共查询到20条相似文献,搜索用时 31 毫秒
1.
Adam Mieczkowski Tomasz Frączyk Mateusz Psurski Patrycja Wińska Paweł Siedlecki Monika Dziełak Damian Trzybiński Marcin Wilczek Maciej Bagiński Bartosz Bieszczad Krzysztof Woźniak 《化学与生物多样性》2021,18(1):e2000733
Currently available chemotherapeutic treatments for blood cancers (leukemia) usually have strong side effects. More selective, efficient, and less toxic anticancer agents are needed. We synthesized seven, new, optically pure (12aS)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione derivatives and examined their cytotoxicity towards eight cancer cell lines, including urinary bladder (TCC-SUP, UM-UC-3, KU-19-9), colon (LoVo), and breast (MCF-7, MDA-MB-231) cancer representatives, as well as two leukemic cell lines (MV-4-11, CCRF-CEM) and normal murine fibroblasts (Balb/3T3) as reference cell line. Three of the seven newly-obtained compounds ((12aS)-8-bromo-2-(3-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, (12aS)-8,9-dimethoxy-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione and (12aS)-8-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione, showed enhanced activity and selectivity toward the leukemic MV-4-11 cell lines when compared to our previously reported compounds, with IC50 values in the range of 2.9–5.6 μM. Additionally, (12aS)-9-nitro-2-(4-phenylbenzoyl)-1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione exhibited a strong cytotoxic effect against the leukemic CCRF-CEM (IC50=6.1 μM) and MV-4-11 (IC50=11.0 μM) cell lines, a moderate cytotoxic effect toward other tumor lines (IC50=31.8–55.0 μM) and very weak cytotoxic effect toward the Balb/3T3 reference cell lines. Selected compounds were further evaluated for their potential to induce apoptotic cell death in MV-4-11 cells by measuring caspase-3 activity. We also established the crystal structure of three products and investigated the effect of 22 derivatives of 1,3,4,12a-tetrahydropyrazino[2,1-c][1,4],12(2H,11H)-dione on the activity of the cancer-associated enzyme autotaxin. All compounds proved to be weak inhibitors of autotaxin, although some (R) and (S) enantiomers had Ki values of 10–19 μM. The obtained results showed that the tested compounds exhibited a selective antileukemic effect, which appeared not to be related directly to autotaxin. Molecular targets responsible for this effect remain to be identified. The newly obtained compounds can be used in the search for new, selective anticancer therapies. 相似文献
2.
B. Choodamani Karla G. Cano Hernandez Sujeet Kumar Ann Maria Tony Austre Y. Schiaffino Bustamante Renato J. Aguilera Dominique Schols C. Gopi Mohan Subhas S. Karki 《化学与生物多样性》2021,18(2):e2000800
In this study, we synthesized 22 compounds in a series with various substitution on imidazo[2,1-b][1,3,4]thiadiazole. The potential cytotoxic activity of these compounds investigated in leukemia cell lines by Differential Nuclear Staining (DNS). Our results identified two compounds, 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate and 6-(4-chlorophenyl)-2-(4-methoxybenzyl)imidazo[2,1-b][1,3,4]thiadiazole-5-carbaldehyde, exhibited the most cytotoxic effect against murine leukemia cells (L1210), human T-lymphocyte cells (CEM) and human cervix carcinoma cells (HeLa) with IC50 values ranging between 0.79 and 1.6 μM. The results indicate that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate is inducing phosphatidylserine externalization and caspase-3 activation which are both a hallmark of apoptosis. Docking studies showed that 2-(4-methoxybenzyl)-6-(2-oxo-2H-chromen-3-yl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl thiocyanate binds within the active sites of transforming growth factor beta (TGF-β) type I receptor kinase domain by strong hydrogen binding and hydrophobic interactions. 相似文献
3.
Ahmed Kamal J. Surendranadha Reddy M. Janaki Ramaiah E. Vijaya Bharathi D. Dastagiri M. Kashi Reddy S.N.C.V.L. Pushpavalli Manika Pal-Bhadra 《Bioorganic & medicinal chemistry letters》2010,20(17):5232-5236
A series of new anilino substituted pyrimidine linked pyrrolo[2,1-c][1,4]benzodiazepine (PBD) conjugates were prepared and evaluated for their anticancer activity. The effects of four promising PBD conjugates on cell cycle of cancerous cell line A375 were investigated. These compounds showed the characteristic features of apoptosis like enhancement in the levels of p53, release of cytochrome c, and cleavage of PARP. 相似文献
4.
