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51.
52.
Wei Wang Lin Ao Elizabeth R. Rayburn Hongxia Xu Xiangrong Zhang Xu Zhang Subhasree Ashok Nag Xuming Wu Ming-Hai Wang Hui Wang Erwin G. Van Meir Ruiwen Zhang 《PloS one》2012,7(9)
The purpose of the present study was to determine the in vitro and in vivo anti-cancer activity and pharmacological properties of 3,4-dimethoxy-N-[(2,2-dimethyl-2H-chromen-6-yl)methyl]-N-phenylbenzenesulfonamide, KCN1. In the present study, we investigated the in vitro activity of KCN1 on cell proliferation and cell cycle distribution of pancreatic cancer cells, using the MTT and BrdUrd assays, and flow cytometry. The in vivo anti-cancer effects of KCN1 were evaluated in two distinct xenograft models of pancreatic cancer. We also developed an HPLC method for the quantitation of the compound, and examined its stability in mouse plasma, plasma protein binding, and degradation by mouse S9 microsomal enzymes. Furthermore, we examined the pharmacokinetics of KCN1 following intravenous or intraperitoneal injection in mice. Results showed that, in a dose-dependent manner, KCN1 inhibited cell growth and induced cell cycle arrest in human pancreatic cancer cells in vitro, and showed in vivo anticancer efficacy in mice bearing Panc-1 or Mia Paca-2 tumor xenografts. The HPLC method provided linear detection of KCN1 in all of the matrices in the range from 0.1 to 100 µM, and had a lower limit of detection of 0.085 µM in mouse plasma. KCN1 was very stable in mouse plasma, extensively plasma bound, and metabolized by S9 microsomal enzymes. The pharmacokinetic studies indicated that KCN1 could be detected in all of the tissues examined, most for at least 24 h. In conclusion, our preclinical data indicate that KCN1 is a potential therapeutic agent for pancreatic cancer, providing a basis for its future development. 相似文献
53.
Nag S Lehmann L Kettschau G Heinrich T Thiele A Varrone A Gulyas B Halldin C 《Bioorganic & medicinal chemistry》2012,20(9):3065-3071
The aim of this study was to synthesize and evaluate a novel fluorine-18 labeled analogue of rasagiline (6) as a PET radioligand for monoamine oxidase B (MAO-B). The corresponding non-radioactive fluorine-19 ligand, (1S,2S)-2-fluoro-N-(prop-2-yn-1-yl)indan-1-amine (4), was characterized in in vitro assays. The precursor compound (3aS,8aR)-3-(prop-2-yn-1-yl)-3,3a,8,8a-tetrahydroindeno[1,2-d][1,2,3]oxathiazole 2,2-dioxide (3) and reference standard 4 were synthesized in multi-step syntheses. Recombinant human MAO-B and MAO-A enzyme preparations were used in order to determine IC(50) values for compound 4 by use of an enzymatic assay employing kynuramine as substrate. Radiolabeling was accomplished by a two-step synthesis, compromising a nucleophilic substitution followed by hydrolysis of the sulphamidate group. Human whole hemisphere autoradiography (ARG) was performed with [(18)F]fluororasagiline. Blocking experiments with pirlindole (MAO-A), L-deprenyl and rasagiline (MAO-B) were conducted to demonstrate the specificity of the binding. A positron emission tomography (PET) study was carried out in a cynomolgus monkey where time activity curves for whole brain and regions with high and low MAO-B activity were recorded. Radiometabolites were measured in monkey plasma using gradient HPLC. Compound 4 inhibited MAO-B with an IC(50) of 27 nM and MAO-A with an IC(50) of 2.3 μM. Radiolabeling of precursor 3 and subsequent hydrolysis of the protecting group towards (1S,2S)-2-[(18)F]fluoro-N-(prop-2-yn-1-yl)indan-1-amine (6) was successfully accomplished with an radiochemical yield of 40-70%, a radiochemical purity higher than 99% and a specific radioactivity higher than 200GBq/μmol. ARG demonstrated selective binding for [(18)F]fluororasagiline (6) to MAO-B containing brain regions, for example, striatum. The initial uptake in the monkey brain was 250% SUV at 4 min post injection. The highest amounts of radioactivity were observed in the striatum and thalamus as expected whereas in the cortex and cerebellum lower levels were observed. Metabolite studies demonstrated 30% unchanged radioligand at 90 min post injection. Our investigations demonstrated that the new ligand [(18)F]fluororasagiline (6) binds specifically to MAO-B in vitro and has a MAO-B specific binding pattern in vivo. Thus, it could serve as a novel potential candidate for human PET studies. 相似文献
54.
