May 12, 2011
Indomethacin analogues that enhance doxorubicin cytotoxicity in multidrug resistant cells without cox inhibitory activity
ACS Medicinal Chemistry Letters
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- Volume
- 2
- Number
- 5
- First page
- 353
- Last page
- 357
- Language
- Publishing type
- Research paper (scientific journal)
- DOI
- 10.1021/ml100292y
Conformationally restricted indomethacin analogues were designed and prepared from the corresponding 2-substituted indoles, which were synthesized by a one-pot isomerization/enamide-ene metathesis as the key reaction. Conformational analysis by calculations, NMR studies, and X-ray crystallography suggested that these analogues were conformationally restricted in the s-cis or the s-trans form due to the 2-substituent as expected. Their biological activities on cyclooxygenase-1 (COX-1) inhibition, cyclooxygenase-2 (COX-2) inhibition, and modulation of MRP-1-mediated multidrug resistance (MDR) are described. Some of these indomethacin analogues enhanced doxorubicin cytotoxicity, although they do not have any COX inhibitory activity, which suggests that the MDR-modulating effect of an NSAID can be unassociated with its COX-inhibitory activity. This may be an entry into the combination chemotherapy of doxorubicin with a MDR modulator. © 2011 American Chemical Society.
- Link information
- ID information
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- DOI : 10.1021/ml100292y
- eISSN : 1948-5875
- SCOPUS ID : 79956090533