Steven D. Fidanze Dachun Liu Robert A. Mantei Lisa A. Hasvold John K. Pratt George S. Sheppard Le Wang James H. Holms Yujia Dai Ana Aguirre Andrew Bogdan Justin D. Dietrich Jasmina Marjanovic Chang H. Park Charles W. Hutchins Xiaoyu Lin Mai H. Bui Xiaoli Huang Keith F. McDaniel 《Bioorganic & medicinal chemistry letters》2018,28(10):1804-1810
Novel conformationally constrained BET bromodomain inhibitors have been developed. These inhibitors were optimized in two similar, yet distinct chemical series, the 6-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (A) and the 1-methyl-1H-pyrrolo[2,3-c]pyridin-7(6H)-ones (B). Each series demonstrated excellent activity in binding and cellular assays, and lead compounds from each series demonstrated significant efficacy in in vivo tumor xenograft models. 相似文献
5.
6.
N. Strojny C.V. Puglisi J.A.F. de Silva 《Journal of chromatography. B, Analytical technologies in the biomedical and life sciences》1984,336(1)
A rapid, sensitive and selective high-performance liquid chromatographic (HPLC) assay was developed for the determination of the antiallergenic compound N-[4-(1H-imidazol-1-yl)butyl]-2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxamide (I), and its major metabolite, 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid (I-A), in plasma. The assay involves precipitation of the plasma proteins with aceto-nitrile—methanol (9:1), followed by the analysis of an aliquot of the protein-free filtrate by reversed-phase ion-pair HPLC with fluorescence detection for quantitation. The analogous compound, N-[6-(1H-imidazol-1-yl)hexyl]-2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]-quinazoline-8-carbonxamide (II), is used as the internal standard. The overall recovery of compounds I and I-A from plasma is 107.0 ± 8.6% and 107.0 ± 10.0%, respectively. The sensitivity limits of quantitation are 20 ng of I, and 10 ng of I-A per ml of plasma using a 0.5-ml aliquot. The assay was used to monitor the plasma concentrations of I and of I-A in a dog following a 5 mg/kg intravenous infusion of I · 2HCl, a 10mg/kg oral dose of I · 2HCl and of metabolite I-A. 相似文献
7.
Mariateresa Badolato Gabriele Carullo Biagio Armentano Salvatore Panza Rocco Malivindi Francesca Aiello 《Bioorganic & medicinal chemistry letters》2017,27(14):3092-3095
In this study, we investigate the anti-proliferative activity of a small library of 7-substituted 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one derivatives, against a panel of human cancer cell lines. We reported the synthesis of these compounds in a previous work. 7-Bromo-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-5-one showed a promising anti-proliferative effect. As starting material for Suzuki-Miyaura cross coupling reaction, it was selected for the design and the synthesis of six further derivatives, with the aim to better define structure-activity relationships. The anti-proliferative MTT assay revealed a dose-dependent reduction of cell viability, especially for 7-([1,1′-biphenyl]-4-yl)-5H-benzo[d]pyrrolo[2,1-b][1,3]oxazin-5-one. Cell cycle and western blotting analysis suggested apoptosis as possible mechanism for its anti-proliferative activity. These preliminary results encourage our interest for further optimizations. 相似文献
8.
《Bioorganic & medicinal chemistry letters》2014,24(14):3199-3203
A series of TRPA1 antagonists is described having a 4-aryloxy-1H-pyrrolo[3,2-c]pyridine or a 1-aryloxyisoquinoline scaffold. These compounds have high ligand efficiency and favorable physical properties and may thus serve as scaffolds for further optimization. 相似文献
9.
György Szabó Róbert Kiss Dóra Páyer-Lengyel Krisztina Vukics Judit Szikra Andrea Baki László Molnár János Fischer György M. Keserű 《Bioorganic & medicinal chemistry letters》2009,19(13):3471-3475
Hit-to-lead optimization of a novel series of N-alkyl-N-[2-oxo-2-(4-aryl-4H-pyrrolo[1,2-a]quinoxaline-5-yl)-ethyl]-carboxylic acid amides, derived from a high throughput screening (HTS) hit, are described. Subsequent optimization led to identification of in vitro potent cannabinoid 1 receptor (CB1R) antagonists representing a new class of compounds in this area. 相似文献
10.
