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91.
Zopf DA das Neves LA Nikula KJ Huang J Senese PB Gralinski MR 《European journal of pharmacology》2011,(1):195-203
Pulmonary arterial hypertension (PAH) is a chronic disease characterized by sustained elevation of pulmonary arterial pressure that leads to right ventricle failure and death. Pulmonary resistance arterioles in PAH undergo progressive narrowing and/or occlusion. Currently approved therapies for PAH are directed primarily at relief of symptoms by interfering with vasoconstrictive signals, but do not halt the microvascular cytoproliferative process. In this study we show that C-122 (2-amino-N-(2-{4-[3-(2-trifluoromethyl-phenothiazin-10-yl)-propyl]-piperazin-1-yl}-ethyl)-acetamide trihydrochloride, a novel antagonist of serotonin receptor 5-HT2B (Ki = 5.2 nM, IC50 = 6.9 nM), when administered to rats for three weeks in daily oral 10 mg/kg doses, prevents not only monocrotaline (MCT)-induced elevations in pressure in the pulmonary arterial circuit (19 ± 0.9 mm Hg vs. 28 ± 2 mm Hg in MCT-vehicle group, P < 0.05) and hypertrophy of the right ventricle (right ventricular wt./body wt. ratio 0.52 ± 0.02 vs. 0.64 ± 0.04 in MCT-vehicle group, P < 0.05), but also muscularization of pulmonary arterioles (23% vs. 56% fully muscularized in MCT-vehicle group, P < 0.05), and perivascular fibrosis in the lung. C-122 is orally absorbed in the rat, and partitions strongly into multiple tissues, including heart and lung. C-122 has significant off-target antagonist activity for histamine H-1 and several dopamine receptors, but shows no evidence of crossing the blood–brain barrier after a single 10 mg/kg oral dose in rats. We conclude that C-122 can prevent microvascular remodeling and associated elevated pressures in the rat MCT model for PAH, and offers promise as a new therapeutic entity to suppress vascular smooth muscle cell proliferation in PAH patients. 相似文献
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Demetrio Raffa Benedetta Maggio Stella Cascioferro Maria Valeria Raimondi Giuseppe Daidone Salvatore Plescia Domenico Schillaci Maria Grazia Cusimano Lucina Titone Claudia Colomba Manlio Tolomeo 《Archiv der Pharmazie》2009,342(5):265-273
A series of N‐1H‐indazole‐1‐carboxamides has been synthesized and their effects on both CDK1 / cyclin B and the K‐562 (human chronic myelogenus leukemia) cell line were evaluated. Using a computational model, we have observed that all the most active compounds 9e , f , i – n exhibited the same binding mode of purvanalol A in the ATP‐binding cleft. Although they were able to moderately inhibit the leukemic cell line K‐562 and to show inhibitory activity against the Cdc2‐Cyclin B kinase in the low micromolar range, they turned out to be non‐cytotoxic against HuDe (IZSL) primary cell cultures from human derm. These preliminary results are quite encouraging in view of the low toxicity demonstrated by the above‐mentioned compounds. 相似文献
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Alleca S Corona P Loriga M Paglietti G Loddo R Mascia V Busonera B La Colla P 《Il Farmaco; edizione pratica》2003,58(9):639-650
Twenty eight pyrrolo[1,2-a]quinoxalines bearing at position 4 various substituents related to the moieties present in classical and non classical antifolic agents were prepared and evaluated in vitro for antiproliferative activity. In an in vitro screening performed at NCI, several compounds emerged as potent antiproliferative agents at concentrations ranging between 10 and 100 microM. Interestingly, some of these compounds proved active also against bovine and murine DHFR (Farmaco 53 (1998) 480). More recently, a compound of classical antifolate type has been reported to be a potent inhibitor of hDHFR in vitro (Farmaco 58 (2003) 51). We then synthesized new derivatives that, in our hands, were endowed with in vitro antiproliferative activities as low as 3.4 microM against a panel of cell lines derived from hematological and solid tumours. In addition, a complete screening of cytotoxicity, antiretroviral HIV-1 and antimicrobial activity has been carried out. 相似文献
97.
