- Simple method for preparing ellipticine or substituted ellipticine
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The invention relates to a synthesis process for preparing ellipticine. Ellipticine is obtained through six steps of reaction and three steps of crystallization separation, the target product total yield is high, column chromatography separation is not needed for an intermediate product and the target product, and the method is particularly suitable for large-scale preparation.
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Paragraph 0039; 0047
(2020/05/14)
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- SMALL MOLECULES TARGETING REPEAT r(CGG) SEQUENCES
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The invention provides a series of bioactive small molecules that target expanded r(CGG) repeats, termed r(CGG)exp, that causes Fragile X-associated Tremor Ataxia Syndrome (FXTAS). The compound was identified by using information on the chemotypes and RNA motifs that interact. Specifically, 9-hydroxy-5,11-dimethyl-2-(2-(piperidin-1-yl)ethyl)-6H-pyrido[4,3-b]carbazol-2-ium, binds the 5′CG/3′GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Specifically, dimeric compounds incorporating two 9-hydroxyellipticine analog structures can even more potently bind the 5′CGG/3′GGC motifs in r(CGG)exp and disrupts a toxic r(CGG)exp-protein complex. Structure-activity relationships (SAR) studies determined that the alkylated pyridyl and phenolic side chains are important chemotypes that drive molecular recognition of r(CGG) repeats, such as r(CGG)exp. Importantly, the compound is efficacious in FXTAS model cellular systems as evidenced by its ability to improve FXTAS-associated pre-mRNA splicing defects and to reduce the size and number of r(CGG)exp-protein aggregates.
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Paragraph 0198
(2015/11/16)
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- Synthesis and evaluation of novel ellipticines as potential anti-cancer agents
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Drugs that inhibit DNA topoisomerase I and DNA topoisomerase II have been widely used in cancer chemotherapy. We report herein the results of a focused medicinal chemistry effort around novel ellipticinium salts which target topoisomerase I and II enzymes with improved solubility. The salts were prepared by reaction of ellipticine with the required alkyl halide and evaluated for DNA intercalation, topoisomerase inhibition and growth inhibition against 12 cancer cell lines. Results from the topoisomerase I relaxation assay indicated that all novel ellipticine derivatives behaved as intercalating agents. At a concentration of 100 μM, specific topoisomerase I inhibition was not observed. Two of the derivatives under investigation were found to fully inhibit the DNA decatenation reaction at a concentration of 100 μM, indicative of topoisomerase II inhibition. N-Alkylation of ellipticine was found to enhance the observed growth inhibition across all cell lines and induce growth inhibition comparable to that of Irinotecan (CPT-11; GI50 1-18 μM) and in some cell lines better than Etoposide (VP-16; GI50 = 0.04-5.2 μM). 6-Methylellipticine was the most potent growth inhibitory compound assessed (GI50 = 0.47-0.9 μM). N-Alkylation of 6-methylellipticine was found to reduce this response with GI50 values in the range of 1.3-28 μM.
- Deane, Fiona M.,O'Sullivan, Elaine C.,Maguire, Anita R.,Gilbert, Jayne,Sakoff, Jennette A.,McCluskey, Adam,McCarthy, Florence O.
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supporting information
p. 1334 - 1344
(2013/05/21)
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- Modifications to the Vilsmeier-Haack formylation of 1,4-dimethylcarbazole and its application to the synthesis of ellipticines
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Figure represented. An improved method for the preparation of 3-formyl-1,4-dimethylcarbazole, a key intermediate in the synthesis of ellipticine, is presented. Conditions of the Vilsmeier-Haack reaction have been modified to facilitate the production of 3-formyl-1,4-dimethylcarbazole as a major product leading to an overall improvement in yield of ellipticine from 3% to 14%. This approach was also applied to the synthesis of 6-methylellipticine and 9-methoxyellipticine.
- Deane, Fiona M.,Miller, Charlotte M.,Maguire, Anita R.,McCarthy, Florence O.
