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Seiichi Inayama - One of the best experts on this subject based on the ideXlab platform.
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Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-Nitroimidazole hypoxic cell radiosensitizers.
Bioorganic & medicinal chemistry, 2004Co-Authors: Cheng-zhe Jin, Seiichi Inayama, Mariko Shimamura, Hideko Nagasawa, Yoshihiro Uto, Yoshio Takeuchi, Kenneth L. Kirk, Hitoshi HoriAbstract:(R)- and (S)-Epichlorohydrins were used to prepare the enantiomers of sterically diverse haloacetylcarbamoyl-2-Nitroimidazoles that function as hypoxic cell radiosensitizers. The synthetic design allowed for introduction of a side chain of varying bulk that permitted an examination of the steric effects on enantio-discrimination in biological assay systems. The single stereocenter also connected the two pharmacophores––a 2-Nitroimidazole moiety critical to hypoxic cell radiosensitization, and a haloacetylcarbamoyl group to function as an anti-angiogenesis pharmacophore. In the chick embryo chorioallantoic membrane (CAM) assay, the R-enantiomers possessing the bulky p-tert-butylphenyl group showed higher anti-angiogenic activity than the corresponding S-enantiomers, while there were no differences in the activity between the enantiomers containing the less bulky methyl and tert-butyl groups. Among the compounds we report, R-p-tert-butylphenyl-bromoacetylcarbamoyl-2-Nitroimidazole, TX-1898, was found to be the most promising candidate for further development of as anti-angiogenic hypoxic cell radiosensitizer.
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A novel hypoxia-dependent 2-Nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors
British journal of cancer, 2003Co-Authors: Mariko Shimamura, HIROTSUGU ASHINO, Tadahiko Hazato, Hideko Nagasawa, Y Yamamoto, Hitoshi Hori, Yoshihiro Uto, Seiichi InayamaAbstract:A novel hypoxia-dependent 2-Nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors
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A novel hypoxia-dependent 2-Nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors
British Journal of Cancer, 2003Co-Authors: Mariko Shimamura, HIROTSUGU ASHINO, Tadahiko Hazato, H Hori, H. Nagasawa, Y Yamamoto, Seiichi InayamaAbstract:Tumour angiogenesis is initiated by angiogenic factors that are produced in large amounts by hypoxic tumour cells. The inhibition of this step may lead to tumour-specific antiangiogenesis because normal tissues are not usually hypoxic. On the other hand, blocking a biological function of endothelial cells is known to result in angiogenic inhibition. To produce a tumour-specific and powerful antiangiogenesis, we determined whether potent angiogenic inhibition could be achieved by inhibiting the production of angiogenic factors by hypoxic tumour cells and simultaneously blocking certain angiogenic steps in endothelial cells under normoxia. We focused on the 2-Nitroimidazole moiety, which is easily incorporated into hypoxic cells and exhibits its cytotoxicity as hypoxic cytotoxin. We designed and synthesised 2-Nitroimidazole derivatives designated as KIN compounds, and investigated their antiangiogenic activities under normoxia using a chick embryo chorioallantoic membrane. KIN-841 (2-Nitroimidazole 1-acetylhydroxamate) showed a potent angiogenic inhibition in a dose-dependent manner. This compound inhibited the proliferation of bovine pulmonary arterial endothelial (BPAE) cells more strongly than that of tumour cells, such as Lewis lung carcinoma (3LL) cells, under normoxia. The inhibition of cell proliferation by KIN-841 under hypoxia increased about five-fold compared to that under normoxia. Moreover, under hypoxia, KIN-841 significantly decreased the excessive production of vascular endothelial cell growth factors induced by 3LL cells as determined by tritium-labelled thymidine ([^3H]thymidine) incorporation into BPAE cells and by ELISA. Intraperitoneal administration of KIN-841 suppressed 3LL-cell-induced in vivo angiogenesis in the mouse dorsal air sac system. These results indicate that the regulation of the production of angiogenic factors by hypoxic tumour cells is a useful target for tumour-specific angiogenesis inhibition, and that KIN-841, which causes simultaneous direct inhibition of endothelial cell function and production of angiogenic factors by hypoxic tumour cells, is a very potent inhibitor of tumour-specific angiogenesis. Thus, the potential for clinical use of KIN-841 as an antitumour drug is very high.
