- Two novel camptothecin derivatives inhibit colorectal cancer proliferation via induction of cell cycle arrest and apoptosis in vitro and in vivo
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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.
- 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
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Read Online
- A preparation method of irinotecan hydrochloride (by machine translation)
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The invention relates to a preparation method of irinotecan hydrochloride. Its steps are: parent ring to camptothecin as raw material generated by the reaction with the aldehyde 7 - ethyl camptothecin; hydrogen peroxide oxidation then N - oxide - 7 - ethyl camptothecin; by the illumination rearrangement 7 - ethyl - 10 - hydroxy camptothecin; 4 - piperidyl with dimethyl carbonate reaction to produce 4 - piperidyl carbonic acid methyl ester; 7 - ethyl - 10 - hydroxy camptothecin with 4 - piperidyl carbonic acid methyl ester reaction generating irinotecan monomer; irinotecan monomers with hydrochloric salt to obtain the finished product of the irinotecan hydrochloride. Compared with the prior art, the present invention avoid the use of phosgene in the reaction process, chloroform poisonous substance, in production with safe, convenient, less pollution and the like; in addition, the synthetic method avoids the need of the prior process in the defects of the chromatographic column separation and purification, reduces the production cost of the irinotecan, has great economic benefit. (by machine translation)
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Paragraph 0027-0028; 0034-0035; 0041-0042
(2019/06/27)
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- Irinotecan Hydrochloride impurity as well as synthesis method and application thereof
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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.
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Paragraph 0031; 0039; 0043; 0044
(2018/09/21)
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- Photoredox-mediated Minisci C-H alkylation of N-heteroarenes using boronic acids and hypervalent iodine
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A photoredox-mediated Minisci C-H alkylation reaction of N-heteroarenes with alkyl boronic acids is reported. A broad range of primary and secondary alkyl groups can be efficiently incorporated into various N-heteroarenes using [Ru(bpy)3]Cl2 as photocatalyst and acetoxybenziodoxole as oxidant under mild conditions. The reaction exhibits excellent substrate scope and functional group tolerance, and offers a broadly applicable method for late-stage functionalization of complex substrates. Mechanistic experiments and computational studies suggest that an intramolecularly stabilized ortho-iodobenzoyloxy radical intermediate might play a key role in this reaction system.
- Li, Guo-Xing,Morales-Rivera, Christian A.,Wang, Yaxin,Gao, Fang,He, Gang,Liu, Peng,Chen, Gong
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p. 6407 - 6412
(2016/09/28)
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- 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
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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.
- 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
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supporting information
p. 7902 - 7910
(2013/11/06)
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- PROCESS FOR PRODUCTION OF CAMPTOTHECIN DERIVATIVE
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Disclosed is a process for production of 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycampto thecin from a camptothecin composition containing 18,19-dehydrocamptothecin without producing any vinyl form of the compound. The process is characterized by catalytically reducing at least one compound selected from a compound (1) and others in the process of producing a compound (5) from a composition containing the compound (1).
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Page/Page column 10-11
(2009/01/24)
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- New route for conversion of camptothecin to 7-ethylcamptothecin and 7-propylcamptothecin
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In this article, a new route for conversion of camptothecin to 7-ethylcamptothecin and 7-propylcamptothecin is described. Compared with previous reports, the reaction time of the new synthetic route was greatly shortened to 30 min, and the products were obtained in high yield. Copyright Taylor & Francis Group, LLC.
- Wang, Xin,Wu, Xiaojing,Cheng, Ning,Zhao, Huiqing,Gu, Zhihong,Shen, Xiang
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p. 519 - 523
(2007/10/03)
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- AN IMPROVED PROCESS FOR THE PREPARATION OF IRINOTECAN HYDROCHLORIDE TRIHYDRATE
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The invention relates to an improved process for the preparation of Irinotecan hydrochloride trihydrate of formula (4) of enhanced yield, purity by contacting 1-chlorocarbonyl-4-piperidinopiperidine hydrochloride with 7-ethyl-10 hydroxy-camptothecin [IRT-3 (synthetic)] to obtain crude Irinotecan which is subsequently purified by solvent treatment, obtaining purified irinotecan which is converted into irinotecan hydrochloride trihydrate and the invention also relates to a report of the compound 1-chlorocorbonyl-4-iperidinopiperidine hydrochloride of formula (1) and its process for preparation.
