Arisawa Mitsuhiro, Kasaya Yayoi, Obata Tohru, Sasaki Takuma, Ito Mika, Abe Hiroshi, Ito Yoshihiro, Yamano Akihito, Shuto Satoshi
Faculty of Pharmaceutical Sciences, Hokkaido University , Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan.
School of Pharmacy, Aichi Gakuin University , 1-100 Kusumoto-cho, Chikusa-ku, Nagoya 464-8650, Japan.
ACS Med Chem Lett. 2011 Mar 17;2(5):353-7. doi: 10.1021/ml100292y. eCollection 2011 May 12.
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.
设计并从相应的2-取代吲哚制备了构象受限的吲哚美辛类似物，这些2-取代吲哚通过一锅异构化/烯胺-烯复分解反应作为关键反应合成。通过计算、核磁共振研究和X射线晶体学进行的构象分析表明，正如预期的那样，由于2-取代基的存在，这些类似物在s-顺式或s-反式构象中受到限制。描述了它们对环氧合酶-1（COX-1）抑制、环氧合酶-2（COX-2）抑制以及对MRP-1介导的多药耐药性（MDR）调节的生物活性。尽管其中一些吲哚美辛类似物没有任何COX抑制活性，但它们增强了阿霉素的细胞毒性，这表明非甾体抗炎药的MDR调节作用可能与其COX抑制活性无关。这可能是阿霉素与MDR调节剂联合化疗的一个切入点。
