075-0.27 microM). Compound 7a showed good efficacy in a B16 metastasis model. 相似文献
11.
Muheim R Buterin T Colgate KC Kolbanovsij A Geacintov NE Naegeli H 《Biochemistry》2003,42(11):3247-3254
Previous reports showed that methylated CpG sites are primary targets of bulky lesions induced by UV radiation, benzo[a]pyrene (B[a]P), or other environmental genotoxic agents. This study was performed to determine whether the repair of DNA damage formed preferentially at CpG dinucleotides is sensitive to 5-methylcytosine substitutions. Reactivation assays using UV- or B[a]P diol epoxide-damaged shuttle vectors established that human nucleotide excision repair enzymes are able to process fully methylated target DNA molecules. Repair reactions in human cell extracts suggested that 5-methylcytosines modulate local repair efficiency in a seemingly unpredictable manner. In fact, excision of the predominant (+)-trans-anti-B[a]P-dG adduct situated in a mutational hot spot sequence (codon 273 of the p53 gene) was stimulated by CpG methylation. Interestingly, excision activity was increased by a single 5-methylcytosine residue flanking the adduct in the damaged strand, but the same stimulatory effect was also induced by a single 5-methylcytosine residue located opposite the adduct in the undamaged strand. No such stimulation was observed when the (+)-trans-anti-B[a]P-dG lesion was placed in a different site containing a sequence of contiguous guanines, and strong inhibition was detected when a representative of the rare (+)-cis-anti-B[a]P-dG isomer was tested in the same assay. These results raise the possibility that 5-methylcytosines in CpG dinucleotides modulate not only the distribution of bulky DNA lesions but, at least in some cases, also the kinetics of subsequent excision repair reactions. This study confirms that the efficiency of bulky lesion repair is determined by the configuration of base pairs at damaged sites. 相似文献
12.
New thiourea derivatives incorporating two benzo[d][1,3]dioxol-5-yl moieties have been synthesized through the reaction of two molecules of benzo[d][1,3]dioxol-5-yl isothiocyanate with one molecule of various diamino derivatives. The synthesized compounds were examined for their cytotoxic effects using SRB assay on three cancer cell lines HepG2, HCT116 and MCF-7. Most of compounds showed significant antitumor activity and some compounds showed strong results greater than the reference drug. As example, IC50 values of 1,1′-(1,4-phenylene)bis(3-(benzo[d][1,3]dioxol-5-yl)thiourea) 5 were 2.38 µM for HepG2, 1.54 µM for HCT116 and 4.52 µM for MCF7, while the IC50 values of standard drug doxorubicin were 7.46, 8.29 and 4.56 µM, respectively. Interestingly, these compounds were non cytotoxic toward the tested normal cell line (IC50 value > 150 µM). The anticancer mechanisms were studied via EGFR inhibition assessment, annexin V-FITC apoptosis assessment, cell cycle analysis and study the effect on mitochondrial apoptosis pathway proteins Bax and Bcl-2 as well as molecular docking studies. 相似文献
13.
Ondrej Benek Lukas Hroch Laura Aitken Frank Gunn-Moore Lucie Vinklarova Kamil Kuca 《Journal of enzyme inhibition and medicinal chemistry》2018,33(1):665-670
Several neurodegenerative disorders including Alzheimer’s disease (AD) have been connected with deregulation of casein kinase 1 (CK1) activity. Inhibition of CK1 therefore presents a potential therapeutic strategy against such pathologies. Recently, novel class of CK1-specific inhibitors with N-(benzo[d]thiazol-2-yl)-2-phenylacetamide structural scaffold has been discovered. 1-(benzo[d]thiazol-2-yl)-3-phenylureas, on the other hand, are known inhibitors amyloid-beta binding alcohol dehydrogenase (ABAD), an enzyme also involved in pathophysiology of AD. Based on their tight structural similarity, we decided to evaluate series of previously published benzothiazolylphenylureas, originally designed as ABAD inhibitors, for their inhibitory activity towards CK1. Several compounds were found to be submicromolar CK1 inhibitors. Moreover, two compounds were found to inhibit both, ABAD and CK1. Such dual-activity could be of advantage for AD treatment, as it would simultaneously target two distinct pathological processes involved in disease’s progression. Based on PAMPA testing both compounds were suggested to permeate the blood-brain barrier, which makes them, together with their unique dual activity, interesting lead compounds for further development. 相似文献
14.