Garuti L Roberti M Pizzirani D Pession A Leoncini E Cenci V Hrelia S 《Il Farmaco; edizione pratica》2004,59(8):663-668
Ten benzimidazole-4,7-diones were synthesized and tested in vitro on two tumor cell lines. Several compounds showed a significant antiproliferative activity on K562 cells, although to a different extent, whereas compound 1i showed a highly significant activity on SW620 cells, comparable to that of doxorubicin. Both the substituents in the quinone ring and the position of the nitrogen atom in the pyridine moiety play a crucial role for the biological activity. 相似文献
98.
The Apoptotic Properties of Leaf Extracts of Simarouba glauca against Human Leukemic Cancer Cells 下载免费PDF全文
Vikas BibaSujathan KunjiramanSuja Somasekharan Nair RajamSukumaran Anil 《Asian Pacific journal of cancer prevention》2021,22(4):1305-1312
Background and objective: Simarouba glauca is a plant belonging to the family of Simaroubaceae. It is a potent source of secondary metabolites. The aim of this study was to evaluate the apoptotic properties of leaf extracts of Simarouba glauca against human leukemic cancer cells. Materials and Methods: Cytotoxicity of Simarouba glauca was assessed in the leaf extract of petroleum ether against leukemic cells by MTT assay. To detect the apoptotic features, fluorescence microscopy analysis was done with dual acridine orange/ethidium bromide fluorescent staining and Hoechst staining. To determine the externalization of phosphatidylserine, annexin v staining was done. Mitochondrial or death receptor activation was confirmed by caspase 3 analysis by flow cytometry. Results: This study revealed that Simarouba glauca was able to treat leukemia. Among the four extracts, petroleum ether extract showed a higher order of in vitro anticancer activity. The petroleum ether extract strongly inhibited the proliferation of K562 cell lines with IC50 values of 186 µg/ml. Dual acridine orange/ethidium bromide fluorescent staining and Hoechst staining revealed the characteristic features of apoptosis. Annexin V confirmed early and late stage apoptosis. Caspase-3 analysis revealed that cell death was due to mitochondrial or death receptor activation in mitochondrial pathway. Conclusion: These findings suggested that Simarouba glauca leaf extracts inhibited leukemic cells in a time- and dose-dependent manner either through mitochondrial or death receptor activation. The leaf extracts of Simarouba glauca was found to be nontoxic to lymphocytes. It can be concluded that Simarouba glauca is an important source of phytochemicals posing efficacy against leukemic cancer cells. 相似文献
99.
Bernini R Crisante F Merendino N Molinari R Soldatelli MC Velotti F 《European journal of medicinal chemistry》2011,46(1):439-446
A novel ester of hydroxytyrosol and α-lipoic acid was synthesized in satisfactory yield by original and simple procedures and evaluated about its antiproliferative activity on the human colorectal adenocarcinoma HT-29 cell line. The compound exhibited a cell growth inhibitory activity significantly more potent than the corresponding parent natural compounds, very likely due to the induction of cell cycle arrest in the G2/M phase. These data suggest that the novel ester might exert a more effective antitumour activity than hydroxytyrosol and α-lipoic acid. 相似文献
100.
Parekh S Bhavsar D Savant M Thakrar S Bavishi A Parmar M Vala H Radadiya A Pandya N Serly J Molnár J Shah A 《European journal of medicinal chemistry》2011,46(5):1942-1948
A new series of benzofuran-2-yl(4,5-diydro-3,5-substituted diphenylpyrazol-1-yl) methanone derivatives 8a-x by the reaction of the benzofuran-2-carbohydrazides 7 with various chalcone derivatives 3a-x using microwave irradiation has been described. The effect of synthesized compounds 8a-v was studied against human cancer cell lines for their antiproliferative activity and reversal of multidrug resistance on human MDR1-gene transfected mouse lymphoma cells. Among the 24 compounds, the 8c and 8h showed good antiproliferative activity 8b, 8f and 8k were exhibited good MDR reversal activity. The main significance of the process is easy workup process, short reaction time and high yield of the new compounds for biological interest. However, the studies on genetically modified multidrug resistant cancer cells are costly and time consuming. 相似文献