Elliptinium

C17H14N2O 51131-85-2) see Elliptinium acetate 3-hydroxyestra-l,3,5(10),6-tetraen-17-one (CijHtoOj 2208-72-0) see Estrone 17P-hydroxy-4-estrene... 

C,gH 6N20 10371-86-5) see Elliptinium acetate (liP)-ll-methoxyestra-4,9-diene-3,17-dione (C19H24O3 21391-55-9) see Moxestrol (17P)-3-methoxyestra-2,5(10)-dien-17-ol (C i)H2g02 1091-93-6) see Nandrolone 3-methoxyestra-l,3,5(10),16-tetraen-17-ol acetate (C21H26O3 6038-28-4) see Estriol (17P)-3-methoxyestra-l,3,5(10)-trien-17-ol (C19H26O2 1035-77-4) see Nandrolone... 

Samadi-Boboli, M., G. Favre, P. Canal, andG. Soula. 1993. Low density lipoprotein for cytotoxic drug targeting improved activity of elliptinium derivative against B16 melanoma in mEbeJ. Cancei68 319-326. 

CisH -IN20 58447-24-8) sec Elliptinium acetate embonic acid... 

Meunier and co-workers (709) also studied the oxidation of elliptinium (5) in the presence of aminocarboxylic acids with HRP/H2O2 as a preparative route to the novel oxazolopyridocarbazole acids 267. Photooxidation of 5 in the presence of leucine also gives the oxazopyridocarbazole adduct (770). Archer and colleagues (84) used this facile oxidation-amine trapping protocol to prepare ox-azole 268. 

The synthesis of N-2 trideuteriomethyl elliptinium (5) in 96% isotopic purity has been reported by Gouyette (137) for use in a study of the metabolism of 5 in rats. This compound was prepared in 90% yield by allowing 9-hydroxyellipticine (3) to react with CD3I in DMF at room temperature. A combination of liquid... 

Arteaga and co-workers (144) have utilized a human tumor cloning system to evaluate in vitro the effects of elliptinium (5) against 282 tumor lines, in order to determine which human tumors should be clinically treated with 5. The results indicated that phase II trials in patients with renal cell carcinoma, breast cancer, non small-cell lung cancer, and small-cell lung cancer should be pursued. 

In performing its role in the cleavage and rejoining of DNA strands (catenation, decatenation, relaxation, unknotting), topoisomerase II bonds to the 5 -phosphate on adjacent DNA strands four base pairs apart to form an enzyme-DNA complex. It is the interaction between this complex and certain drugs, such as ellipticine (1), that results in the stabilization of the complex and the formation of a cleavable complex which leads eventually to the cleavage of double-stranded DNA. Pommier et al. 157,158) have shown that low concentrations of elliptinium (5) (<10 xAf) produce DNA double-strand breaks in mammalian cells, but higher concentrations (>10 pAf) produce no such breaks and, in fact. 

The interaction of ellipticine derivatives with topoisomerase II enzymes in Plasmodium berghei (163), a parasite of mouse red blood cells, mouse lymphoma L5178Y cells (164), simian virus 40 CV-1 cells (165), Trypanosoma cruzi (166,167), and the human small-cell lung cancer cell line NCI N417 (168,169) has been studied. In the latter study, the highest in vitro activity in the topoisomerase II-DNA cleavage reaction and decatenation was observed for elliptinium (5) and datelliptium (384) (769). 

Potier and co-workers (and some members of the Meunier group) (777,778) have explored the chemistry of quinone imines 6 and 256 and oxygen nucleophiles including sugars. They found that 256 can be generated from elliptinium with Cu2Cl2/pyridine/air, as well as with HRP/H2O2. The structure of the product formed between 256 and methanol has been revised as 396 instead of... 

To rationalize the remarkable regioselectivity and stereoselectivity of these alkylation reactions, Potier and co-workers (777,775) proposed that a stacking interaction occurs between quinone imine 256 and the nucleic acid base prior to covalent bond formation. Moreover, the appropriate intermolecular NOE is observed to support this contention. The fact that these ribonucleotide adducts form so easily may suggest that ellipticine quinone imines could alkylate at the 3 end of transfer RNA or at similar sites on other RNA molecules to inhibit protein synthesis. Thus, RNA would seem to be a reasonable target for elliptinium and related ellipticines (775). 

It has been found by Dugue and Meunier (779) that the combination of Fe(IU)-EDTA-H202 in the presence of elliptinium (5) is capable of degrading deoxyguanosine apparently by generating hydroxyl radical (Scheme 64). The isolated products are guanine (398) and 8-hydroxydeoxyguanosine (399). Other nucleosides and nucleotides behave similarly, but Cu(II) is much less effective... 

Several studies have reported on ellipticine- or elliptinium-DNA interactions. The effects of elliptinium on chromatin in vitro or in the nuclei are an unfolding of the overall structure and a disorganization of the partial structure of the core, leading to an unwrapping of the DNA from the histone core 181). The kinetics and thermodynamics of ellipticine and ellipticinium (protonated ellipticine) binding to calf thymus DNA have been carefully investigated 182). It was... 

The effect of ellipticine derivatives on membranes and model membranes continues to be of interest to Sautereau and co-workers (184-186), who included 3ip-NMR techniques in their study (185). The ellipticine derivatives, such as 5, are deeply embedded in the acyl chain region of cardiolipin-containing model membranes. Sautereau et al. (186) studied the effects of elliptinium (5) on Streptococcus pneumoniae and concluded that the toxicity of 5 is related to its intracellular concentration. 

Ellipticine and several derivatives were able to displace 7,12-dimethyl-benz[a]anthracene from binding to bovine and human serum albumin using the fluorescence-quenching technique (192,193). The site of binding of ellipticines appears to be on the hydrophobic regions of the enzyme. A fast kinetic experimental technique, namely, temperature-jump spectroscopy, has been developed in order to study the interaction of elliptinium, and other molecules, with biological macromolecules (194). 

Whereas the quatemarized ellipticines have no bactericidal activity, the nonintercalating 9-bromoellipticine is a strong bactericidal agent, which apparently causes the lysis of the bacteria. When malignant liver cell cultures are treated with elliptinium, the level of spermidine increases, apparently as a result of decreased nuclear-bound polyamines connected to RNA (796). Ellipticine inhibits poly(ADP-ribose) glycohydrolase activity (797) and decreases DDT-induced tremors in rats 198). In the latter study, it was postulated that ellipticine acts directly on nerve or muscle tissue. 

The binding characteristics of oxazolopyridocarbazoles toward bacterial DNA have been studied (275). It was found that these ellipticine derivatives invariably exhibit DNA intercalation but with no sequence specificity. The new clinical candidate datelliptium (384) shows increased lipophilicity but no difference in binding or intercalation to DNA compared to elliptinium (5) (750). This new... 

---