TY - JOUR
T1 - 1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, a novel compound class with potent chemoreversal activity
AU - Hung, Hsin Yi
AU - Ohkoshi, Emika
AU - Goto, Masuo
AU - Nakagawa-Goto, Kyoko
AU - Lee, Kuo Hsiung
N1 - Funding Information:
This study was supported by grant CA-17625-32 from the National Cancer Institute, NIH, awarded to K. H. Lee. Support in part was also due to the Cancer Research Center of Excellence (CRC) (DOH-100-TD-C-111-005). We would like to thank Dr. Mitch Eddy (NIEHS/NIH) for providing a fluorescence microscope, and also Dr. Susan Morris-Natschke for her valuable suggestions and help in preparation of this manuscript.
PY - 2012/12/15
Y1 - 2012/12/15
N2 - 1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, which share a fragment from (±)-3′-O-4′-O-bis(3,4-dimethoxycinnamoyl)-cis- khellactone (DMDCK) and 3′R,4′R-disubstituted-2′,2′- dimethyldihydropyrano[2,3-f]chromone (DSP), exhibited remarkable chemoreversal activity on multidrug resistant human nasopharyngeal carcinoma (KB) when combined with three anticancer drugs, paclitaxel, vincristine and doxorubicin. Among 15 novel synthesized analogs, bis-trimethoxybenzoyl derivative 15 was the most active (340-fold more active than verapamil when used with vincristine) followed by two di-cinnamoyl derivatives, 10 and 11, and then di-cyclohexanecarbonyl derivative 9. All aliphatic chain derivatives, 3-5, showed no activity. Structure-activity relationship study indicated that a di-ester structure was critical to enhance the activity resulting from the maintenance of the spatial arrangement proposed by the pharmacophore based on the verapamil-binding site. Further mechanism of action study showed 15 inhibited mainly P-glycoprotein efflux pump function, while 13 exhibited an additional multidrug resistance-associated protein efflux pump function.
AB - 1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, which share a fragment from (±)-3′-O-4′-O-bis(3,4-dimethoxycinnamoyl)-cis- khellactone (DMDCK) and 3′R,4′R-disubstituted-2′,2′- dimethyldihydropyrano[2,3-f]chromone (DSP), exhibited remarkable chemoreversal activity on multidrug resistant human nasopharyngeal carcinoma (KB) when combined with three anticancer drugs, paclitaxel, vincristine and doxorubicin. Among 15 novel synthesized analogs, bis-trimethoxybenzoyl derivative 15 was the most active (340-fold more active than verapamil when used with vincristine) followed by two di-cinnamoyl derivatives, 10 and 11, and then di-cyclohexanecarbonyl derivative 9. All aliphatic chain derivatives, 3-5, showed no activity. Structure-activity relationship study indicated that a di-ester structure was critical to enhance the activity resulting from the maintenance of the spatial arrangement proposed by the pharmacophore based on the verapamil-binding site. Further mechanism of action study showed 15 inhibited mainly P-glycoprotein efflux pump function, while 13 exhibited an additional multidrug resistance-associated protein efflux pump function.
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U2 - 10.1016/j.bmcl.2012.09.096
DO - 10.1016/j.bmcl.2012.09.096
M3 - Article
C2 - 23122817
AN - SCOPUS:84870253038
SN - 0960-894X
VL - 22
SP - 7726
EP - 7729
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 24
ER -