Endo Satoshi, Xia Shuang, Suyama Miho, Morikawa Yoshifumi, Oguri Hiroaki, Hu Dawei, Ao Yoshinori, Takahara Satoyuki, Horino Yoshikazu, Hayakawa Yoshihiro, Watanabe Yurie, Gouda Hiroaki, Hara Akira, Kuwata Kazuo, Toyooka Naoki, Matsunaga Toshiyuki, Ikari Akira
Laboratory of Biochemistry, Gifu Pharmaceutical University , Gifu 501-1196, Japan.
Graduate School of Innovative Life Science, University of Toyama , Toyama 930-8555, Japan.
J Med Chem. 2017 Oct 26;60(20):8441-8455. doi: 10.1021/acs.jmedchem.7b00830. Epub 2017 Oct 13.
Aldo-keto reductase 1B10 (AKR1B10) is overexpressed in several extraintestinal cancers, particularly in non-small-cell lung cancer, where AKR1B10 is a potential diagnostic marker and therapeutic target. Selective AKR1B10 inhibitors are required because compounds should not inhibit the highly related aldose reductase that is involved in monosaccharide and prostaglandin metabolism. Currently, 7-hydroxy-2-(4-methoxyphenylimino)-2H-chromene-3-carboxylic acid benzylamide (HMPC) is known to be the most potent competitive inhibitor of AKR1B10, but it is nonselective. In this study, derivatives of HMPC were synthesized by removing the 4-methoxyphenylimino moiety and replacing the benzylamide with phenylpropylamide. Among them, 4c and 4e showed higher AKR1B10 inhibitory potency (IC 4.2 and 3.5 nM, respectively) and selectivity than HMPC. The treatments with the two compounds significantly suppressed not only migration, proliferation, and metastasis of lung cancer A549 cells but also metastatic and invasive potentials of cisplatin-resistant A549 cells.
醛糖酮还原酶1B10（AKR1B10）在几种肠外癌症中过表达，尤其是在非小细胞肺癌中，其中AKR1B10是一种潜在的诊断标志物和治疗靶点。由于化合物不应抑制参与单糖和前列腺素代谢的高度相关的醛糖还原酶，因此需要选择性AKR1B10抑制剂。目前，已知7-羟基-2-（4-甲氧基苯基亚氨基）-2H-色烯-3-羧酸苄基酰胺（HMPC）是AKR1B10最有效的竞争性抑制剂，但它是非选择性的。在本研究中，通过去除4-甲氧基苯基亚氨基部分并用苯丙基酰胺取代苄基酰胺来合成HMPC的衍生物。其中，4c和4e显示出比HMPC更高的AKR1B10抑制效力（分别为IC 4.2和3.5 nM）和选择性。用这两种化合物处理不仅显著抑制了肺癌A549细胞的迁移、增殖和转移，还抑制了顺铂耐药A549细胞的转移和侵袭潜能。
