The Experts below are selected from a list of 42 Experts worldwide ranked by ideXlab platform
Kuo Hsiung Lee - One of the best experts on this subject based on the ideXlab platform.
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Antitumor agents. 144. New Gamma-Lactone Ring-modified arylamino etoposide analogs as inhibitors of human DNA topoisomerase II.
Journal of medicinal chemistry, 1994Co-Authors: Xiao Ming Zhou, Kenneth Jiann Hung Lee, Ji Cheng, Hong Xing Chen, Xin Guo, Yung-chi Cheng, Kuo Hsiung LeeAbstract:The trans-fused Gamma-Lactone Ring of etoposide is readily epimerized to its cis epimer, which is biologically inactive, or is metabolized to the inactive Ring-opened hydroxy acids. Modification of this Gamma-Lactone Ring of 4 beta-(arylamino)-4'-O-demethyl-4-desoxypodophyllotoxin resulted in several compounds (15-16, 21-22, and 24) that should block this epimerization and the resulting biological deactivation. In a topoisomerase II inhibition assay, compounds 21, 22, and 24 showed comparable activity to etoposide. In a protein-linked DNA complex formation assay, compounds 21 and 22 were more active than etoposide.
Masato Abe - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Inhibition Mechanism of Δlac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I†
Biochemistry, 2005Co-Authors: Naoya Ichimaru, Masato Abe, Takeshi Hamada, Takaaki Nishioka, Masatoshi Murai, Hidefumi Makabe, Yohsuke Yamada, Sae Makino, Asami Makino, Toshihide KobayashiAbstract:We have synthesized Deltalac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an alpha,beta-unsaturated Gamma-Lactone Ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of Deltalac-acetogenins in more detail, we carried out wide structural modifications of original Deltalac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF Rings and the stereochemistry around the hydroxylated bis-THF Rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original Deltalac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that Deltalac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.
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Synthesis and inhibitory activity of ubiquinone-acetogenin hybrid inhibitor with bovine mitochondrial complex I.
Bioorganic & medicinal chemistry letters, 2003Co-Authors: Hiromi Yabunaka, Masato Abe, Atsushi Kenmochi, Takeshi Hamada, Takaaki Nishioka, Hideto MiyoshiAbstract:To elucidate the inhibitory action of acetogenins, the most potent inhibitors of mitochondrial complex I, we synthesized an acetogenin analogue which possesses a ubiquinone Ring (i.e., the physiological substrate of complex I) in place of the alpha,beta-unsaturated Gamma-Lactone Ring of natural acetogenins, and named it Q-acetogenin. Our results indicate that the Gamma-Lactone Ring of acetogenins is completely substitutable with the ubiquinone Ring. This fact is discussed in light of the inhibitory action of acetogenins.
Takeshi Hamada - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Inhibition Mechanism of Δlac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I†
Biochemistry, 2005Co-Authors: Naoya Ichimaru, Masato Abe, Takeshi Hamada, Takaaki Nishioka, Masatoshi Murai, Hidefumi Makabe, Yohsuke Yamada, Sae Makino, Asami Makino, Toshihide KobayashiAbstract:We have synthesized Deltalac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an alpha,beta-unsaturated Gamma-Lactone Ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of Deltalac-acetogenins in more detail, we carried out wide structural modifications of original Deltalac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF Rings and the stereochemistry around the hydroxylated bis-THF Rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original Deltalac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that Deltalac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.
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Synthesis and inhibitory activity of ubiquinone-acetogenin hybrid inhibitor with bovine mitochondrial complex I.
