PDF(Pubmed)
Abstract：
Chalcones and dihydrochalcones (DHCs) are important bioactive natural products (BNPs) isolated from traditional Chinese medicine. In this study, 13 chalcones were designed with the inspiration of Loureirin, a DHC extracted from Resina Draconis, and synthesized by classical Claisen-Schmidt reactions. Afterwards the reduction reactions were carried out to obtain the corresponding DHCs. Cytotoxicity assay indicated chalcones and DHCs possessed selective cytotoxicity against colorectal cancer (CRC) cells. The preliminary structure-activity relationships (SAR) of these compounds suggested the α, β-unsaturated ketone of the chalcones were crucial for the anticancer activity. Interestingly, compounds 3d and 4c exhibited selective anticancer activity against CRC cell line HCT116 with IC50s of 8.4 and 17.9 μM but not normal cell. Moreover, 4c could also inhibit the migration and invasion of CRC cells. Mechanism investigations showed 4c could induce cell cycle G2/M arrest by regulating cell cycle-associated proteins and could also up-regulate Fas cell surface death receptor. The virtual docking further pointed out that compounds 3d and 4c could nicely bind to the Fas/FADD death domain complex (ID: 3EZQ). Furthermore, silencing of Fas significantly enhanced the proliferation of CRC cells and attenuated the cytotoxicity induced by 4c. These results suggested 4c exerted its anticancer activity possibly regulating cell cycle and Fas death receptor. In summary, this study investigated the anticancer activity and mechanism of Loureirin analogues in CRC, suggesting these compounds may warrant further investigation as promising anticancer drug candidates for the treatment of CRC.
摘要：
查耳酮和二氢查耳酮（DHCs）是分离自中药的重要生物活性天然产物（BNPs）。在这项研究中,13个查尔酮的设计灵感来自Loureirin,从ResinaDraconis中提取的DHC，并通过经典的Claisen-Schmidt反应合成。然后进行还原反应以获得相应的DHC。细胞毒性实验表明，查耳酮和DHC对大肠癌（CRC）细胞具有选择性的细胞毒性。这些化合物的初步结构-活性关系（SAR）表明α，查耳酮的β-不饱和酮对抗癌活性至关重要。有趣的是,化合物3d和4c对CRC细胞系HCT116表现出选择性抗癌活性，IC50为8.4和17.9μM，但不正常细胞。此外，4c还可以抑制CRC细胞的迁移和侵袭。机制研究表明，4c可以通过调节细胞周期相关蛋白诱导细胞周期G2/M阻滞，也可以上调Fas细胞表面死亡受体。虚拟对接进一步指出，化合物3d和4c可以很好地结合Fas/FADD死亡域复合物（ID：3EZQ）。此外，沉默Fas可显著增强CRC细胞的增殖，并减弱4c诱导的细胞毒性。这些结果表明4c发挥了其抗癌活性，可能调节细胞周期和Fas死亡受体。总之,这项研究调查了Loureirin类似物在CRC中的抗癌活性和机制，提示这些化合物作为有希望的候选抗癌药物用于CRC的治疗可能需要进一步研究.