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new antimetastatic hypoxic cell radiosensitizers design synthesis and biological activities of 2 Nitroimidazole acetamide tx 1877 and its analogues
Bioorganic & Medicinal Chemistry, 2001Co-Authors: Soko Kasai, Hideko Nagasawa, Yoshihiro Uto, Mao Yamashita, Mie Masui, Hideki Kuwasaka, Tomoko Oshodani, Taisuke Inomata, Shigenori Oka, Seiichi InayamaAbstract:We designed, based on the molecular orbital (MO) calculation, synthesized, and evaluated the biological activities of the new antimetastatic hypoxic cell radiosensitizer, 2-Nitroimidazole-acetamide, TX-1877, and its analogues. Each analogue has an electron-affinic imidazole group, an acetamide group and a certain hydrophilic group to control its biological effect, toxicity, and pharmacokinetics. In in vitro radiosensitization assay, most TX-1877 analogues, which have an electron affinity (EA) of more than 0.9 eV and partition coefficient (P) of more than 0.021, showed satisfactory enhancement ratios (ER > 1.60) at doses of I mM. On the other hand, imidazole analogues, such as TX-1908 (EA = 0.67 eV), TX-1910 (EA = -0.34 eV) and TX-1931 (EA = -0.37 eV), which have low electron affinities, had an ER of 1.31 or less. TX-1877 and KIN-806 effectively inhibited tumor regrowth when administered with irradiation in vivo at a dose of 0.4 mg/g. Tumor lung metastasis was inhibited by treatment with either TX-1877 or KIN-806 without irradiation at a dose of 0.4 mg/g. TX-1877 reduced markedly the mean number of metastatic lung nodules in comparison with KIN-806. Moreover, TX-1877 and KIN-806 enhanced macrophage and helper T lymphocyte infiltration for 3 weeks after drug treatment. TX-1877 shows a high EA value and has the C2 of HOMO localizing on N-methylamide and the C2 of LUMO localizing on 2-Nitroimidazole group. The MO data might be useful for designing a bifunctional hypoxic cell radiosensitizer. TX-1877 and its analogues are potential antimetastatic hypoxic cell radiosensitizers, which would improve the efficiency of radiotherapy and quality of life in cancer treatment.
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Studies of methyl 2-Nitroimidazole-1-acetohydroxamate (KIN-804) 2: effect on certain antioxidant enzyme systems in mice bearing Ehrlich ascites carcinoma.
Biological & pharmaceutical bulletin, 2000Co-Authors: Medhat Abu-zeid, Hitoshi Hori, Hideko Nagasawa, Yoshihiro Uto, Seiichi InayamaAbstract:In order to decrease toxicity and/or increase radiosensitizing activity, a new 2-Nitroimidazole derivative, methyl 2-Nitroimidazole-1-acetohydroxamate (KIN-804), was synthesized to solve the problem of tumor hypoxia. Evaluation of the efficiency of KIN-804 was carried out through studying the antioxidant enzyme system: The superoxide dismutase (SOD), catalase and lipid peroxide levels provide a rough index of the balance between free radical generation and scavenging. Female albino mice were inoculated with Ehrlich ascites carcinoma (EAC) in the thigh. The administration of KIN-804 (i.p. 80 mg/kg body weight) was carried out 20 min before localized irradiation of 10 Gy. In general, the data revealed that KIN-804 administration, followed or not by gamma irradiation, exerted significant inhibition of SOD and catalase activities accompanied by a significant increase in lipid peroxide level in tumor-bearing mice.
Seiichi Nishimoto - One of the best experts on this subject based on the ideXlab platform.