The in vitro cytotoxic potentials of Furo[3,2-c]pyran-4-one derivatives in human lymphocytes were investigated. Blood samples were obtained from six healthy donors, non-smoking
volunteers, which were incubated and exposed to increasing concentrations (0.05, 0.1, 0.5, 1 and 2 mg/mL) of Furo[3,2-c]pyran-4-one derivatives which are methyl 2-methoxy-7-(4-methylbenzoyl)-6-(4-methylphenyl)-4-oxo-4H-furo[3,2-c]pyran-3-carboxylate (1a) and methyl 2-methoxy-7-(4-methoxybenzoyl)-6-(4-methoxyphenyl)-4-oxo-4H-furo[3,2-c]pyran-3-carboxylate (1b). Compounds 1a and 1b induced micronucleus, mitotic and replication indexes in human lymphocytes
(1 and 2 mg/mL). The increases of micronucleus, mitotic and replication indexes show that compounds at high concentrations
may become cytotoxic, genotoxic and carcinogenic. 相似文献
11.
《Journal of Chromatography B: Biomedical Sciences and Applications》1984,305(1):301-311
A rapid, sensitive and selective high-performance liquid chromatographic (HPLC) assay was developed for the determination of the antiallergenic compound N-[4-(1H-imidazol-1-yl)butyl]-2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxamide (I), and its major metabolite, 2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b] quinazoline-8-carboxylic acid (I-A), in plasma. The assay involves precipitation of the plasma proteins with aceto-nitrile—methanol (9:1), followed by the analysis of an aliquot of the protein-free filtrate by reversed-phase ion-pair HPLC with fluorescence detection for quantitation. The analogous compound, N-[6-(1H-imidazol-1-yl)hexyl]-2-(1-methylethyl)-11-oxo-11H-pyrido[2,1-b]-quinazoline-8-carbonxamide (II), is used as the internal standard. The overall recovery of compounds I and I-A from plasma is 107.0 ± 8.6% and 107.0 ± 10.0%, respectively. The sensitivity limits of quantitation are 20 ng of I, and 10 ng of I-A per ml of plasma using a 0.5-ml aliquot. The assay was used to monitor the plasma concentrations of I and of I-A in a dog following a 5 mg/kg intravenous infusion of I · 2HCl, a 10mg/kg oral dose of I · 2HCl and of metabolite I-A. 相似文献
12.
Wang T Liu J Zhong H Chen H Lv Z Zhang Y Zhang M Geng D Niu C Li Y Li K 《Bioorganic & medicinal chemistry letters》2011,21(11):3381-3383
A series of ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates were prepared through the metal-catalyzed domino reaction of alkylidene malonates and 1,4-butynediol under a one-pot reaction condition at room temperature. Their in vitro anti-proliferative activities were subsequently evaluated in A549, QGY and HeLa cells. The majority of the compounds showed potent anti-tumor activity against HeLa cells. In particular, compound 3l was the most potent compound with IC50 value of 5.4 μM. For the first time, the X-ray structure of the anti-tumor ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates is determined. 相似文献
13.
Manuel Koller David A. Carcache David Orain Peter Ertl Dirk Behnke Sandrine Desrayaud Grit Laue Ivo Vranesic 《Bioorganic & medicinal chemistry letters》2012,22(20):6454-6459
1H-pyrrolo[2,3-c]pyridine-7-carboxamides constitute a new series of allosteric mGluR5 antagonists. Variation of the substituents attached to the heterocyclic scaffold allowed to improve the physico-chemical parameters for optimization of the aqueous solubility while retaining high in vitro potency. 相似文献
14.
Weidong Hu Qinghua Yang Shuyang Wang Gang Huang Yueteng Zhang Jingjing Dong 《Nucleosides, nucleotides & nucleic acids》2013,32(7):389-395
A new route for the synthesis of the anti-HCV nucleoside analogue, 4-amino-5-fluoro-7-(2′-deoxy-2′-fluoro-2′-C-methyl-β-d-ribofuranosyl)-1H-pyrrolo[2,3-d]pyrimidine 1, was developed. 相似文献
15.
