State Key Laboratory of Bioactive Substance and Function of Natural Medicines and Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
Curr Pharm Des. 2019;25(33):3578-3589. doi: 10.2174/1381612825666190404122650.
For decades, a great deal of research work has been done to synthesize ellipticine and its derivatives because of their potential antitumor properties and anti-HIV activities. However, the resonance structures in different media, a low level of solubility at physiological pH and systemic toxicity have prevented the use of ellipticine as a therapeutic agent. Besides, the low yield and complex steps of ellipticine synthesis limit its application.
A high-yield synthetic procedure of ellipticine has been optimized, and the total yield was up to 50% without silica gel column chromatography. Novel hexacyclic ellipticine derivatives were synthesized by coupling ellipticine with o-aminobenzoic acid. Their cytotoxicities against HCT116, MGC803, HT29 and MCF-7 tumor cells were evaluated.
The synthesis process of ellipticine was optimized, and the total yield of the synthetic route was increased to 50% through several operation steps optimization. Fourteen ellipticine hexacyclic derivatives were synthesized. The synthetic compounds were screened for anti-tumor activity in vivo and in vitro, and some of the derivatives had good anti-tumor activity.
Compared with ellipticine, the compound 1l showed higher antitumor activity and better tolerance to tumor models. The compound 1l treatment increased the percentage of late apoptotic cells from 3.1% (DMSO) to 21.6% (20.0 μM) in NCI-H460 cells. It also was observed the effect of 1l on G2 phase arrest was similar as that of ellipticine. The mechanism of action indicated compound 1l could be a topoisomerase IIα poison. These studies provided the basis for the pharmacodynamics and toxicology of ellipticine, and further clarifies the structureactivity relationship of antitumor activity of ellipticine.
几十年来，由于具有潜在的抗肿瘤特性和抗 HIV 活性，人们进行了大量的研究工作来合成椭圆素及其衍生物。然而，不同介质中的共振结构、生理 pH 下的低溶解度和全身毒性阻止了椭圆素作为治疗剂的使用。此外，椭圆素合成的低产率和复杂步骤限制了其应用。
优化了椭圆素的高产合成工艺，总收率达到 50%，无需硅胶柱层析。通过将椭圆素与邻氨基苯甲酸偶联，合成了新型六环椭圆素衍生物。评价了它们对 HCT116、MGC803、HT29 和 MCF-7 肿瘤细胞的细胞毒性。
优化了椭圆素的合成工艺，通过对几个操作步骤的优化，将合成路线的总收率提高到 50%。合成了 14 个椭圆素六环衍生物。对合成化合物进行了体内和体外抗肿瘤活性筛选，部分衍生物具有良好的抗肿瘤活性。
与椭圆素相比，化合物 1l 表现出更高的抗肿瘤活性和对肿瘤模型更好的耐受性。化合物 1l 处理将 NCI-H460 细胞中晚期凋亡细胞的百分比从 3.1%（DMSO）增加到 21.6%（20.0 μM）。还观察到 1l 对 G2 期阻滞的作用与椭圆素相似。作用机制表明化合物 1l 可能是拓扑异构酶 IIα 毒物。这些研究为椭圆素的药效学和毒理学提供了依据，并进一步阐明了椭圆素抗肿瘤活性的构效关系。
