title: Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cox Inhibitory Activity.
abstract: 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.
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University , Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Arisawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University , Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Kasaya
authors.affiliation: School of Pharmacy, Aichi Gakuin University , 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Obata
authors.affiliation: School of Pharmacy, Aichi Gakuin University , 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University , Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan ; Nano Medical Engineering Laboratory, RIKEN Advanced Science Institute, 2-1, Hirosawa, Wako 351-0198, Japan.
authors.forename: Mika
authors.initials: M
authors.lastname: Ito
authors.affiliation: Nano Medical Engineering Laboratory, RIKEN Advanced Science Institute, 2-1, Hirosawa, Wako 351-0198, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Abe
authors.affiliation: Nano Medical Engineering Laboratory, RIKEN Advanced Science Institute, 2-1, Hirosawa, Wako 351-0198, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Rigaku Corporation , X-ray Research Laboratory, 3-9-12 Matsubara-cho, Akishima, Tokyo 196-8666, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yamano
authors.affiliation: Faculty of Pharmaceutical Sciences, Hokkaido University , Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shuto
keywords: Cancer; conformation analysis; cytotoxicity; drug design; nitrogen heterocycles