Wu Guanzhao, Mai Xiaoyuan, Liu Feng, Lin Mingming, Dong Xueyang, Xu Qingliang, Hao Cui, Zhang Lijuan, Yu Rilei, Jiang Tao
Key Laboratory of Marine Drugs, Chinese Ministry of Education, School of Medicine and Pharmacy, Ocean University of China 5 Yushan Road Qingdao 266003 China
Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology Qingdao 266003 China.
RSC Adv. 2019 Apr 9;9(20):11142-11150. doi: 10.1039/c9ra00315k.
10,11-Methylenedioxy-camptothecin (FL118) is a novel camptothecin analogue that possesses exceptional antitumor efficacy in human tumor xenograft models. The aim of the current study was to develop novel 20-substituted FL118 derivatives coupled with glycosyl-succinic acid esters with improved antitumor efficacy. These FL118 glycoside derivatives were designed, synthesized and their cytotoxicity evaluated in three tumor cell lines (A-549, MDA-MB-231 and RM-1). All of the derivatives showed superior cytotoxic activity and were more potent than irinotecan in A549 and MDA-MB-231 cells. In mouse prostate cancer cells RM-1, 10,11-methylenedioxy-camptothecin rhamnoside 11b displayed significant activities with IC of 48.27 nM. Western blot analysis demonstrated that 11b inhibited survivin expression and induced cancer cells apoptosis. Further cell cycle analyses clearly showed 11b induced G2/M phase cell cycle arrest. Molecule docking studies suggested that the binding mode of 11b was different from that of the crystal complex of ligand topotecan in Top1/DNA. Importantly, 11b showed high antitumor efficacy in the RM-1 mouse model with transplantation of prostate cancer (TGI = 44.9%) at dose of 9 mg kg without apparent toxicity.
10,11-亚甲基二氧基喜树碱（FL118）是一种新型喜树碱类似物，在人肿瘤异种移植模型中具有卓越的抗肿瘤功效。本研究的目的是开发新型的20-取代FL118衍生物，其与糖基琥珀酸酯偶联，具有更高的抗肿瘤功效。设计并合成了这些FL118糖苷衍生物，并在三种肿瘤细胞系（A-549、MDA-MB-231和RM-1）中评估了它们的细胞毒性。所有衍生物均表现出优异的细胞毒性活性，并且在A549和MDA-MB-231细胞中比伊立替康更具效力。在小鼠前列腺癌细胞RM-1中，10,11-亚甲基二氧基喜树碱鼠李糖苷11b表现出显著活性，IC为48.27 nM。蛋白质印迹分析表明，11b抑制存活素表达并诱导癌细胞凋亡。进一步的细胞周期分析清楚地显示，11b诱导G2/M期细胞周期阻滞。分子对接研究表明，11b的结合模式与拓扑替康配体在Top1/DNA晶体复合物中的结合模式不同。重要的是，11b在剂量为9 mg/kg的RM-1前列腺癌移植小鼠模型中显示出高抗肿瘤功效（TGI = 44.9%），且无明显毒性。
