Univ Brest, CEMCA UMR CNRS 6521, 6 Avenue Victor Le Gorgeu, F-29238, Brest, France.
Univ Tours, Inserm U1069 Nutrition, Croissance et Cancer (N2C), Faculté de pharmacie, 10 Boulevard Tonnellé, 37032, Tours Cedex, France.
Eur J Med Chem. 2021 Jan 1;209:112894. doi: 10.1016/j.ejmech.2020.112894. Epub 2020 Oct 6.
We report the synthesis of three bioactive pyrene-based fluorescent analogues of Ohmline which is the most efficient and selective inhibitor of SK3 ion channel. The interaction of these Ohmline-pyrene (OP1-3) with liposomes of different composition reveals that only OP2 and OP3 are readily integrated into liposomes. Fluorescence measurements indicate that, depending on their concentration, OP2 and OP3 exist either as monomer or as a mixture of monomer and excimers within the liposome bilayer. Among the three Ohmline Pyrene compounds (OP1-3) only OP2 is able to reduce SK3 currents and is the first efficient fluorescent modulator of SK3 channel as revealed by patch clamp measurements (- 71.3 ± 13.3% at 10 μM) and by its inhibition of SK3-dependent cancer cell migration at (-32.5% ± 4.8% at 1 μM). We also report the first fluorescence study on living breast cancer cells (MDA-MB-231) showing that OP2 is rapidly integrated in bio-membranes followed by cell internalization.
我们报告了三种生物活性基于苝的 Ohmline 荧光类似物的合成，Ohmline 是 SK3 离子通道最有效和选择性的抑制剂。这些 Ohmline-苝（OP1-3）与不同组成的脂质体的相互作用表明，只有 OP2 和 OP3 容易整合到脂质体中。荧光测量表明，取决于它们的浓度，OP2 和 OP3 在脂质体双层内要么以单体存在，要么以单体和激基复合物的混合物存在。在这三种 Ohmline 苝化合物（OP1-3）中，只有 OP2 能够减少 SK3 电流，并且通过膜片钳测量（在 10 μM 时为-71.3 ± 13.3%）和抑制 SK3 依赖性癌细胞迁移（在 1 μM 时为-32.5% ± 4.8%）首次揭示其为 SK3 通道的有效荧光调节剂。我们还报告了对活乳腺癌细胞（MDA-MB-231）的首次荧光研究，表明 OP2 迅速整合到生物膜中，随后发生细胞内化。
