78287-27-1Relevant articles and documents
Two novel camptothecin derivatives inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo
Du, Hongzhi,Huang, Yue,Hou, Xiaoying,Quan, Xingping,Jiang, Jingwei,Wei, Xiaohui,Liu, Yang,Li, Hongyang,Wang, Puhai,Zhan, Meixiao,Ai, Xun,Lu, Ligong,Yuan, Shengtao,Sun, Li
, p. 546 - 559 (2018)
At present, chemotherapy is still to be the preferred and most significant therapeutic strategy for cancer patients in clinical practice. Although Camptothecin (CPT) has been discovered for over half century, a series of CPT derivatives such as Topotecan (TPT) and irinotecan (CPT-11) have been approved and are still to be the first-line medicines for clinical application. Up to now, the topoisomerase 1 inhibitor continues to be a significant drug development research field. Based on previous study of the structure-activity relationship, we consider that the introduction of lipophilic group at C7 position can prolong the retention time and the hydroxyl esterification at C20 can eliminate the hydrogen bond interaction, stabilize the E-lactone form and promote the anti-cancer effect. In this study, we carried out an optimization at C7 and C20 positions to afford two CPT derivatives 3g and 3j. Firstly, we predicted the possibly binding sites of two compounds with topoisomerase 1 by molecular docking. Then we evaluated the anti-proliferation effect of the two novel derivatives and compared the IC50 with CPT-11. Furthermore, the induction of cell cycle arrest and apoptosis was explored through karyomorphology, flow cytometry (FCM) and Western blot analysis. At last, we evaluated the anti-cancer effect and detected the mechanism in colorectal cancer xenograft model. In brief, all the data showed that the novel CPT derivatives (3g and 3j) could inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo. It suggested that the two agents may be a new potential therapeutic strategy in the future.
Irinotecan Hydrochloride impurity as well as synthesis method and application thereof
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Paragraph 0031; 0039; 0043; 0044, (2018/09/21)
The invention discloses an irinotecan Hydrochloride impurity which has a structural formula (1) as shown in the specification. In addition, the invention discloses a synthesis method and application of the impurity. The impurity is novel in structure and beneficial to quality control on an irinotecan Hydrochloride raw material medicine, and meanwhile, the synthesis method of the impurity has the characteristics of being simple in operation, an obtained sample is relatively high in purity and can be applied to control group study, and the like.
A new strategy to improve the metabolic stability of lactone: Discovery of (20 S,21 S)-21-fluorocamptothecins as novel, hydrolytically stable topoisomerase i inhibitors
Miao, Zhenyuan,Zhu, Lingjian,Dong, Guoqiang,Zhuang, Chunlin,Wu, Yuelin,Wang, Shengzheng,Guo, Zizao,Liu, Yang,Wu, Shanchao,Zhu, Shiping,Fang, Kun,Yao, Jianzhong,Li, Jian,Sheng, Chunquan,Zhang, Wannian
supporting information, p. 7902 - 7910 (2013/11/06)
Lactone is a common structural motif in biologically active natural products. However, the metabolic instability of lactone significantly reduces their in vivo potency. In the present investigation, a new strategy to improve the metabolic stability of lactone was provided by the design of α-fluoro ether as a novel bioisostere of lactone. The effectiveness of the α-fluoro ether/lactone replacement was validated by the discovery of (20S,21S)-21-fluorocamptothecins as hydrolytically stable topoisomerase I inhibitors. A highly potent camptothecin derivative, 8l, was successfully identified, which showed excellent in vitro and in vivo antitumor activities and represents a promising lead for the discovery of novel antitumor agents. Interestingly, this study also provided a new structure-activity relationship for the C21-carbonyl group of camptothecin, which has been regarded as an essential pharmacophore. Our results revealed that the conserved C21-carbonyl group can be replaced by a fluorine substituent. α-Fluoro ether may have general application in improving the metabolic stability of lactone.