Rapid mineralization of benzo[a]pyrene by a microbial consortium growing on diesel fuel 总被引:14,自引:0,他引:14
Kanaly RA Bartha R Watanabe K Harayama S 《Applied and environmental microbiology》2000,66(10):4205-4211
A microbial consortium which rapidly mineralized the environmentally persistent pollutant benzo[a]pyrene was recovered from soil. The consortium cometabolically converted [7-(14)C]benzo[a]pyrene to (14)CO(2) when it was grown on diesel fuel, and the extent of benzo[a]pyrene mineralization was dependent on both diesel fuel and benzo[a]pyrene concentrations. Addition of diesel fuel at concentrations ranging from 0.007 to 0.2% (wt/vol) stimulated the mineralization of 10 mg of benzo[a]pyrene per liter 33 to 65% during a 2-week incubation period. When the benzo[a]pyrene concentration was 10 to 100 mg liter(-1) and the diesel fuel concentration was 0.1% (wt/vol), an inoculum containing 1 mg of cell protein per liter (small inoculum) resulted in mineralization of up to 17.2 mg of benzo[a]pyrene per liter in 16 days. This corresponded to 35% of the added radiolabel when the concentration of benzo[a]pyrene was 50 mg liter(-1). A radiocarbon mass balance analysis recovered 25% of the added benzo[a]pyrene solubilized in the culture suspension prior to mineralization. Populations growing on diesel fuel most likely promoted emulsification of benzo[a]pyrene through the production of surface-active compounds. The consortium was also analyzed by PCR-denaturing gradient gel electrophoresis of 16S rRNA gene fragments, and 12 dominant bands, representing different sequence types, were detected during a 19-day incubation period. The onset of benzo[a]pyrene mineralization was compared to changes in the consortium community structure and was found to correlate with the emergence of at least four sequence types. DNA from 10 sequence types were successfully purified and sequenced, and that data revealed that eight of the consortium members were related to the class Proteobacteria but that the consortium also included members which were related to the genera Mycobacterium and Sphingobacterium. 相似文献
15.
Zhao H Thurkauf A He X Hodgetts K Zhang X Rachwal S Kover RX Hutchison A Peterson J Kieltyka A Brodbeck R Primus R Wasley JW 《Bioorganic & medicinal chemistry letters》2002,12(21):3105-3109
Optimization of the lead compound 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2,3-dihydro-indol-1-yl)-ethanone 1 by systematic structure-activity relation (SAR) studies lead to two potent compounds 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 2n and 2-[-4-(4-chloro-benzyl)-piperazin-1-yl]-1-(2-methy-2,3-dihydro-indol-1-yl)-ethanone 7b. Their related synthesis was also reported. 相似文献
16.
Quantitation of protein-benzo[a]pyrene adducts represent a more sensitive analysis method than quantitation of benzo[a]pyrene-DNA adducts. By accurate analysis of benzo[a]pyrene-protein adducts several different molecular adduct forms can be studied. Male Wistar rats were injected i.p. with benzo[a]pyrene, and serum albumin was isolated and subjected to acid hydrolysis at 90 degrees C for 3 h. The hydrolysate was analyzed by HPLC with fluorescence detection. The HPLC profiles obtained after albumin hydrolysis from benzo[a]pyrene exposed animals were compared to similar HPLC profiles from in vitro adducted bovine serum albumin (BSA) and direct hydrolysis of both r-10,t-9-dihydrodiol-c-7,8-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (syn-BPDE-III) and r-10,t-9-t-dihydrodiol-t-7,8-oxy-7,8,9,10-tetrahydrobenzo[a]pyrene (anti-BPDE-III). After acid hydrolysis of albumin from benzo[a]pyrene exposed rats, 6 fluorescent peaks were separated. Four of the peaks were isomers of benzo[a]pyrene-tetrahydrotetrols, (+/-)-benzo[a]pyrene-r-7,t-8,9,10-tetrahydrotetrol, (+/-)-benzo[a]pyrene-r-7,t-8,9,c-10-tetrahydrotetrol, (+/-)-benzo[a]pyrene-r-7,t-8,c-9,t-10-tetrahydrotetrol and (+/-)-benzo[a]pyrene-r-7,t-8,c-9,10-tetrahydrotetrol. In addition we found two fluorescent peaks, named X1 and X2 with retention times similar to the benzo[a]pyrene-tetrols. The unknown fluorescent peaks reacted similar to the four known tetrols in both dose response experiments and time course experiments. Fluorescent material with retention times equal to X1 and X2 were found after acid hydrolysis of syn-BPDE-III and anti-BPDE-III in acid and in hydrolysates from BSA treated in vitro with syn-BPDE-III and anti-BPDE-III. The ratio X1/X2 was relatively constant indicating epimerization equilibrium between these to species. Synchronous fluorescence analysis of fractions containing X1 or X2 from both in vivo and in vitro experiments showed fluorescence spectra characteristic of benzo[a]pyrene tetrols using a wavelength difference of 34 nm. 相似文献
17.