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propargylic sulfones possessing a 2 Nitroimidazole function novel hypoxic cell radiosensitizers with intracellular non protein thiol depletion ability
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Kazuhito Tanabe, Ryusuke Kojima, Hiroshi Hatta, Seiichi NishimotoAbstract:Abstract Propargylic sulfones ( 1a – c ) containing a 2-Nitroimidazole structure were synthesized, and their non-protein thiol (NPSH) depletion abilities were investigated. Propargylic sulfones 1a , c containing an electron withdrawing p -nitrophenyl group showed high reactivity toward capturing glutathione (GSH), a typical intracellular NPSH, in phosphate buffer. Among the three propargylic sulfones 1a – c , carboxylic acid derivative 1c showed the most potent radiosensitizing activity toward hypoxic EMT6/KU tumor cells. In view of these results and the partition coefficients between 1-octanol and water, we concluded that appropriate NPSH-depletion ability and lipophilicity are both important in achieving potent hypoxic-cell radiosensitization by propargylic sulfones possessing a 2-Nitroimidazole function in biological systems.
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propargylic sulfones possessing a 2 Nitroimidazole function novel hypoxic cell radiosensitizers with intracellular non protein thiol depletion ability
Bioorganic & Medicinal Chemistry Letters, 2004Co-Authors: Kazuhito Tanabe, Ryusuke Kojima, Hiroshi Hatta, Seiichi NishimotoAbstract:Abstract Propargylic sulfones ( 1a – c ) containing a 2-Nitroimidazole structure were synthesized, and their non-protein thiol (NPSH) depletion abilities were investigated. Propargylic sulfones 1a , c containing an electron withdrawing p -nitrophenyl group showed high reactivity toward capturing glutathione (GSH), a typical intracellular NPSH, in phosphate buffer. Among the three propargylic sulfones 1a – c , carboxylic acid derivative 1c showed the most potent radiosensitizing activity toward hypoxic EMT6/KU tumor cells. In view of these results and the partition coefficients between 1-octanol and water, we concluded that appropriate NPSH-depletion ability and lipophilicity are both important in achieving potent hypoxic-cell radiosensitization by propargylic sulfones possessing a 2-Nitroimidazole function in biological systems.
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A fluorinated 2-Nitroimidazole, KU-2285, as a new hypoxic cell radiosensitizer.
International journal of radiation oncology biology physics, 1991Co-Authors: Keisuke Sasai, Seiichi Nishimoto, Yuta Shibamoto, Kazuhiro Shimokawa, Yorisato Hisanaga, Yoshizumi Kitakabu, Lin Zhou, Jun Wang, Masaji Takahashi, Tsutomu KagiyaAbstract:Abstract To develop new hypoxic cell radiosensitizers, we incorporated fluorine atoms into the side chain of the 2-Nitroimidazole. Of the resulting compounds, KU-2285 (a 2-Nitroimidazole with an N1-substituent of CH2CF2CONHCH2CH2OH) was considered the most useful as a hypoxic cell radiosensitizer. In this study, its in vivo radiosensitizing activity and acute toxicity were compared with those of etanidazole. The reduction potentials of KU-2285 and etanidazole were −0.96 V and −1.05 V vs Ag Ag + in N,N-dimethylformamide, respectively, and their respective octanol/water partition coefficients were 0.25 and 0.040. The in vivo radiosensitizing activity of KU-2285 was found to be similar to that of etanidazole at the same administration dose when assayed by an in vivo-in vitro assay, a growth delay assay, and a tumor control assay using SCC VII tumor or transplanted mammary tumor in C3H He mice. Although the radiosensitizing activity of etanidazole was reduced when it was administered orally, there was no significant difference in the radiosensitizing activity of KU-2285 whether it was administered intravenously, intraperitoneally, or orally. The acute toxicity measured as the LD 50 7 in 8-week-old female C3H HeJ mice was found to be 2.4 g/kg (intravenously), 2.1 g/kg (intraperitonealy), and 4.25 g/kg (orally) for KU-2285, whereas it was 4.75 g/kg (intravenously) for etanidazole.
Taiwei Chu - One of the best experts on this subject based on the ideXlab platform.
