Ellipticine conjugates

An obvious means by which to increase the affinity of a molecule for DNA is to link the molecule to a short segment of nucleic acid. Such a plan has been pursued by Paoletti and co-workers (129,130). To prepare the tetrathymidylate-ellipticine conjugate 348, these workers synthesized the appropriate ox-azolopyridocarbazole carboxylic acid, as described previously (i.e., 267), and coupled it to the appropriate tetradeoxynucleotide. A second method of linking ellipticine to a nucleic acid involves condensation of the aldehyde moiety of 3 -apurinic octathymidylate with 9-aminoellipticine, followed by reduction of the imine with sodium cyanoborohydride (130). This reaction is depicted in a different context in Scheme 66 (see Section VIII). 

Milder, S. J., Ding, L, Etemad-Moghadam, G., Meunier, B., Paillous, N. (1990). Dramatic enhancement of the photoactivity of zinc porphyrin-ellipticine conjugates by DNA, J. Chem. Soc., Chem. Comm., p. 1131. 

Searle F, Gac-Breton S, Keane R, Dimitrijevic S, Brocchini S, Duncan R. Al-(2-hydroxypropyl)methacrylamide copolymer-6-(3-aminopropyl)-ellipticine conjugates synthesis characterisation preliminary in vitro and in vivo studies. Bioconj Chem 2001 12 711-718. 

F. Searle, S. Gac-Breton, R. Keane, S. Dimitrijevic, S. Brocchini, E. A. Sausville and R. Dimcan, N-(2-hydroxypropyl)metha-crylamide copolymer-6-(3-aminopropyl)-ellipticine conjugates. Synthesis, in vitro, and preliminary in vivo evaluation, Bioconjugate Chem., 12, 711-718 (2001). 

Intramolecular Mannich type reaction of the conjugated iminium salt 426 should lead to ellipticine (228) via an intermediate 427. Alternatively, the conjugated iminium salt 426 could hydrolyze to afford the 2-vinylsubstituted indole 428, which, on cyclization through an intermediate 429, would lead to guatambuine (233). This alkaloid, on demethylation and dehydrogenation, should afford olivacine (238a) (375) (Scheme 3.11). 

Scheme 55. Rigaudy et al. synthesis of ellipticine-enkephalin conjugate 341 (124).

The metabolism of 6-methylelliptinium (420) in rats (bile and urine) gives rise to the O-sulfate and O-glucuronide conjugates, but no demethylation of the N-6 methyl group (260) (Scheme 68). Likewise, the HRP/H2O2 system gives rise to the ort/io-quinone 421 and the oxazolopyridocarbazole 422, when alanine is present, but not to N-6 demethylation (261). The metabolism of olivacine (4) in rats and microsomes is faster than that of ellipticine, and leads to hydroxylation at the C-7 and C-9 positions (as conjugates) (55). 

Carbon-carbon bond formation by intramolecular cyclization of conjugated iminium ions is also possible, as illustrated by the transformation of amine oxide (36) to (37), a key intermediate in the synthesis of the pyridocarbazole alkaloid ellipticine (38 Scheme 7). ... 

Another chromophore, namely oxazolopyridocarbazole (OPC) (Figure 49d), related to the ellipticine series, is a strong, reversible intercalator with no major preference for any DNA sequence [129]. This, upon conjugation at the 5 -ends of TFOs, showed a higher stabilization of both Y RY and R-RY motifs, with the target being the HIV-1 U3 (human immunodeficiency virus type 1, gene... 

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