Sekimoto Kazuaki, Kinjo Hanaka, Murakami Mizuki, Ohashi Akiko, Fukui Rei, Nagasaki-Maeoka Eri, Inagaki Yoshinori, Takayama Tadateru, Ikeda Kazuhiro, Takayama Ken-Ichi, Inoue Satoshi, Tsuji Motonori, Otsuki Joe, Fujiwara Kyoko
Department of Anatomy, Nihon University School of Dentistry, Chiyoda-ku, Tokyo, 101-8310, Japan.
Department of Materials and Applied Chemistry, College of Science and Technology, Nihon University, Chiyoda-ku, Tokyo, 101-8308, Japan.
Biochem Biophys Rep. 2025 Mar 20;42:101981. doi: 10.1016/j.bbrep.2025.101981. eCollection 2025 Jun.
4'-Iodobiphenyl nonaethylene glycol ether (9bw) is a novel small molecule, composed of a biphenyl unit and 9 ethylene glycol (EG) units. Recently, we found that 9bw induces apoptosis in cancer cells by inhibiting mitochondrial respiratory complex I (CI) and accordingly reducing cellular ATP level. In addition, 9bw shows little effect on normal cells, suggesting that 9bw is a potential antitumor agent with few adverse effects. However, the exact molecular mechanisms by which 9bw acts on CI are still elusive. To clarify the molecular structure critical for 9bw's function, we tested the function of 9bw analogues on human oral squamous cell carcinoma lines HSC4 and Ca9-22. The analogues were 4-hydroxy-4'-iodobiphenyl (HIOP), I-BP-EG3, I-BP-EG6, and I-BP-EG12 containing 0, 3, 6, and 12 EG units, respectively. Our results demonstrated that I-BP-EG6 and I-BP-EG12 inhibited CI to a similar extent as 9bw, whereas I-BP3 and HIOP showed no effect on CI activity. These observations indicate that the number of EG units is crucial for the activity of 9bw and its analogues. As high-performance liquid chromatography (HPLC) analysis demonstrated that both HIOP and I-BP-EG3 could be incorporated into mitochondria abundantly, the number of EG units probably affects CI inhibitory function of 9bw and its analogues rather than their efficacy to enter cell and mitochondria.
4'-碘代联苯九聚乙二醇醚（9bw）是一种新型小分子，由一个联苯单元和9个乙二醇（EG）单元组成。最近，我们发现9bw通过抑制线粒体呼吸复合体I（CI）并相应降低细胞ATP水平来诱导癌细胞凋亡。此外，9bw对正常细胞几乎没有影响，这表明9bw是一种潜在的副作用较少的抗肿瘤药物。然而，9bw作用于CI的确切分子机制仍不清楚。为了阐明对9bw功能至关重要的分子结构，我们测试了9bw类似物对人口腔鳞状细胞癌系HSC4和Ca9-22的功能。这些类似物分别是含有0、3、6和12个EG单元的4-羟基-4'-碘代联苯（HIOP）、I-BP-EG3、I-BP-EG6和I-BP-EG12。我们的结果表明，I-BP-EG6和I-BP-EG12对CI的抑制程度与9bw相似，而I-BP3和HIOP对CI活性没有影响。这些观察结果表明，EG单元的数量对9bw及其类似物的活性至关重要。由于高效液相色谱（HPLC）分析表明HIOP和I-BP-EG3都可以大量进入线粒体，EG单元的数量可能影响9bw及其类似物对CI的抑制功能，而不是它们进入细胞和线粒体的效率。