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biodistribution of 99tcmo labeled mag3 2 Nitroimidazole hypoxia imaging agents with different spacers in s180 scarcoma bearing mice
Chinese Journal of Nuclear Medicine and Molecular Imaging, 2017Co-Authors: Lei Mei, Zhi Yang, Taiwei ChuAbstract:Objective To evaluate the hypoxia selectivity of 99TcmO-labeld MAG3-Nitroimidazole complexes with different spacers. Methods Four kinds of 99TcmO-labeled MAG3-2-Nitroimidazole hypoxia imaging agents with different spacers were synthesized and radiolabeled. The stability and lipid solubility of BzMAG3-2NIEA(1), BzMAG3-2NIPA(2), BzMAG3-2NIHA(3) and BzMAG3-2NIUA(4) were measured. The uptake was investigated by biodistribution experiment using S180-bearing mice. Two-sample t test was used for statistical analysis. Results All 4 99TcmO-MAG3 complexes were stable and negatively charged, showing an increasing trend in fat solubility with the increase of spacer length. In biodistribution study, tumor uptake of 99TcmO-1 and 99TcmO-2 with medium- and short-carbon chain were (0.67±0.18) and (0.65±0.18) %ID/g 2 h post injection, which were (0.19±0.03) and (0.39±0.05) %ID/g for 99TcmO-3 and 99TcmO-4 with long-carbon chain (t=2.78-5.88, all P<0.05). Conclusion Molecular structure of spacers has a significant effect on the physicochemical properties and tumor targeting of 99TcmO-labeled MAG3-2-Nitroimidazole hypoxia imaging agents, such that the medium- and short-carbon chain spacers show the best hypoxia-selective property. Key words: Nitroimidazoles; Isotope labeling; Technetium; Scarcoma; Radionuclide imaging; Mice
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Biodistribution of 99TcmO-labeled MAG3-2-Nitroimidazole hypoxia imaging agents with different spacers in S180 scarcoma-bearing mice
Chinese Journal of Nuclear Medicine and Molecular Imaging, 2017Co-Authors: Lei Mei, Zhi Yang, Taiwei ChuAbstract:Objective To evaluate the hypoxia selectivity of 99TcmO-labeld MAG3-Nitroimidazole complexes with different spacers. Methods Four kinds of 99TcmO-labeled MAG3-2-Nitroimidazole hypoxia imaging agents with different spacers were synthesized and radiolabeled. The stability and lipid solubility of BzMAG3-2NIEA(1), BzMAG3-2NIPA(2), BzMAG3-2NIHA(3) and BzMAG3-2NIUA(4) were measured. The uptake was investigated by biodistribution experiment using S180-bearing mice. Two-sample t test was used for statistical analysis. Results All 4 99TcmO-MAG3 complexes were stable and negatively charged, showing an increasing trend in fat solubility with the increase of spacer length. In biodistribution study, tumor uptake of 99TcmO-1 and 99TcmO-2 with medium- and short-carbon chain were (0.67±0.18) and (0.65±0.18) %ID/g 2 h post injection, which were (0.19±0.03) and (0.39±0.05) %ID/g for 99TcmO-3 and 99TcmO-4 with long-carbon chain (t=2.78-5.88, all P
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Synthesis and radiolabeling of 64Cu-labeled 2-Nitroimidazole derivative 64Cu-BMS2P2 for hypoxia imaging
Bioorganic & medicinal chemistry letters, 2016Co-Authors: Zheng Luo, Hua Zhu, Xinfeng Lin, Taiwei Chu, Ruyi Luo, Yunhua Wang, Zhi YangAbstract:The objective of this study was to develop a positron emission tomography (PET) probe with hypoxia targeting specificity and a relatively long half-life. The synthesis, (64)Cu-labeling in vitro and in vivo study of the novel 2-Nitroimidazole complex (64)Cu-BMS2P2 is presented in this study. The hypoxia targeting capacity of (64)Cu-BMS2P2 in vitro was evaluated and compared with the (64)Cu-BMS181321, and confirmed by PET imaging in vivo and immunohistochemistry for carbonic anhydrase 9 (CA9) in a tumor mouse model. These results suggest that (64)Cu-BMS2P2 is a promising candidate for PET hypoxia imaging and worthy of further investigations in dynamic hypoxia imaging.
