Ellipticine

Several of the naturally occurring indoles also have clinical importance. The dimeric vinca alkaloid vincristine and closely related compounds were among the first of the anti-mitotic class of chemotherapeutic agents for cancer[14]. The mitomycins[15] and derivatives of ellipticine[16] are other examples of compounds having anti-tumour activity. Reserpine, while not now a major drug, was one of the first compounds to show beneficial effects in treatment of mental disorders[17]... 

Kondrat eva pyridine synthesis. This methodology to pyridine rings continues to be applied in total synthesis. An approach to the antitumor compound ellipticine 34 ° makes use of a Diels-Alder reaction of acrylonitrile and oxazole 32 to form pyridiyl derivative 33. Addition of methyllithium and hydrolysis transforms 33 into 34. 

Photolysis of derivatives of compounds 4 and 5 has been further studied as a route to azacarbazoles. The example 264 shows normal behavior as well as elimination of an alkoxy group, and the report includes examples of derivatives of compound 5 as well as references to earlier work (93JCS(P1)1261). Production of an intermediate for an anti-tumour ellipticine analogue is shown by example 265 (84MI1), and incorporation of acetonitrile solvent by example 266 (91TL323). 

C19H23IN8012P)2(Ci7Hi5N2)2 (CH j 20 HsO Ellipticine 5-iodocyt-idylyl-(3 — 5,)-guanosine, methanolate, eicosahydrate (EICGUA)180... 

The range of these aza-ellipticine analogues, although by now extensive, is still insufficient to permit a systematic evaluation of their structure-activity relationships. It is established, however, that the three methylated compounds 11-13 are all less active than ellipticine toward a range of tumor cell lines <2004AP434>. 

Several complexes that involve intercalation of an acridine in a portion of a nucleic acid have been studied by X-ray crystallographic techniques. These include complexes of dinucleoside phosphates with ethidium bromide, 9-aminoacridine, acridine orange, proflavine and ellipticine (65-69). A representation of the geometry of an intercalated proflavine molecule is illustrated in Figure 6 (b) this is a view of the crystal structure of proflavine intercalated in a dinucleoside phosphate, cytidylyl- -S ) guano-sine (CpG) (70, TV). For comparison an example of the situation before such intercalation is also illustrated in Figure 6 (a) by three adjacent base pairs found in the crystal structure of a polynucleotide (72, 73). In this latter structure the vertical distance (parallel to the helix axis) between the bases is approximately... 

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... 

Microbial transformations of ellipticine (15) and 9-methoxyellipticine (16) were reported by Chien and Rosazza (143, 144). Of 211 cultures screened for their abilities to transform 9-methoxyellipticine (16), several, including Botrytis alii (NRRL 2502), Cunninghamella echinulata (NRRL 1386), C. echinulata (NRRL 3655), and Penicillium brevi-compactum (ATCC 10418), achieved O-demethylation of 16 in good yield (Scheme 9). P. brevi-compactum was used to prepare 9-hydroxyellipticine (22) from the methoxylated precursor, and 150 mg of product was obtained from 400 mg of starting material (37% yield). The structure of the metabolite was confirmed by direct comparison with authentic 9-hydroxyellipticine (143). O-Demethylation is a common microbial metabolic transformation with 16 and many other alkaloids (143). Meunier et al. have also demonstrated that peroxidases catalyze the O-demethylation reaction with 9-methoxyellipticine (145). 

Reinhold and Bruni studied the metabolism of 7,9-dideuterioellipticine (17) in rats and found that deuterium originally at position 9 was completely lost during the mammalian hydroxylation process (147). Proton and carbon-13 NMR and mass spectral analyses confirmed the complete elimination of deuterium at position 9, thus ruling out the occurrence of an NIH shift mechanism in the hydroxylation of ellipticine. An oxygen-insertion process was rationalized to account for the mechanism of aromatic hydroxylation in rats since this would not be expected to display the NIH shift but should demonstrate an isotope effect. It was... 

Scheme 9. Metabolism of ellipticine by Aspergillus alliaceus NRRL 315. 

Oxidations of 9-Hydroxyellipticine. 9-Hydroxyellipticine is the major metabolite of ellipticine formed by mammalian cytochrome P-450 hydroxylation (147,153). The reaction is a good example of a bioactivation process because 9-hydroxyellipticine is many times more active as an antineoplastic agent than is ellipticine itself (154). Auclair, Meunier, Paoletti, and co-workers have extensively studied further oxidations of 9-hydroxyellipticine and its derivatives (155-158). 

Ellipticine, 9-methoxy- O-Demethylation Cunninghamella (2), Penicillium, Botrytis. 143... 

O N +, HSO4- Inhibitor of reverse transcriptase (Ellipticin analogue) 1996BML2831... 

Ellagic acid, antioxidant useful in cosmetics, 7 830t Ellipsometry, 24 72 for MOCVD, 22 155 Ellipticine, 2 98... 

The major class of topoisomerase I inhibitors comprise of the camptothecins, while topoisomerase II inhibitors fall into several classes - anthracyclines (e.g. doxorubicin), anthracenediones (mitoxantrone), anthrapyrazoles (bianthrazole), actinomycins (actinomycin D), acridines (m-AMSA), ellipticines (9-hydroxy-ellipticine) and epidophyllotoxins (Etoposide (VP-16) and VM-26). The chemical... 

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