1H-Pyrrolo[2′,3′:4,5]furo[3,2-c]pyridine-2-carboxylic acid (6a) and its 1-methyl (6b) and 1-benzyl (6c) derivatives were synthesized. 3-(5-Methoxycarbonyl-4H-furo[3,2-b]-pyrrole-2-yl)propenoic acid (1) was converted to the corresponding azide 2, which in turn was cyclized to give 3 by heating in diphenylether. The pyridone 3 obtained was aromatized with phosphorus oxychloride, then reduced with zinc in acetic acid to give methyl 1H-pyrrolo[2′,3′:4,5]furo[3,2-c]pyridine-2-carboxylate (5), which by hydrolysis gave the corresponding carboxylic acid 6a. 相似文献
16.
Sh. H. Abdel-Hafez 《Russian Journal of Bioorganic Chemistry》2010,36(3):370-376
Synthesis of 3-[4-(N-substituted sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyri-do[3′,2′:4,5]selenolo[3,2-d]pyrimidines,7-[4-(N-substituted sulfamoyl)phenyl]-7,8-dihydro-8-oxo-3,4-diphenylpyrimido[4′,5′:4,5]selenolo [2,3-c]pyridazines and 1-[4-(N-substituted sulfamoyl)phenyl]-1,11-dihydro 11-oxo-4-methylpyrimido[4′,5′:4,5]selenolo[2,3-b]quinolines is reported. 4-Amino-N-pyrimidine-2-ylbenzene sulfonamide (a), 4-amino-N-(2,6-dimethylpyrimidin-4-yl)benzene sulfonamide (b), N-[(4-aminophenyl)sulfonyl] acetamide (c) with N-ethoxymethyleneamino of selenolo pyridine, selenolo pyridazine and selenolo quinoline derivatives respectively were obtained
starting from 1-amino-N
4-substituted sulfanilamides. Spectroscopic data (IR, 1H NMR, 13C NMR and Mass spectral) confirmed the structure of the newly synthesized compounds. Substituted
pyrimidines, pyridazines and quinolines were screened for antibacterial activity against gram-positive and gram-negative bacteria. Selenolo derivative of N-[(4-aminophenyl)sulfonyl] acetamide (substitutent of sulfacetamide c) showed strong bactericidal effect against all the tested
organisms. Selenolo[3,2-d]pyrimidin (substitutent a) showed a good bactericidal effect against Serratia marcescens, Staphylococcus aureus and Escherichia coli. Compounds selenolo[2,3-c]pyridazine (substitutent b), selenolo[2,3-b]quinoline(substitutents c)) exhibited a moderate bactericidal effect against Serratia marcescens. None of the synthesized seleno pyridazines has a considerable antimicrobial activity against the tested organisms. The minimum
inhibitory concentration (MIC) of the most active compound-3-[4-(N-acetyl sulfamoyl)phenyl]-3,4-dihydro-4-oxo-7,9-dimethylpyrido[3′,2′:4,5]selenolo [3,2-d]pyrimidine was 10 mg ml−1. 相似文献
17.
Katarzyna Grychowska Rafał Kurczab Paweł Śliwa Grzegorz Satała Krzysztof Dubiel Mikołaj Matłoka Rafał Moszczyński-Pętkowski Jerzy Pieczykolan Andrzej J. Bojarski Paweł Zajdel 《Bioorganic & medicinal chemistry》2018,26(12):3588-3595
Based on pyrroloquinoline scaffold bearing 5-HT2C agonists, a series of arylsulfonamide derivatives of 1H-pyrrolo[2,3-f]quinoline and 1H-pyrrolo[3,2-h]quinoline, substituted at position 3 with tetrahydropyridine, were synthesized and evaluated in vitro for their affinity for 5-HT6 receptors. A structure–activity relationship study showed that the 1H-pyrrolo[3,2-h]quinoline scaffold was more favorable for 5-HT6R binding than the 1H-pyrrolo[2,3-f]quinoline one, suggesting dependence upon the type of condensation of the pyrrole and quinoline rings. As revealed by quantum-chemical calculations and molecular dynamic studies, position of the quinoline nitrogen atom in the planar pyrroloquinoline skeleton might affect the spatial orientation of the arylsulfonyl fragment, as a result of structure stabilization by internal hydrogen bonds. 相似文献
18.
