Jingjing Lin, Mei Tang, Ru Zhao, Qianqian Du, Longying Shen, Guohua Du, Yafen Zhang, Yan Li* and Xiandao Pan* Pages 3578 - 3589 ( 12 )
Background: 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.
Methods: 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. Results: 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. Conclusion: 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.Ellipticine, hexacyclic derivatives, synthesis, antitumor activity, topoisomerase IIα inhibitor, xenograft model.
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, 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, 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, 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, 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, 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, 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, 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, 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