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In vivo click reaction between Tc-99m-labeled azadibenzocyclooctyne-MAMA and 2-Nitroimidazole-azide for tumor hypoxia targeting.
Bioorganic & medicinal chemistry letters, 2015Co-Authors: Wenjing Sun, Taiwei ChuAbstract:The bioactivity of Nitroimidazole in Tc-99m-labeled 2-Nitroimidazole, a traditional solid tumor hypoxia-imaging agent for single photon emission computed tomography (SPECT), is reduced by the presence of large ligand and metallic radionuclide, exhibiting lower tumor-to-nontumor ratios. In an effort to solve this general problem, a pretargeting strategy based on click chemistry (strain-promoted cyclooctyne-azide cycloaddition) was applied. The functional click synthons were synthesized as pretargeting components: an azide group linked to 2-Nitroimidazole (2NIM-Az) serves for tumor hypoxia-targeting and azadibenzocyclooctyne conjugated with monoamine monoamide dithiol ligand (AM) functions as radiolabeling and binding group to azides in vivo. 2NIM-triazole-MAMA was obtained from in vitro click reaction with a reaction rate constant of 0.98M(-1)s(-1). AM and 2NIM-triazole-MAMA were radiolabeled with Tc-99m. The hypoxia-pretargeting biodistribution was studied in Kunming mice bearing S180 tumor; (99m)Tc-AM and (99m)Tc-triazole-2NIM were used as blank control and conventional control. Compared to the control groups, the pretargeting experiment exhibits the best radio-uptake and retention in tumor, with higher tumor-to-muscle and tumor-to-blood ratios (up to 8.55 and 1.44 at 8h post-(99m)Tc-complex-injection, respectively). To some extent, the pretargeting strategy protects the bioactivity of Nitroimidazole and therefore provides an innovative approach for the development of tumor hypoxia-SPECT imaging agents.
Sharmila Banerjee - One of the best experts on this subject based on the ideXlab platform.
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modulation of in vivo distribution through chelator synthesis and evaluation of a 2 Nitroimidazole dipicolylamine 99mtc co 3 complex for detecting tumor hypoxia
Bioorganic & Medicinal Chemistry Letters, 2016Co-Authors: Madhava B. Mallia, Sweety Mittal, Haladhar Dev Sarma, Sharmila BanerjeeAbstract:Previous studies have clearly demonstrated strong correlation between in vivo distribution and blood clearance of radiopharmaceuticals for the detection of hypoxia. Present study describes an attempt to improve the in vivo distribution of a previously reported 2-Nitroimidazole-(99m)Tc(CO)3 complex by tuning its blood clearance pattern through structural modification of the ligand. Herein, a 2-Nitroimidazole-dipicolylamine ligand (2-Nitroimidazole-DPA) was synthesized in a two-step procedure and radiolabeled with (99m)Tc(CO)3 core. Subsequently, the complex was evaluated in Swiss mice bearing fibrosarcoma tumor. As intended by its design, 2-Nitroimidazole-DPA-(99m)Tc(CO)3 complex was more lipophilic than previously reported 2-Nitroimidazole-DETA-(99m)Tc(CO)3 complex (DETA-diethylenetriamine) and showed slower blood clearance. Consequently it showed higher tumor uptake than 2-Nitroimidazole-DETA-(99m)Tc(CO)3 complex. Significantly, despite structural modifications, other parameters such as the tumor to blood ratio and tumor to muscle ratio of the 2-Nitroimidazole-DPA-(99m)Tc(CO)3 complex remained comparable to that of 2-Nitroimidazole-DETA-(99m)Tc(CO)3 complex. Present study demonstrates the feasibility of structural modifications for improving in vivo tumor uptake of hypoxia detecting radiopharmaceuticals. This might encourage researchers to improve suboptimal properties of a potential radiopharmaceuticals rather than ignoring it altogether.