Pulmonary surfactant provides for a lipid rich film at the lung air-water interface, which prevents alveolar collapse at the end of expiration. The films are likely enriched in the major surfactant component dipalmitoylphosphatidylcholine (DPPC), which, due to its saturated fatty acid chains, can withstand high surface pressures up to 70 mN/m, thereby reducing surface tension in that interface to very low values (close to 1 mN/m). Despite many experimental measurements in situ, as well as in vitro for native lung surfactant films, the exact mechanism by which other fluid lipid components of surfactant, in combination with surfactant proteins, allow for such low surface tension values to be reached is not well understood. We have performed molecular dynamics simulation of films composed of DPPC alone and in mixtures with other fluid and acidic lipid components of surfactant at the high densities relevant to the low surface tension regime. 10-50 ns simulations were performed with the software GROMACS, with 40-64 lipids molecules plus water, using 5 different lipid compositions and 7 different areas per lipid. The primary focus was to learn how differences in lipid composition affect the response of the monolayer to compression, such as the development of curvature or the loss of lipids to the exterior of the monolayer. The systems studied exhibit features of two of the major schools of thought of lung surfactant mechanisms, in that although unsaturated lipids did not appear to prevent the monolayers from achieving high surface pressure, POPG did appear to be selectively squeezed out of the DPPC/POPG monolayers at high lipid densities. 相似文献
55.
Role of Auxin and Polyamines in Adventitious Root Formation
in Relation to Changes in Compounds Involved in Rooting 总被引:18,自引:0,他引:18
apd: 3 July 2001 相似文献
56.
57.
Summary Embryonic chick cardiac cell cultures, plated on collagen-coated dishes, containing serum-free synthetic media proliferate
actively. The basic medium contained Ham's F12 nutrient mixture, fetuin, ascorbic acid, and bovine serum albumin. This medium
was supplemented with various combinations of factors; endothelial cell growth supplement (ECGS), epidermal growth factor
(EGF), insulin (I), transferrin (T), selenium (S), hydrocortisone, and thyroxine or supplemented alone. Basic medium supplemented
with ECGS alone contributes to the highest final cell density among all other factors used in various combinations or alone.
The final cell density of the control culture with 2% fetal bovine serum was higher than those of all experimental cultures
and an additional control culture grown in the basic medium. Combinations of factors without ECGS do not promote significant
cell proliferation. Thyroxine is required to induce optimal differentiation and contractility of cardiac myocytes in vitro.
Fibronectin and laminin did not show any more influence than collagen did on the growth and maintenance of cardiac myocytes
in serum-free media. The proportion of cardiac muscle cells in ECGS-containing media was higher than those in other experimental
media and control media with the exception of ECGS and ITS-containing medium that showed lower proportion of cardiac myocytes
than that of serum-containing medium on Days 3 and 5. The profiles of incorporation of [3H]thymidine into DNA of heart cells in experimental and control cultures showed a peak in incorporation values within the
first week of culture and subsequently declined. Autoradiography studies revealed that cardiac myocytes in culture supplemented
with ECGS alone attained a peak in labeling index on Day 1 with approximately 62% labeled cells. Subsequently, the labeling
indices declined. Cardiac myocytes grown in media without ECGS showed significantly lower labeling indices than those in ECGS-containing
media. This study has demonstrated the influence of ECGS, EGF and ITS in promoting the growth of cardiac myocytes and also
in contributing to the maintenance of contractile cardiac myocytes in serum-free, long-term culture. The influence of ECGS
on heart cell proliferation is considered to be superior to that of EGF and ITS.
This study was supported in part by a grant HL-25482 from the National Heart Lung and Blood Institute and a grant from the
American Heart Association of Michigan. 相似文献
58.
59.
Mihir K. Dutt 《Histochemistry and cell biology》1971,25(1):60-62
Summary The results presented in this paper indicate that following fixation of rat liver in either 40% (w/v) or 10% formalin solution, Feulgen staining is far greater in the tissue fixed in the former fixative as compared with the same fixed in the latter. A possible mode of action of formalin towards fixation and subsequent Feulgen staining is suggested. 相似文献
60.