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experimental part
p. 814 - 823
(2011/10/04)
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- Efficient microwave-assisted synthesis of ellipticine through N-(1,4-dimethyl-9h-carbazol-3-ylmethyl)-n-tosylaminoacetaldehyde diethyl acetal
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The long-lasting problematic low yield in the D-ring cyclization of ellipticine (1a) was dramatically improved through N-(1,4-dimethylcarbazol-3- ylmethyl)-N-tosylaminoacetaldehyde diethyl acetal with microwave irradiation. The overall yield of 1a starting from indole was significantly increased by 25-fold. This new approach is superior to reported methods in yields and, reaction time, and it provides efficient access to a broad spectrum of ellipticine derivatives.
- Lee, Hsueh-Yun,Chen, Grace Shiahuy,Chen, Chien-Shu,Cherna, Ji-Wang
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experimental part
p. 454 - 458
(2010/06/19)
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- Intramolecular cyclization of ortho-(cyclohex-2-enyl)anilines. Modified synthesis of ellipticine
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It was found that the reactions of arylamines with 3-bromocyclohexene afforded hydrocarbazole compounds in 64-78% yields. A modified procedure for the synthesis of antitumor alkaloid ellipticine was proposed.
- Mustafin,Khalilov,Ismagilov,Baimetov,Spirikhin,Abdrakhmanov,Tolstikov
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p. 2121 - 2126
(2007/10/03)
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- INTRAMOLECULAR CYCLIZATION OF ortho-(CYCLOHEX-2-ENYL)ANILINES SYNTHESIS OF ELLIPTICINE
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A convenient method is proposed for the synthesis of the alkaloid ellipticine, which possesses a pronounced antitumoral activity.The interaction of 3-bromocyclohexene (1 equiv.) and 2,5-xylylidine (4 equiv., 150 deg C, 5 h) gave a mixture of hexa- and tetrahydrocarbazoles which was dehydrogenated in the presence of Pd/C to the key synthon 1,4-dimethylcarbazole.The formylation of the carbazole by the Vilsmeier-Haack reaction, interaction with 2,2-diethoxyethylamine, and reduction of the imine formed over Raney nickel led to 3-(2,2-diethoxyethylaminomethyl)-1,4-dimethylcarbazole, the boiling of the N-tosylate of which gave ellipticine in high yield.
- Mustafin, A. G.,Khalilov, I. N.,Tal'vinskii, E. V.,Abdrakhmanov, I. B.,Spirikhin, L. V.,Tolstikov, G. A.
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p. 479 - 483
(2007/10/02)
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- Synthetic Studies of Indoles and Related Compounds, Part 221. The Vilsmeier-Haack Reaction of N-Benzyl-1,2,3,4-tetrahydrocarbazoles and its Synthetic Application to Olivacine and Ellipticine2
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Vilsmeier-Haack reaction of 9-benzyl-1,2,3,4-tetrahydrocarbazole (18a) at 120 deg C gave 9-benzyl-1-methylcarbazole-3-carbaldehyde (19a) and 9-benzyl-1-(N,N-(dimethylamino)methyl)carbazole-3-carbaldehyde (22a) in moderate yields, whereas, the same reaction at 0 deg C gave 9-benzyl-1,2,3,4-tetrahydrocarbazole-1-carbaldehyde (20a) in very good yield.The aldehyde (20a) was converted into 9-benzyl-1-methylcarbazole (21a) by another Vilsmeier-Haack reaction.This carbazole (21a) unexpectedly underwent non-regioselective formylation under similar reaction conditions to give a mixture of compound (19a) and 9-benzyl-8-methylcarbazole-3-carbaldehyde (23a).On the basis of the above results, a mechanism of the formation of the aromatic aldehyde (19a) was proposed, which involves 1,5-sigmatropic rearrangement of an N-methylidene dimethylammonium cation from the 4a-position to the 3-position as a key step.Vilsmeier-Haack reaction of 9-benzyl-1,2,3,4-tetrahydro-4-methylcarbazole (18b) at 100 deg C also gave 9-benzyl-1,4-dimethylcarbazole-3-carbaldehyde (19b) in moderate yield.The total syntheses of two antitumor alkaloids, olivacine (10) and ellipticine (11), were achieved by utilizing compounds (19a) and (19b) as key intermediates.
- Yokoyama, Yuusaku,Okuyama, Naomi,Iwadate, Shinji,Momoi, Tokuko,Murakami, Yasuoki
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p. 1319 - 1329
(2007/10/02)
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