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Modulation of in vivo distribution through chelator: Synthesis and evaluation of a 2-Nitroimidazole–dipicolylamine–99mTc(CO)3 complex for detecting tumor hypoxia
Bioorganic & medicinal chemistry letters, 2015Co-Authors: Madhava B. Mallia, Sweety Mittal, Haladhar Dev Sarma, Sharmila BanerjeeAbstract:Previous studies have clearly demonstrated strong correlation between in vivo distribution and blood clearance of radiopharmaceuticals for the detection of hypoxia. Present study describes an attempt to improve the in vivo distribution of a previously reported 2-Nitroimidazole-(99m)Tc(CO)3 complex by tuning its blood clearance pattern through structural modification of the ligand. Herein, a 2-Nitroimidazole-dipicolylamine ligand (2-Nitroimidazole-DPA) was synthesized in a two-step procedure and radiolabeled with (99m)Tc(CO)3 core. Subsequently, the complex was evaluated in Swiss mice bearing fibrosarcoma tumor. As intended by its design, 2-Nitroimidazole-DPA-(99m)Tc(CO)3 complex was more lipophilic than previously reported 2-Nitroimidazole-DETA-(99m)Tc(CO)3 complex (DETA-diethylenetriamine) and showed slower blood clearance. Consequently it showed higher tumor uptake than 2-Nitroimidazole-DETA-(99m)Tc(CO)3 complex. Significantly, despite structural modifications, other parameters such as the tumor to blood ratio and tumor to muscle ratio of the 2-Nitroimidazole-DPA-(99m)Tc(CO)3 complex remained comparable to that of 2-Nitroimidazole-DETA-(99m)Tc(CO)3 complex. Present study demonstrates the feasibility of structural modifications for improving in vivo tumor uptake of hypoxia detecting radiopharmaceuticals. This might encourage researchers to improve suboptimal properties of a potential radiopharmaceuticals rather than ignoring it altogether.
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On the structural modification of 2-Nitroimidazole-99mTc(CO)3 complex, a hypoxia marker, for improving in vivo pharmacokinetics
Nuclear medicine and biology, 2012Co-Authors: Madhava B. Mallia, Haladhar Dev Sarma, Chandan Kumar, Anupam Mathur, Sharmila BanerjeeAbstract:Abstract Introduction A 2-Nitroimidazole- 99m Tc(CO) 3 complex reported earlier showed promise with respect to its uptake and retention in hypoxic tumor. However, significant uptake and slow clearance from liver imposed severe limitations towards advocating its possible practical utility. In an attempt to improving its liver clearance, an ether linkage, which is known to help in liver clearance, was introduced in the molecule. Methods The 2-Nitroimidazole iminodiacetic acid (IDA) derivative containing an ether linkage was synthesized in a five step procedure from 2-Nitroimidazole. This derivative was radiolabeled using [ 99m Tc(CO) 3 (H 2 O) 3 ] + precursor complex. The corresponding Re(CO) 3 analogue was also synthesized in the macroscopic level for structural characterization. The 99m Tc(CO) 3 complex was evaluated in an animal model bearing fibrosarcoma tumor. Results The in vivo evaluation of the complex indicated that, as envisaged, introduction of the ether linkage has improved clearance from the liver. The complex also showed higher retention in tumor compared to the 2-Nitroimidazole-IDA- 99m Tc(CO) 3 complex reported earlier. Though the tumor to muscle ratio improved with time, the tumor to blood ratio did not show any significant improvement. Despite improved liver clearance, there was significant liver activity present even at 3h p.i. attributable to gradual accumulation of activity cleared from muscle and blood. Conclusions Though the introduction of ether linkage improved liver clearance of the modified 2-Nitroimidazole complex, it was found that a single ether linkage was not sufficient to achieve the desirable level of clearance. Probably, a linker with multiple ether groups, such as a di- or tri-ethylene glycol spacer, may be a possible solution to this issue.
Mariko Shimamura - One of the best experts on this subject based on the ideXlab platform.
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Angiogenesis inhibitor TX-1898: syntheses of the enantiomers of sterically diverse haloacetylcarbamoyl-2-Nitroimidazole hypoxic cell radiosensitizers.