T Saijo J Maeda T Okauchi J Maeda Y Morio Y Kuwahara M Suzuki N Goto T Fukumura T Suhara M Higuchi 《PloS one》2012,7(8):e42589
A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT(1A)) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT(1A) receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT(1A) receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT(1A) receptors. In addition, [(35)S]guanosine 5'-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT(1A) receptors. This finding has lent support to reports that diverse partial agonists for 5-HT(1A) receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants. 相似文献
18.
Heinrich T Böttcher H Schiemann K Hölzemann G Schwarz M Bartoszyk GD van Amsterdam C Greiner HE Seyfried CA 《Bioorganic & medicinal chemistry》2004,12(18):4843-4852
The dual serotonin (5-HT) re-uptake inhibitor and 5-HT(1A) receptor agonist vilazodone was found to increase central serotonin levels in rat brain. In the course of structural modifications of vilazodone 3-[4-[4-(2-oxo-2H-1-benzopyran-6-yl)-1-piperazinyl]-butyl]-1H-indole-5-carbonitrile 8i and its fluorine analogue 6-[4-[4-(5-fluor-3-indolyl)-butyl]-1-piperazinyl]-2H-1-benzopyran-2-one have been identified. These unsubstituted chromenones are equally potent at the 5-HT(1A) receptor and 5-HT transporter. The implementation of nitrogen functionalities in position 3 of the chromenones resulted in compounds acting as agonists at the 5-HT(1A) receptor and as 5-HT re-uptake inhibitors like vilazodone. Ex vivo 5-HT re-uptake inhibition and in vitro 5-HT agonism were determined in the PCA- and GTPgammaS-assay, respectively. The potential of these chromenones to increase central 5-HT levels was measured in microdialysis studies and especially the derivatives 3-[4-[4-(3-amino-2-oxo-2H-chromen-6-yl)-piperazin-1-yl]-butyl]-1H-indole-5-carbonitrile 8f, ethyl (6-[4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl]-2-oxo-2H-chromen-3-yl)-carbamate 8h and N-(6-[4-[4-(5-cyano-1H-indol-3-yl)-butyl]-piperazin-1-yl]-2-oxo-2H-chromen-3-yl)-acetamide 8k give rise to rapid development of increased serotonin levels in rat brain cortex, lasting longer than 3h. 相似文献
19.