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Page/Page column 9-10
(2010/10/20)
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- Chemical modification of antitumor alkaloids, 20(S)-camptothecin and 7-ethylcamptothecin: Reaction of the E-lactone ring portion with hydrazine hydrate
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The structure of the N-amino pyridone (4a) obtained by the reaction of camptothecin (1a) with hydrazine was determined by X-ray crystallography. A mixture of 7-ethylcamptothecin (1b) and hydrazine hydrate was stirred at room temperature, and the hydrazide (2b) was isolated as its diacetate 2c. Treatment of the 17-O-acetyl amide (5a) with hydrazine gave 1b (74% yield) and the N-amino lactam 6 (11% yield). Compounds with bulky acyl groups, 5c-e, gave 6 in modest yields. The N-amino lactam 6 was smoothly dehydrated into the pyridone 4d by refluxing in hydrazine hydrate.
- Yaegashi,Sawada,Furuta,Yokokura,Yamaguchi,Miyasaka
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p. 971 - 974
(2007/10/02)
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- Chemical modification of an antitumor alkaloid camptothecin: Synthesis and antitumor activity of 7-C-substituted camptothecins
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A radical substitution reaction of 20(S)-camptothecin (1) with methanol furnished 7-hydroxymethylcamptothecin (2). Reaction of 1 with primary alcohols higher than methanol gave 7-alkylcamptothecins (4), of which alkyl groups were one carbon less than the alcohols used and also 7-hydroxyalkylcamptothecins (5). For the preparation of 7-alkylcamptothecin (4), aldehydes were used as a radical source and several alkylated derivatives were synthesized. 7-Acyloxymethyl derivatives (6), 7-carbaldehyde (7), iminomethyl derivatives (10), acid (11), esters (12) and amides (13) were synthesized starting from 2. 7-Ethyl- (4b) and 7-propylcamptothecin (4c), acyloxymethyl compounds 6a, 6c and ethyl ester (12b) exhibited higher antitumor activity than 1 against L1210 in mice.
- Sawada,Nokata,Furuta,Yokokura,Miyasaka
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p. 2574 - 2580
(2007/10/02)
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- Synthesis and antitumor activity of 20(S)-camptothecin derivatives: Carbamate-linked, water-soluble derivatives of 7-ethyl-10-hydroxycamptothecin
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Novel 36 derivatives (6), bonding the phenolic hydroxyl group of 7-ethyl-10-hydroxycamptothecin (4) with diamines through a monocarbamate linkage, were synthesized and their antitumor activity was evaluated in vivo. The derivatives were soluble in water as their HCl salts with the E lactone ring intact and exhibited significant antitumor activity. One of the derivatives, 6-27 showed excellent activity against L1210 leukemia and other murine tumors. The structure of its hydrochloride trihydrate (CPT-11) was determined by spectroscopic and crystallographic methods.
- Sawada,Okajima,Aiyama,Nokata,Furuta,Yokokura,Sugino,Yamaguchi,Miyasaka
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p. 1446 - 1454
(2007/10/02)
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- Camptothecin derivatives
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New camptothecin derivatives possessing either or both of high anti-tumor activity and slight toxicity, represented by the general formula: STR1 wherein X is H, CH2 OH, COOH, an alkyl group, an aralkyl group or the grouping CH2 OR1 or COOR2 wherein R1 is an alkyl group or an acyl group and R2 is a lower alkyl group, Y is H, OH or the grouping OR3 wherein R3 is a lower alkyl group or an acyl group, and Z is H or an acyl group, with the proviso that when X is CH2 OH, an alkyl group or an aralkyl group, both Y and Z are H, that when X is the grouping CH2 OR1 or COOR2, Y is H, that when Y is OH, both X and Z are H, and that when Y is the grouping OR3, X is H, and water-soluble alkali metal salts thereof. These camptothecin derivatives are prepared by treating camptothecin with sulfuric acid and a persulfate or with sulfuric acid and a peroxide, if necessary, with an organic compound corresponding to the organic moiety of the substituent to be introduced directly into camptothecin, in an aqueous medium in the presence or absence of a transition metal ion, and optionally treating the resultant products, if necessary, after oxidation of the introduced substituent, with an alkylating agent or an acylating agent.
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