Synthesis ellipticine alkaloids

Gribble GW (1990) Synthesis and antitumour activity of ellipticine alkaloids and related compounds. The Alkaloids, Chemistry and Pharmacology (ed Brossi A) Vol 39. Academic, San Diego, pp 239-352. 

SYNTHESIS AND ANTITUMOR ACTIVITY OF ELLIPTICINE ALKALOIDS AND RELATED COMPOUNDS... 

Ellipticine alkaloids and related compounds synthesis and antitumor activity of, 39, 239 (1990)... 

Chapter 7. Synthesis and Antitumor Activity of the Ellipticine Alkaloids and Related Compounds... 

Carbazoles can be prepared by photocyclisation of diphenylamines and this has now been applied to the synthesis of ellipticine alkaloid precursors. The ultra-violet light irradiation of N-tosyl amines (261) in ethanol is also said to give the corresponding carbazoles (262). Photolysis of the antiinflammatory drug diclofenac (263) in water or methanol has been... 

Eburnane alkaloid synthesis, 54 Elaeokanine A, 63-64 Ellipticine, 303 Enamine, 257... 

Gribble, G. W., Synthesis and antitumor activity of ellipticine alkaloids and related compounds, in The Alkaloids, Vol. 39 (A. Brossi, ed.), 239-352, Academic Press, New York, 1990. 

The t-butoxycarbonyl group also favours o-lithiation as in N-(t-butoxy-carbonyl)aniline subsequent reaction with electrophiles provides a route to o-functionalized anilines.Pyridines substituted at the 2- or 3-positions with dialkylcarboxylic acid amides and halogens undergo regiospecific lithiation and then electrophilic attack. In both cases the 2-substituent gives reaction at the 3-position, whereas the 3-substituted pyridine undergoes attack exclusively at the 4-position. The o-lithiated benzamide (15) has been used in the synthesis of polycyclic aromatic hydrocarbons and ellipticine alkaloids by reaction with aromatic aldehydes. ... 

The antitumor alkaloid ellipticine (5,1 l-dimethyl-6//-pyrido[4,3-b]carbazole) has been isolated from many species of Ochrosia and Aspidosperma. Ellipticine and its derivatives are highly active versus several experimental neoplasms, and the compound has been widely subjected to studies devoted to its total synthesis, the preparation of derivatives, and metabolism. Metabolic transformation studies with ellipticines have been conducted, using microorganisms, in vivo and in vitro... 

The strong interest in the synthesis of pyrido[4,3-h]carbazole alkaloids started in the late 1960s with the disclosure of the antitumor activity of ellipticine (228) and 9-methoxyellipticine (229) (see Scheme 2.56) in several animal and human tumor systems. This discovery made these alkaloids to important synthetic targets and induced extensive studies of structure modification. These synthetic efforts have... 

A synthesis of the antitumor agent elliptidne has utilized the indolyl-substituted oxazole (351) as a key intermediate (77JOC2039). Diels-Alder reaction of (351) with acrylonitrile in acetic acid afforded a pyridinecarbonitrile (352) which was reacted with methyllithium, and the ketimine salt was hydrolyzed and cyclized to ellipticine (353 Scheme 76). Other Diels-Alder reactions of this type, particularly intramolecular cycloadditions of oxazoles with alkenic dienophiles should provide rapid access to a variety of alkaloid systems. 

Generally high yields of substituted carbazoles can be obtained by oxidative cyclization of diphenylamines using Pd(OAc)2 to effect cyclization (equation 59) (75JOC1365). This method has been used, for example, to close the carbazole ring in the synthesis of the anti-tumor alkaloid ellipticine (equation 60) (80TL3319). 

Ellipticine inhibits DNA, RNA and protein synthesis. The inhibition is not reversible by removal of the alkaloid. It has no appreciable effects on thymidine and uridine kinases or on RNA polymerase, but it markedly inhibits DNA polymerase activity [240, 241]. The actual mechanism of action of ellipticine and related compounds has not yet been elucidated. Ellipticine and derivatives have been found to interact with bacterial membranes [242]. Many investigators have categorized these compounds as DNA-interacting or intercalating agents [230, 235, 237,243-246]. It has recently been postulated that mammalian DNA topoisomerase II may be a common target of these antitumour compounds [247],... 

A variety of alkaloids bind to or intercalate with DNA or DNA/RNA processing enzymes and affect either transcription or replication (quinine, harmane alkaloids, melinone, berberine), act at the level of DNA and RNA polymerases (vinblastine, coralyne, avicine), inhibit protein synthesis (sparteine, tubulosine, vincrastine, lupanine), attack electron chains (pseudane, capsaicin, solenopsine), disrupt biomembranes and transport processes (berbamine, ellipticine, tetrandrine), and inhibit ion channels and pumps (nitidine, caffeine, saxitoxin). In addition, these natural products attack a variety of other systems that can result in serious biochemical destabilization... 

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