Bioorganic & medicinal chemistry letters, 2003Co-Authors: Hiromi Yabunaka, Masato Abe, Atsushi Kenmochi, Takeshi Hamada, Takaaki Nishioka, Hideto MiyoshiAbstract:To elucidate the inhibitory action of acetogenins, the most potent inhibitors of mitochondrial complex I, we synthesized an acetogenin analogue which possesses a ubiquinone Ring (i.e., the physiological substrate of complex I) in place of the alpha,beta-unsaturated Gamma-Lactone Ring of natural acetogenins, and named it Q-acetogenin. Our results indicate that the Gamma-Lactone Ring of acetogenins is completely substitutable with the ubiquinone Ring. This fact is discussed in light of the inhibitory action of acetogenins.
Takaaki Nishioka - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Inhibition Mechanism of Δlac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I†
Biochemistry, 2005Co-Authors: Naoya Ichimaru, Masato Abe, Takeshi Hamada, Takaaki Nishioka, Masatoshi Murai, Hidefumi Makabe, Yohsuke Yamada, Sae Makino, Asami Makino, Toshihide KobayashiAbstract:We have synthesized Deltalac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an alpha,beta-unsaturated Gamma-Lactone Ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of Deltalac-acetogenins in more detail, we carried out wide structural modifications of original Deltalac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF Rings and the stereochemistry around the hydroxylated bis-THF Rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original Deltalac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that Deltalac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.
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Synthesis and inhibitory activity of ubiquinone-acetogenin hybrid inhibitor with bovine mitochondrial complex I.
Bioorganic & medicinal chemistry letters, 2003Co-Authors: Hiromi Yabunaka, Masato Abe, Atsushi Kenmochi, Takeshi Hamada, Takaaki Nishioka, Hideto MiyoshiAbstract:To elucidate the inhibitory action of acetogenins, the most potent inhibitors of mitochondrial complex I, we synthesized an acetogenin analogue which possesses a ubiquinone Ring (i.e., the physiological substrate of complex I) in place of the alpha,beta-unsaturated Gamma-Lactone Ring of natural acetogenins, and named it Q-acetogenin. Our results indicate that the Gamma-Lactone Ring of acetogenins is completely substitutable with the ubiquinone Ring. This fact is discussed in light of the inhibitory action of acetogenins.
Toshihide Kobayashi - One of the best experts on this subject based on the ideXlab platform.
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Synthesis and Inhibition Mechanism of Δlac-Acetogenins, a Novel Type of Inhibitor of Bovine Heart Mitochondrial Complex I†
Biochemistry, 2005Co-Authors: Naoya Ichimaru, Masato Abe, Takeshi Hamada, Takaaki Nishioka, Masatoshi Murai, Hidefumi Makabe, Yohsuke Yamada, Sae Makino, Asami Makino, Toshihide KobayashiAbstract:We have synthesized Deltalac-acetogenins that are new acetogenin mimics possessing two n-alkyl tails without an alpha,beta-unsaturated Gamma-Lactone Ring and suggested that their inhibition mechanism may be different from that of common acetogenins [Hamada et al. (2004) Biochemistry 43, 3651-3658]. To elucidate the inhibition mechanism of Deltalac-acetogenins in more detail, we carried out wide structural modifications of original Deltalac-acetogenins and characterized the inhibitory action with bovine heart mitochondrial complex I. In contrast to common acetogenins, both the presence of adjacent bis-THF Rings and the stereochemistry around the hydroxylated bis-THF Rings are important structural factors required for potent inhibition. The inhibitory potency of a derivative possessing an n-butylphenyl ether structure (compound 7) appeared to be superior to that of the original Deltalac-acetogenins and equivalent to that of bullatacin, one of the most potent natural acetogenins. Double-inhibitor titration of steady-state complex I activity showed that the extent of inhibition of compound 7 and bullatacin is not additive, suggesting that the binding sites of the two inhibitors are not identical. Competition tests using a fluorescent ligand indicated that the binding site of compound 7 does not overlap with that of other complex I inhibitors. The effects of compound 7 on superoxide production from complex I are also different from those of other complex I inhibitors. Our results clearly demonstrate that Deltalac-acetogenins are a novel type of inhibitor acting at the terminal electron-transfer step of bovine complex I.
