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18 results on '"Sugasawa, Keizo"'

6. Improved Dose-Response Relationship of (+)-Discodermolide-Taxol Hybrid Congeners

Author

Nadaradjane, Celine, Yang, Chia-Ping Huang, Rodriguez-Gabin, Alicia, Ye, Kenny, Sugasawa, Keizo, Atasoylu, Onur, Smith, Amos B., Horwitz, Susan Band, and McDaid, Hayley M.

Abstract

(+)-Discodermolide is a microtubule-stabilizing agent with potential for the treatment of taxol-refractory malignancies. (+)-Discodermolide congeners containing the C-3′-phenyl side chain of taxol (paclitaxel) were synthesized based on computational docking models predicting this moiety would fill an aromatic pocket of β-tubulin insufficiently occupied by (+)-discodermolide, thereby conferring improved ligand–target interaction. It was recently demonstrated, however, that the C-3′-phenyl side chain occupied a different space, instead extending toward the M-loop of β-tubulin, where it induced a helical conformation, hypothesized to improve lateral contacts between adjacent microtubule protofilaments. This insight led us to evaluate the biological activity of hybrid congeners using a panel of genetically diverse cancer cell lines. Hybrid molecules retained the same tubulin-polymerizing profile as (+)-discodermolide. Since (+)-discodermolide is a potent inducer of accelerated senescence, a fate that contributes to drug resistance, congeners were also screened for senescence induction. Flow cytometric and transcriptional analysis revealed that the hybrids largely retained the senescence-inducing properties of (+)-discodermolide. In taxol-sensitive cell models, the congeners had improved dose-response parameters relative to (+)-discodermolide and, in some cases, were superior to taxol. However, in cells susceptible to senescence, EMaxincreased without concomitant improvements in EC50such that overall dose-response profiles resembled that of (+)-discodermolide.

Published
2017
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9. Discovery of N-[2-Hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (Darexaban, YM150) as a Potent and Orally Available Factor Xa Inhibitor

Author

Hirayama, Fukushi, primary, Koshio, Hiroyuki, additional, Ishihara, Tsukasa, additional, Hachiya, Shunichiro, additional, Sugasawa, Keizo, additional, Koga, Yuji, additional, Seki, Norio, additional, Shiraki, Ryouta, additional, Shigenaga, Takeshi, additional, Iwatsuki, Yoshiyuki, additional, Moritani, Yumiko, additional, Mori, Kenichi, additional, Kadokura, Takeshi, additional, Kawasaki, Tomihisa, additional, Matsumoto, Yuzo, additional, Sakamoto, Shuichi, additional, and Tsukamoto, Shin-ichi, additional

Published
2011
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18. Synthesis and structure–activity relationships of a series of benzazepine derivatives as 5-HT2C receptor agonists

Author

Shimada, Itsuro, Maeno, Kyoichi, Kondoh, Yutaka, Kaku, Hidetaka, Sugasawa, Keizo, Kimura, Yasuharu, Hatanaka, Ken-ichi, Naitou, Yuki, Wanibuchi, Fumikazu, Sakamoto, Shuichi, and Tsukamoto, Shin-ichi

Subjects
*CARDIOVASCULAR system, *NEUROTRANSMITTERS, *SEROTONIN, *BENZENE
Abstract

Abstract: To identify potent and selective 5-HT2C receptor agonists, a series of novel benzazepine derivatives were synthesized, and their structure–activity relationships examined. The compounds were evaluated for their 5-HT2C, 5-HT2A, and 5-HT2B receptor binding affinity and intrinsic activity for the 5-HT2C and 5-HT2A receptors. Among these compounds, 6,7-dichloro-2,3,4,5-tetrahydro-1H-3-benzazepine (6) was effective in a rat penile erection model when administered po, which is a symptom of the serotonin syndrome reflecting 5-HT2C receptor activation. Moreover, compound 6 was characterized as a partial agonist of 5-HT2A receptors; therefore, it had little effect on the cardiovascular system. [Copyright &y& Elsevier]

Published
2008
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