- 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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Read Online
- Selective phenolic acylation of 10-hydroxycamptothecin using poly (ethylene glycol) carboxylic acid
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Selective acylation of the phenolic hydroxyl group of 10-hydroxycamptothecin has been accomplished using phenyl dichlorophosphate. Additional modification of the 10-OH as an ether permits a 20-acyl derivative to be synthesized. This result along with data from a 6-hydroxyquinoline model strongly suggests that powerful intermolecular hydrogen bonding exists in the parent molecule.
- Greenwald, Richard B.,Choe, Yun H.,Wu, Dechun
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Read Online
- CONJUGATES OF A CELL-BINDING MOLECULE WITH CAMPTOTHECIN ANALOGS
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Provided are conjugates of camptothecin analogs with a cell-binding molecule of formula (I), wherein R1, R2, R3, R4, R5, X, L, n, m, T and ----- are defined herein. It also provides methods of making the conjugates of camptothecin analogs to a cell-binding agent, as well as methods of using the conjugates in targeted treatment of cancer, infection, and immunological disorders.
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Page/Page column 144
(2021/10/30)
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- Water-soluble anti-tumor compounds
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The invention relates to a water-soluble antitumor compound represented by the formula (I), and further relates to a preparation method of the compound and an application of the compound in preparation of antitumor drugs. Stable prodrug with a good water
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Paragraph 0228-0233
(2019/05/04)
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- Visible-Light-Induced Radical Cascade Cyclization: Synthesis of (20S)-Camptothecin, SN-38 and Irinotecan
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(20S)-Camptothecin, irinotecan and SN-38 were successfully synthesized by a photocatalyzed radical cascade cyclization from an N-propargyl iodopyridinone and an arylisonitrile under visible light with a ruthenium catalyst. This synthetic method provided a useful entry into composing camptothecin family of antitumor agents in good yields under mild reaction conditions without the use of heavy metal reagents.
- Yuan, Yao,Dong, Wuheng,Gao, Xiaoshuang,Xie, Xiaomin,Curran, Dennis P.,Zhang, Zhaoguo
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p. 1035 - 1040
(2018/09/25)
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- Short protecting group-free syntheses of camptothecin and 10-hydroxycamptothecin using cascade methodologies
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A convergent protecting group-free total synthesis route of camptothecin and 10-hydroxycamptothecin has been developed in this work. Cascade oxidation of 3-(hydroxymethyl)furan-2(5 H)-one and in situ intermolecular oxa Diels-Alder reaction with vinyl ether was developed and applied to construct the E-ring, and TMSCl-promoted cascade closure of the D-ring delivered the whole skeleton of the alkaloids in the total synthesis. The new short syntheses were advantageous with regard to step economy, low cost, easily available starting materials and reagents, and convenient operations.
- Xu, Peng,Chen, Dong-Sheng,Xi, Jie,Yao, Zhu-Jun
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p. 976 - 981
(2015/04/14)
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- Synthesis and anticancer evaluation of novel 10-methoxycamptothecin derivatives
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As part of our continuing search for potential anticancer drug candidates, we have synthesized four 10-methoxycamptothecin derivatives. The compounds were synthesized by facile procedures and characterized by 1H NMR, 13C NMR and mass spectra study. The synthesized compounds were examined for their cytotoxic effect on a panel of five human cancer cell lines. Three out of five compounds were found to exhibit moderate anticarcinogenic activities in all cell lines. The result of the present investigation encourage us to develop more other related compounds and to screen them for a wide range of biological activity.
- Zhu, Meixuan,Jing, Lijia,Wang, Shaoming,Zhang, Sheng,Wang, Yang
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p. 932 - 934
(2015/02/05)
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- Synthesis of 9-allyl-10-hydroxycamptothecin via Suzuki reaction
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A facile and eco-friendly approach for synthesizing 9-allyl-10- hydroxycamptothecin (2), a key intermediate for the preparation of camptothecin analogs, is described. The product was obtained in good yield and high purity (≥99% HPLC) under mild Suzuki reaction condition.
- Luo, Yu,Yu, Shanbao,Huang, Qingqing,Lu, Wei
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p. 1133 - 1136
(2014/08/05)
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- Total synthesis of camptothecin and SN-38
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A new practical and concise total synthesis of enantiopure camptothecin and SN-38 (14% overall yield, 99.9% ee and 99.9% purity) was described, starting from inexpensive and readily available materials. The development of column chromatography-free purification was achieved in all steps, which offers an economic industrial process to the camptothecin-family alkaloids.
- Yu, Shanbao,Huang, Qing-Qing,Luo, Yu,Lu, Wei
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p. 713 - 717
(2012/03/11)
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- Synthesis of new cytotoxic E-ring modified camptothecins
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In an effort to decrease the toxicity and improve the stability of the E-ring of camptothecin, new analogues with an 'inverted' lactone ring were designed and synthesized. The compounds retained a good cytotoxic activity on human non-small lung cancer cel
- Cananzi, Salvatore,Dallavalle, Sabrina,Bargiotti, Alberto,Merlini, Lucio,Artali, Roberto,Beretta, Giovanni Luca
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scheme or table
p. 6489 - 6492
(2011/02/22)
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- 7-Cycloalkylcamptothecin derivatives: Preparation and biological evaluation
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A series of 7-cycloalkylcamptothecin derivatives were synthesized from camptothecin with two methods. Their biological activities in vitro were evaluated with sulforhodamine-B (SRB) method on four types of human tumor cell lines A549/ATCC, HT29, NCI-H460
- Li, Mingzong,Jin, Wei,Jiang, Chen,Zheng, Chao,Tang, Weidong,You, Tianpa,Lou, Liguang
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experimental part
p. 4107 - 4109
(2010/04/26)
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- Expeditious total syntheses of camptothecin and 10-hydroxycamptothecin
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(Chemical Equation Presented) New expeditious total syntheses of (S)-camptothecin (16% overall yield, 95% ee) and (S)-10-hydroxycamptothecin (14% overall yield, 99% ee) have been accomplished, respectively, starting from readily available and inexpensive materials. Development, optimization, and successful application of the cascade reaction consisting of a pyrrolidine-catalyzed Michael addition, an intramolecular aldol condensation, and an oxidative aromatization, the intramolecular oxa Diels-Alder cycloaddition, and the Sharpless asymmetric dihydroxylation make these two new syntheses more efficient and straightforward.
