Antitumor agents. 280. Multidrug resistance-selective desmosdumotin B analogues

Kyoko Nakagawa-Goto; Po Cheng Chang; Chin Yu Lai; Hsin Yi Hung; Tzu Hsuan Chen; Pei Chi Wu; Hao Zhu; Alexander Sedykh; Kenneth F. Bastow; Kuo Hsiung Lee

doi:10.1021/jm100846r

Antitumor agents. 280. Multidrug resistance-selective desmosdumotin B analogues

Kyoko Nakagawa-Goto, Po Cheng Chang, Chin Yu Lai, Hsin Yi Hung, Tzu Hsuan Chen, Pei Chi Wu, Hao Zhu, Alexander Sedykh, Kenneth F. Bastow, Kuo Hsiung Lee

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

22 Scopus citations

Abstract

6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR selectivity. Three new disubstituted analogues, 35, 37, and 49, also had high collateral sensitivity (CS) indices of 273, 250, and 100, respectively. Furthermore, 2-4 also displayed MDR selectivity in an MDR hepatoma-cell system. While 2-4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.

Original language	English (US)
Pages (from-to)	6699-6705
Number of pages	7
Journal	Journal of medicinal chemistry
Volume	53
Issue number	18
DOIs	https://doi.org/10.1021/jm100846r
State	Published - Sep 23 2010
Externally published	Yes

All Science Journal Classification (ASJC) codes

Molecular Medicine
Drug Discovery

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title = "Antitumor agents. 280. Multidrug resistance-selective desmosdumotin B analogues",

abstract = "6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR selectivity. Three new disubstituted analogues, 35, 37, and 49, also had high collateral sensitivity (CS) indices of 273, 250, and 100, respectively. Furthermore, 2-4 also displayed MDR selectivity in an MDR hepatoma-cell system. While 2-4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.",

author = "Kyoko Nakagawa-Goto and Chang, {Po Cheng} and Lai, {Chin Yu} and Hung, {Hsin Yi} and Chen, {Tzu Hsuan} and Wu, {Pei Chi} and Hao Zhu and Alexander Sedykh and Bastow, {Kenneth F.} and Lee, {Kuo Hsiung}",

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doi = "10.1021/jm100846r",

language = "English (US)",

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AU - Nakagawa-Goto, Kyoko

AU - Chang, Po Cheng

AU - Lai, Chin Yu

AU - Hung, Hsin Yi

AU - Chen, Tzu Hsuan

AU - Wu, Pei Chi

AU - Zhu, Hao

AU - Sedykh, Alexander

AU - Bastow, Kenneth F.

AU - Lee, Kuo Hsiung

PY - 2010/9/23

Y1 - 2010/9/23

N2 - 6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR selectivity. Three new disubstituted analogues, 35, 37, and 49, also had high collateral sensitivity (CS) indices of 273, 250, and 100, respectively. Furthermore, 2-4 also displayed MDR selectivity in an MDR hepatoma-cell system. While 2-4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.

AB - 6,6,8-Triethyldesmosdumotin B (2) was discovered as a MDR-selective flavonoid with significant in vitro anticancer activity against a multidrug resistant (MDR) cell line (KB-VIN) but without activity against the parent cells (KB). Additional 2 analogues were synthesized and evaluated to determine the effect of B-ring modifications on MDR-selectivity. Analogues with a B-ring Me (3) or Et (4) group had substantially increased MDR selectivity. Three new disubstituted analogues, 35, 37, and 49, also had high collateral sensitivity (CS) indices of 273, 250, and 100, respectively. Furthermore, 2-4 also displayed MDR selectivity in an MDR hepatoma-cell system. While 2-4 showed either no or very weak inhibition of cellular P-glycoprotein (P-gp) activity, they either activated or inhibited the actions of the first generation P-gp inhibitors verapamil or cyclosporin, respectively.

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Antitumor agents. 280. Multidrug resistance-selective desmosdumotin B analogues

Abstract

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