Bioorganic & medicinal chemistry, 2004Co-Authors: Cheng-zhe Jin, Seiichi Inayama, Mariko Shimamura, Hideko Nagasawa, Yoshihiro Uto, Yoshio Takeuchi, Kenneth L. Kirk, Hitoshi HoriAbstract:(R)- and (S)-Epichlorohydrins were used to prepare the enantiomers of sterically diverse haloacetylcarbamoyl-2-Nitroimidazoles that function as hypoxic cell radiosensitizers. The synthetic design allowed for introduction of a side chain of varying bulk that permitted an examination of the steric effects on enantio-discrimination in biological assay systems. The single stereocenter also connected the two pharmacophores––a 2-Nitroimidazole moiety critical to hypoxic cell radiosensitization, and a haloacetylcarbamoyl group to function as an anti-angiogenesis pharmacophore. In the chick embryo chorioallantoic membrane (CAM) assay, the R-enantiomers possessing the bulky p-tert-butylphenyl group showed higher anti-angiogenic activity than the corresponding S-enantiomers, while there were no differences in the activity between the enantiomers containing the less bulky methyl and tert-butyl groups. Among the compounds we report, R-p-tert-butylphenyl-bromoacetylcarbamoyl-2-Nitroimidazole, TX-1898, was found to be the most promising candidate for further development of as anti-angiogenic hypoxic cell radiosensitizer.
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A novel hypoxia-dependent 2-Nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors
British journal of cancer, 2003Co-Authors: Mariko Shimamura, HIROTSUGU ASHINO, Tadahiko Hazato, Hideko Nagasawa, Y Yamamoto, Hitoshi Hori, Yoshihiro Uto, Seiichi InayamaAbstract:A novel hypoxia-dependent 2-Nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors
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A novel hypoxia-dependent 2-Nitroimidazole KIN-841 inhibits tumour-specific angiogenesis by blocking production of angiogenic factors
British Journal of Cancer, 2003Co-Authors: Mariko Shimamura, HIROTSUGU ASHINO, Tadahiko Hazato, H Hori, H. Nagasawa, Y Yamamoto, Seiichi InayamaAbstract:Tumour angiogenesis is initiated by angiogenic factors that are produced in large amounts by hypoxic tumour cells. The inhibition of this step may lead to tumour-specific antiangiogenesis because normal tissues are not usually hypoxic. On the other hand, blocking a biological function of endothelial cells is known to result in angiogenic inhibition. To produce a tumour-specific and powerful antiangiogenesis, we determined whether potent angiogenic inhibition could be achieved by inhibiting the production of angiogenic factors by hypoxic tumour cells and simultaneously blocking certain angiogenic steps in endothelial cells under normoxia. We focused on the 2-Nitroimidazole moiety, which is easily incorporated into hypoxic cells and exhibits its cytotoxicity as hypoxic cytotoxin. We designed and synthesised 2-Nitroimidazole derivatives designated as KIN compounds, and investigated their antiangiogenic activities under normoxia using a chick embryo chorioallantoic membrane. KIN-841 (2-Nitroimidazole 1-acetylhydroxamate) showed a potent angiogenic inhibition in a dose-dependent manner. This compound inhibited the proliferation of bovine pulmonary arterial endothelial (BPAE) cells more strongly than that of tumour cells, such as Lewis lung carcinoma (3LL) cells, under normoxia. The inhibition of cell proliferation by KIN-841 under hypoxia increased about five-fold compared to that under normoxia. Moreover, under hypoxia, KIN-841 significantly decreased the excessive production of vascular endothelial cell growth factors induced by 3LL cells as determined by tritium-labelled thymidine ([^3H]thymidine) incorporation into BPAE cells and by ELISA. Intraperitoneal administration of KIN-841 suppressed 3LL-cell-induced in vivo angiogenesis in the mouse dorsal air sac system. These results indicate that the regulation of the production of angiogenic factors by hypoxic tumour cells is a useful target for tumour-specific angiogenesis inhibition, and that KIN-841, which causes simultaneous direct inhibition of endothelial cell function and production of angiogenic factors by hypoxic tumour cells, is a very potent inhibitor of tumour-specific angiogenesis. Thus, the potential for clinical use of KIN-841 as an antitumour drug is very high.