- Liu, Guan-Sai,Dong, Qing-Li,Yao, Yuan-Shan,Yao, Zhu-Jun
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supporting information; experimental part
p. 5393 - 5396
(2009/06/28)
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- Radiosynthesis of carbon-11-labeled camptothecin derivatives as potential positron emission tomography tracers for imaging of topoisomerase I in cancers
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Four carbon-11-labeled camptothecin derivatives, 9-[11C]methoxy- 20(S)-camptothecin ([11C]5), 10-[11C]methoxy-20(S)- camptothecin ([11C]7), 9-nitro-10-[11C]methoxy-20(S)- camptothecin ([11C]9), and 9-[([11C]trimethylamino)methyl] -10-hydroxy-20(S)-camptothecin ([11C]11), have been synthesized as potential positron emission tomography tracers for imaging of topoisomerase I in cancers.
- Gao, Mingzhang,Miller, Kathy D.,Sledge, George W.,Zheng, Qi-Huang
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p. 3865 - 3869
(2007/10/03)
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- A general synthetic approach to the (20s)-camptothecin family of antitumor agents by a regiocontrolled cascade radical cyclization of aryl isonitriles
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A general and efficient synthesis of (20S)-camptothecin (1a) is reported. A key common intermediate containing the pyridone and lactone (DE) rings of camptothecin and most derivatives was constructed from 2-trimethylsilyl-6-methoxypyridine by a series of metalation reactions and a Heck cyclization to provide an achiral bicyclic enol ether. Sharpless asymmetric dihydroxylation followed by lactol oxidation and iododesilylation produced the key intermediate in 94% enantiomeric excess. Alkylation with prop-argyl bromide and a cascade radical reaction with phenyl isonitrile then produced 1a. About 20 other penta-and hexacyclic analogues of camptothecin with differing single or multiple substituents at C7, C9, C10, C11, and/or C12 were made by changing the propargylating agent and the isonitrile. Included among these are several drug candidates and the approved drugs topotecan and irinotecan. The synthesis of the prodrug irinotecan is a direct one that does not pass through the active metabolite. The use of ortho-trimethylsilyl-substituted isonitriles allows the regioselective synthesis of camptothecin analogues in cases where isomeric mixtures are formed from the parent isonitriles. The synthesis of the derivatives relies on the broad scope and functional group tolerance of the key cascade radical reaction.
- Josien, Hubert,Ko, Sung-Bo,Bom, David,Curran, Dennis P.
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- Novel syntheses of camptothecin alkaloids. Part 2. Concise synthesis of (S)-camptothecins
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A 9-step, convergent total synthesis of (S)-camptothecin alkaloids is described. The intramolecular [4 + 2] cycloaddition of an N-arylimidate with an alkyne is used to prepare the alkaloid ABC ring system. The chiral center is derived utilizing Seebach's chemistry for the diastereoselective Michael addition of a chiral dioxolanone enolate to a methylene malonate acceptor. The total synthesis of non-racemic topotecan is accomplished from (S)-10-hydroxycamptothecin in an additional step.
- Fortunak, Joseph M.D.,Kitteringham, John,Mastrocola, Antonietta R.,Mellinger, Mark,Sisti, Nicolas J.,Wood, Jeffery L.,Zhuang, Zhi-Ping
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p. 5683 - 5686
(2007/10/03)
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- Kaskaden-Radikalreaktionen von Isocyaniden: eine zweite Generation der Synthese von (20S)-Camtothecin, Topotecan, Irinotecan und G1-147211C
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Keywords: Camptothecin; Isocyanide; Kaskadenreaktionen; Radikale
- Curran, Dennis P.,Ko, Sung-Bo,Josien, Hubert
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p. 2948 - 2950
(2007/10/03)
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- Synthesis and antitumor activity of 20(S)-camptothecin derivatives: A-ring modified and 7,10-disubstituted camptothecins
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20(S)-Camptothecin derivatives having nitro, amino, chloro, bromo, hydroxyl and methoxyl groups in the A-ring were synthesized. B-Ring hydrogenated camptothecin (2a) was converted into 10-hydroxycamptothecin (6e) by treatment with lead tetraacetate in trifluoroacetic acid. 10-Substituted derivatives (6) were obtained by a photoreaction of N-oxides (9). The cytotoxicity of the A-ring modified camptothecins was evaluated against KB cells in vitro and leukemia L1210 in mice. 7-Ethyl-10-hydroxycamptothecin (6i) was identified as a potential derivative for further modification.
- Sawada,Matsuoka,Nokata,Nagata,Furuta,Yokokura,Miyasaka
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p. 3183 - 3188
(2007/10/02)
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