Therapeutic Innovation Laboratory, UMR7200, CNRS/Universite de Strasbourg, Illkirch, France.
J Med Chem. 2009 Aug 27;52(16):5176-87. doi: 10.1021/jm900365v.
Flavaglines constitute a family of natural anticancer compounds. We present here 3 (FL3), the first synthetic flavagline that inhibits cell proliferation and viability (IC(50) approximately 1 nM) at lower doses than did the parent compound, racemic rocaglaol. Compound 3 enhanced doxorubicin cytotoxicity in HepG2 cells and retained its potency against adriamycin-resistant cell lines without inducing cardiomyocyte toxicity. Compound 3 induced apoptosis of HL60 and Hela cells by triggering the translocation of Apoptosis Inducing Factor (AIF) and caspase-12 to the nucleus. A fluorescent conjugate of 3 accumulated in endoplasmic reticulum (ER), suggesting that flavaglines bind to their target in the ER, where it triggers a cascade of events that leads to the translocation of AIF and caspase-12 to the nucleus and probably inhibition of eIF4A. Our studies highlight structural features critical to their antineoplastic potential and suggest that these compounds would retain their activity in cells refractory to caspase activation.
黄烷类化合物构成了一类天然抗癌化合物。我们在此介绍 3（FL3），这是第一个合成的黄烷类化合物，它在较低剂量下抑制细胞增殖和活力（IC（50）约为 1 nM），比母体化合物罗卡醇的活性更高。化合物 3 增强了多柔比星在 HepG2 细胞中的细胞毒性，并且在不诱导心肌细胞毒性的情况下保留了对阿霉素耐药细胞系的效力。化合物 3 通过触发凋亡诱导因子（AIF）和半胱天冬酶-12向核内易位，诱导 HL60 和 Hela 细胞凋亡。3 的荧光缀合物在内质网（ER）中积累，表明黄烷类化合物在 ER 中与其靶标结合，在 ER 中触发一系列事件，导致 AIF 和半胱天冬酶-12向核内易位，并可能抑制 eIF4A。我们的研究强调了对其抗肿瘤潜力至关重要的结构特征，并表明这些化合物在对半胱天冬酶激活有抗性的细胞中仍将保持其活性。