《Bioorganic & medicinal chemistry letters》2014,24(18):4466-4471
A novel synthesis of the translocator protein (TSPO) ligand 7-chloro-N,N,5-trimethyl-4-oxo-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (SSR180575, 3) was achieved in four steps from commercially available starting materials. Focused structure–activity relationship development about the pyridazinoindole ring at the N3 position led to the discovery of 7-chloro-N,N,5-trimethyl-4-oxo-3(6-fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide (14), a novel ligand of comparable affinity. Radiolabeling with fluorine-18 (18F) yielded 7-chloro-N,N,5-trimethyl-4-oxo-3(6-[18F]fluoropyridin-2-yl)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetamide ([18F]-14) in high radiochemical yield and specific activity. In vivo studies of [18F]-14 revealed this agent as a promising probe for molecular imaging of glioma. 相似文献
19.
Young Ae Yoon Dong Hoon Kim Byoung Moon Lee Tae Kyun Kim Myung Hun Cha Jae Young Sim Jae Gyu Kim 《Bioorganic & medicinal chemistry letters》2010,20(17):5237-5240
A series of 1H-pyrrolo[2,3-c]pyridines as acid pump antagonists (APAs) was synthesized and the inhibitory activities against H+/K+ ATPase isolated from hog gastric mucosa were determined. After elaborating on substituents at N1, C5, and C7 position of 1H-pyrrolo[2,3-c]pyridine scaffold, we have observed that compounds 14f and 14g are potent APAs with H+/K+ ATPase IC50 = 28 and 29 nM, respectively. 相似文献
20.
Małgorzata Sztanke Jolanta Rzymowska Krzysztof Sztanke 《Bioorganic & medicinal chemistry》2013,21(23):7465-7480
The worked out and optimized synthesis routes and remarkable antitumour activities in vitro of novel polynitrogenated derivatives of diethyl (2E)-2-[(2E)-(1-arylimidazolidin-2-ylidene)hydrazono]succinate (7–10) and ethyl (4-oxo-8-aryl-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl)acetate (11–16) are presented. Small molecules based on the privileged 7,8-dihydroimidazo[2,1-c][1,2,4]triazin-4(6H)-one scaffold (11–16) were obtained with fairly modest to good overall yields by very facile addition reactions of the nucleophilic centred 1-aryl-2-hydrazonoimidazolidine hydroiodides to diethyl acetylenedicarboxylate (DEAD) in the presence of triethylamine (TEA) and a subsequent cyclocondensation of the putative intermediate chain hydrazones. Heterobicyclic products 12 and 14–16 could also be prepared in high overall yields by an effective intramolecular cyclocondensation of the isolated stable and antiproliferative active heterocyclic hydrazones, namely, diethyl (2E)-2-[(2E)-(1-arylimidazolidin-2-ylidene)hydrazono]succinates (7–10), performed in refluxing DMF. These intermediates are the first products to be formed in the result of an addition of the nucleophilic reactants, namely, 1-aryl-2-hydrazonoimidazolidines of the 1–6 type, bearing the basic nitrogen atom of the hydrazono moiety (N–NH2), to the carbon–carbon triple bond of the highly electrophilic alkyne, that is, DEAD. Molecular structures of the synthesized compounds (7–16) in the DMSO-d6 solutions were verified by 1H NMR and 13C NMR spectral data. These were finally confirmed based on the advanced 2D HMBC and HMQC NMR experiments, which were performed for the two representatives (8 and 11) of the two synthesized sets of the bioactive substances. Among the majority of antiproliferative active molecules, the disclosed herein ethyl [4-oxo-8-(3-chlorophenyl)-4,6,7,8-tetrahydroimidazo[2,1-c][1,2,4]triazin-3-yl]acetate (14) is proposed as a promising lead structure for the design of novel highly selective antitumour agents because of the distinctly marked lower cytotoxicity towards the primary cell line of normal HSF cells and several-fold higher against cancer cells used. A double fluorochrome mix-staining was performed in order to find out about the possible mode of action by which this novel small heterobicycle reveals remarkable antiproliferative effects in vitro. Taking into account the obtained double staining results, this small molecule was identified as capable of inducing significantly higher levels of necrotic cells in human cancer cell lines (T47D and HeLa) than in normal HSF cells. Furthermore, its cytotoxicity against cells was found to be connected to the predominant induction of necrosis over apoptosis. 相似文献