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1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, a novel compound class with potent chemoreversal activity.


ABSTRACT: 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.

SUBMITTER: Hung HY 

PROVIDER: S-EPMC3508342 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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1-(3,4,5-Trimethoxyphenyl)ethane-1,2-diyl esters, a novel compound class with potent chemoreversal activity.

Hung Hsin-Yi HY   Ohkoshi Emika E   Goto Masuo M   Nakagawa-Goto Kyoko K   Lee Kuo-Hsiung KH  

Bioorganic & medicinal chemistry letters 20121013 24


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 (  ...[more]

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