Synthesis and biological evaluation of c-aromataxane derivatives as p-glycoprotein-mediated multi drug resistance reversal agents

Takayuki Doi; Naoko Yamaguchi; Kosuke Ohsawa; Kazuoki Nakai; Masahito Yoshida; Kazuhiro Satake; Yuji Mitani; Hiroshi Nakagawa; Takashi Takahashi; Toshihisa Ishikawa

doi:10.3987/COM-14-S(K)47

Synthesis and biological evaluation of c-aromataxane derivatives as p-glycoprotein-mediated multi drug resistance reversal agents

Takayuki Doi, Naoko Yamaguchi, Kosuke Ohsawa, Kazuoki Nakai, Masahito Yoshida, Kazuhiro Satake, Yuji Mitani, Hiroshi Nakagawa, Takashi Takahashi, Toshihisa Ishikawa

PHA - Molecular Pharmaceutical Science

Research output: Contribution to journal › Article › peer-review

Abstract

Synthesis and evaluation of C-aromataxane derivatives as P-glycoprotein-mediated MDR reversal agents have been demonstrated. Several derivatives possessing N-benzoylphenylisoserine at the C2 or C14 position of the template 2a were readily synthesized and were evaluated their affinity for P-glycoprotein. Most of the synthesized derivatives exhibited much lower cytotoxicity in both KB-3-1 cells and MDR KB-G2-cells than paclitaxel (1), and it should be noted that the compound (14R)-5a exhibited high k_m and V_max/K_mvalues, and cytotoxicity of paclitaxel (1) in MDR KB-G2 cells was significantly recovered (98% reduction, IC50 30 nM) in the presence of 5a (5.0 μM). The structural features such as endo-cage conformation and the stereochemistry at the C14 position is crucial to exhibit an excellent affinity for P-glycoprotein.

Original language	English
Pages (from-to)	482-501
Number of pages	20
Journal	Heterocycles
Volume	90
Issue number	1
DOIs	https://doi.org/10.3987/COM-14-S(K)47
Publication status	Published - 2015

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title = "Synthesis and biological evaluation of c-aromataxane derivatives as p-glycoprotein-mediated multi drug resistance reversal agents",

abstract = "Synthesis and evaluation of C-aromataxane derivatives as P-glycoprotein-mediated MDR reversal agents have been demonstrated. Several derivatives possessing N-benzoylphenylisoserine at the C2 or C14 position of the template 2a were readily synthesized and were evaluated their affinity for P-glycoprotein. Most of the synthesized derivatives exhibited much lower cytotoxicity in both KB-3-1 cells and MDR KB-G2-cells than paclitaxel (1), and it should be noted that the compound (14R)-5a exhibited high km and Vmax/Kmvalues, and cytotoxicity of paclitaxel (1) in MDR KB-G2 cells was significantly recovered (98% reduction, IC50 30 nM) in the presence of 5a (5.0 μM). The structural features such as endo-cage conformation and the stereochemistry at the C14 position is crucial to exhibit an excellent affinity for P-glycoprotein.",

author = "Takayuki Doi and Naoko Yamaguchi and Kosuke Ohsawa and Kazuoki Nakai and Masahito Yoshida and Kazuhiro Satake and Yuji Mitani and Hiroshi Nakagawa and Takashi Takahashi and Toshihisa Ishikawa",

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doi = "10.3987/COM-14-S(K)47",

language = "English",

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T1 - Synthesis and biological evaluation of c-aromataxane derivatives as p-glycoprotein-mediated multi drug resistance reversal agents

AU - Doi, Takayuki

AU - Yamaguchi, Naoko

AU - Ohsawa, Kosuke

AU - Nakai, Kazuoki

AU - Yoshida, Masahito

AU - Satake, Kazuhiro

AU - Mitani, Yuji

AU - Nakagawa, Hiroshi

AU - Takahashi, Takashi

AU - Ishikawa, Toshihisa

PY - 2015

Y1 - 2015

N2 - Synthesis and evaluation of C-aromataxane derivatives as P-glycoprotein-mediated MDR reversal agents have been demonstrated. Several derivatives possessing N-benzoylphenylisoserine at the C2 or C14 position of the template 2a were readily synthesized and were evaluated their affinity for P-glycoprotein. Most of the synthesized derivatives exhibited much lower cytotoxicity in both KB-3-1 cells and MDR KB-G2-cells than paclitaxel (1), and it should be noted that the compound (14R)-5a exhibited high km and Vmax/Kmvalues, and cytotoxicity of paclitaxel (1) in MDR KB-G2 cells was significantly recovered (98% reduction, IC50 30 nM) in the presence of 5a (5.0 μM). The structural features such as endo-cage conformation and the stereochemistry at the C14 position is crucial to exhibit an excellent affinity for P-glycoprotein.

AB - Synthesis and evaluation of C-aromataxane derivatives as P-glycoprotein-mediated MDR reversal agents have been demonstrated. Several derivatives possessing N-benzoylphenylisoserine at the C2 or C14 position of the template 2a were readily synthesized and were evaluated their affinity for P-glycoprotein. Most of the synthesized derivatives exhibited much lower cytotoxicity in both KB-3-1 cells and MDR KB-G2-cells than paclitaxel (1), and it should be noted that the compound (14R)-5a exhibited high km and Vmax/Kmvalues, and cytotoxicity of paclitaxel (1) in MDR KB-G2 cells was significantly recovered (98% reduction, IC50 30 nM) in the presence of 5a (5.0 μM). The structural features such as endo-cage conformation and the stereochemistry at the C14 position is crucial to exhibit an excellent affinity for P-glycoprotein.

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SN - 0385-5414

VL - 90

SP - 482

EP - 501

JO - Heterocycles

JF - Heterocycles

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ER -

Synthesis and biological evaluation of c-aromataxane derivatives as p-glycoprotein-mediated multi drug resistance reversal agents

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