Synthesis and evaluation of indenoisoquinoline topoisomerase I inhibitors substituted with nitrogen heterocycles
In connection with an ongoing investigation of indenoisoquinoline topoisomerase I (Top1) inhibitors as potential therapeutic agents, the pharmacophore possessing di(methoxy) and methylenedioxy substituents was held constant, and new derivatives were synthesized with nitrogen heterocycles appended to the lactam side chain. Compounds were evaluated for Top1 inhibition and for cytotoxicity in the National Cancer Institute's human cancer cell screen. Some of the more potent derivatives were also screened for in vivo activity in a hollow fiber assay. The results of these studies indicate that lactam substituents possessing nitrogen heterocycles can provide highly cytotoxic compounds with potent Topi inhibition. Molecular modeling of these compounds in complex with DNA and Top1 suggests that some of the lactam substituents are capable of interacting with the DNA base pairs above and below the site of intercalation and/or with Topi amino acid residues, resulting in increased biological activity.
Nagarajan, Muthukaman,Morrell, Andrew,Ioanoviciu, Alexandra,Antony, Smitha,Kohlhagen, Glenda,Agama, Keli,Hollingshead, Melinda,Pommier, Yves,Cushman, Mark
Preparation method of indenoisoquinoline derivative
The invention relates to a preparation method of an indenoisoquinoline derivative as shown in formula (I). The preparation method includes the steps of (A), providing a first reactant as shown in formula (II) and a second reactant as shown in formula (III
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Paragraph 0095-0096; 0127; 0132; 0134; 0137
(2019/05/28)
Synthesis of Biologically Active Indenoisoquinoline Derivatives via a One-Pot Copper(II)-Catalyzed Tandem Reaction
A concise route for the synthesis of indenoisoquinoline derivatives from 2-iodobenzamide and 1,3-indanedione derivatives in the presence of copper(II) chloride and cesium carbonate in acetonitrile solvent is reported. A wide variety of 2-iodobenzamide derivatives and indandiones could be used to synthesize indenoisoquinoline derivatives and other fused indenoisoquinoline in moderate to good yields. This methodology was adapted for the one-step synthesis of a series of clinically active topoisomerase I inhibitors such as NSC 314622, LMP-400, LMP-776.
Synthesis and biological evaluation of new carbohydrate-substituted indenoisoquinoline topoisomerase I inhibitors and improved syntheses of the experimental anticancer agents indotecan (LMP400) and indimitecan (LMP776)
Carbohydrate moieties were strategically transported from the indolocarbazole topoisomerase I (Top1) inhibitor class to the indenoisoquinoline system in search of structurally novel and potent Top1 inhibitors. The syntheses and biological evaluation of 20 new indenoisoquinolines glycosylated with linear and cyclic sugar moieties are reported. Aromatic ring substitution with 2,3-dimethoxy-8,9-methylenedioxy or 3-nitro groups exerted strong effects on antiproliferative and Top1 inhibitory activities. While the length of the carbohydrate side chain clearly correlated with antiproliferative activity, the relationship between stereochemistry and biological activity was less clearly defined. Twelve of the new indenoisoquinolines exhibit Top1 inhibitory activity equal to or better than that of camptothecin. An advanced synthetic intermediate from this study was also used to efficiently prepare indotecan (LMP400) and indimitecan (LMP776), two anticancer agents currently under investigation in a Phase I clinical trial at the National Institutes of Health.
Beck, Daniel E.,Agama, Keli,Marchand, Christophe,Chergui, Adel,Pommier, Yves,Cushman, Mark
p. 1495 - 1512
(2014/03/21)
N-SUBSTITUTED INDENOISOQUINOLINES AND SYNTHESES THEREOF
N-Substituted indenoisoquinoline compounds, and pharmaceutical formulations of N-substituted indenoisoquinoline compounds are described. Also described are processes for preparing N-substituted indenoisoquinoline compounds. Also described are methods for
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Page/Page column 35-36; 38
(2008/06/13)
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