Importance of the route of administration for genetic differences in benzo[a]pyrene-induced in utero toxicity and teratogenicity 总被引:2,自引:0,他引:2
C57BL/6N (Ahb/Ahb) mice have a high-affinity Ah receptor in tissues, whereas AKR/J and DBA/2N (Ahd/Ahd) mice have a poor-affinity Ah receptor. The cytochrome P1-450 induction response (enhanced benzo[a]pyrene metabolism) occurs much more readily in Ahb/Ahb and Ahb/Ahd than in Ahd/Ahd mice, at any given dose of the inducer benzo[a]pyrene. Embryos from the AKR/J X (C57BL/6N)(AKR/J)F1 and the reciprocal backcross were studied during benzo[a]pyrene feeding of the pregnant females. Oral benzo[a]pyrene (120 mg/kg/day) given to pregnant Ahd/Ahd mice between gestational day 2 and 10 produces more intrauterine toxicity and malformations in Ahd/Ahd than Ahb/Ahd embryos. This striking allelic difference is not seen in pregnant Ahb/Ahd mice receiving oral benzo[a]pyrene. Pharmacokinetics studies with [3H]benzo[a]pyrene in the diet and high-performance liquid chromatographic analysis of benzo[a]pyrene metabolism in vitro by the maternal intestine, liver, and ovary and the embryos of control and oral benzo[a]pyrene-treated pregnant females are consistent with "first-pass elimination" kinetics and differences in benzo[a]pyrene metabolism by the embryos and/or placentas versus maternal tissues. In the pregnant Ahd/Ahd mouse receiving oral benzo[a]pyrene, little induction of benzo[a]pyrene metabolism occurs in her intestine and liver; this leads to much larger amounts of benzo[a]pyrene reaching her embryos, and genetic differences in toxicity and teratogenesis are manifest. In the pregnant Ahb/Ahd mouse receiving oral benzo[a]pyrene, benzo[a]pyrene metabolism is greatly enhanced in her intestine and liver; this leads to less benzo[a]pyrene reaching her embryos, much less intrauterine toxicity and malformations, and no genetic differences are manifest. More toxic metabolites (especially benzo[a]pyrene 1,6- and 3,6-quinones) are shown to occur in Ahd/Ahd embryos than in Ahb/Ahd embryos. In additional studies, no prenatal or neonatal "imprinting" effect in C57BL/6N mice by 2,3,7,8-tetrachlorodibenzo-p-dioxin or Aroclor 1254 on benzo[a]pyrene metabolism later in life was detectable. These genetic differences in intrauterine toxicity and teratogenicity induced by oral benzo[a]pyrene are just opposite those induced by intraperitoneal benzo[a]pyrene [Shum et al., '79; Hoshino et al., '81). The data in the present report emphasize the importance of the route of administration when the teratogen induces its own metabolism. 相似文献
20.
Awad LF 《Carbohydrate research》2000,326(1):34-42
Reaction of the oxidation product of L-ascorbic acid, dehydro-L-ascorbic acid, with o-phenylenediamine, followed by 2,4,6-trichlorophenylhydrazine (3) afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-L-threo-2,3,4-trihydroxybut-1-yl]quinoxalin-2(1H)one (4), whose structure was deduced from studying its periodate oxidation, which gave the glyoxal derivative 3-[1-(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one (5) that upon reduction afforded 3-[1-(2,4,6-trichlorophenylhydrazono)-2-hydroxyethy-1-yl]quinoxalin-2(1H)one (6). The reaction of 5 with 3 afforded the bishydrazone 3-[1,2-bis(2,4,6-trichlorophenylhydrazono)glyoxal-1-yl]quinoxalin-2(1H)one. The reaction of 5 with acetic anhydride in pyridine afforded the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-acetoxy-3-[2-acetyl-2-(2,4,6-trichlorophenyl)hydrazono)]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 4 with acetic anhydride in pyridine afforded the acyclic diacetate intermediate 3-[3,4-di-O-acetyl-2-deoxy-1-(2,4,6-trichlorophenylhydra-zono)but-2-en-1-yl]quinoxalin-2(1H)one (12), which was also obtained from the reaction of 4 with boiling acetic anhydride. Compound 12 rearranged under the reaction conditions to give the pyrazole derivatives 3-[5-(ace-toxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (14) and 2-acetoxy-3-[5-(acetoxymethyl)-1-(2,4,6-trichlorophenyl)pyrazol-3-yl)]quinoxaline (15), as well as the 2,3-dihydrofuro[2,3-b]quinoxaline derivative 2-(2-acetoxyethen-2-yl)-3-[2-(2,4,6-trichlorophenyl)hydrazono]-2,3-dihydrofuro[2,3-b]quinoxaline. Acetylation of 3-[5-(hydroxymethyl)-l-(2,4,6-trichlorophenyl)pyrazol-3-yl]quinoxalin-2(1H)one (16) with acetic anhydride in pyridine or 12 with boiling acetic anhydride afforded 15 and 16, respectively. Treatment of 4 with diluted sodium hydroxide afforded the pyrazolo[2,3-b]quinoxaline (flavazole) derivative 1-(2,4,6-trichlorophenyl)-3-(L-threo-glycerol-1-yl)pyrazolo[2,3-b]quinoxaline whose acetylation afforded the acetyl derivative 3-(2,3,4-tri-O-acetyl-L-threo-glycerol-1-yl)-1-(2,4,6-trichlorophenyl)pyrazolo[2,3-b]quinoxaline. The assigned structures were based on spectral analysis. The activity of compound 4 against hepatitis B virus has been studied. 相似文献