Organic compounds -- part of the class 532-570 series – Organic compounds – Rare earth containing
Patent
1997-07-28
1999-07-20
Dees, Jose' G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Rare earth containing
534 10, 534 16, 424 165, 424 169, 424 9363, 424 9362, 546256, 546257, 558260, C07F 500, A61K 5100, C07D21322, C07C 6996
Patent
active
059257440
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to cyclic terpyridine-lanthanide complexes having 8 nitrogen atoms and 10 carbon atoms in the macrocycle and containing a functional group in the terpyridine moiety, to a process for the preparation thereof by condensation of terpyridine hydrazines with pyridine-2,6-dialdehydes or -ketones, to associates of those complexes with oligonucleotides and to methods for the sequence-specific cleavage of RNA using those associates.
The hydrolytic cleavage of RNA under the catalytic action of metal ions has already been known for a long time. The cleavage takes place basically in unpaired regions of the RNA known as "loops". W. J. Krzyzosiak et al., Biochemistry 27:5771-5777 (1988) propose the use of lead diacetate for that purpose. G. J. Murakawa et al., Nucleic Acid Research 17:5361-5375 (1989) describe the use of copper complexes of 1,10-phenanthroline. J. Ciesiolka et al., Eur. J. Biochem. 182:445-450 (1989) disclose europium trichloride for the same purpose for cleaving tRNA.sup.Phe. In J. Am. Chem. Soc., Volume 112, pages 2839 to 2841 (1990), C. S. Chow et al. use for the same RNA ruthenium and rhodium complexes with phenanthroline ligands. In Biochemistry, Volume 29, pages 2515 to 2523, L. S. Behlen et. al. mention tRNA.sup.Phe mutants with lead diacetate. In addition, N. Hayashi et al. describe in Inorg. Chem., Volume 32, pages 5899 to 5900 (1993) that lanthanide metal complexes are also suitable for the cleavage of tRNA.
It has been described by D. Magda et al. in J. Am. Chem. Soc., Volume 116, 7439 to 7440 (1994) that conjugates of europium(III)-texaphyrine and oligonucleotides with DNA building blocks are capable of cleaving a target RNA, a cleavage of only about 30% being observed in the region of the texaphyrine complex in the RNA/oligonucleotide complex. A further disadvantage of those texaphyrine complexes is that in addition hydroxypropyl must be bonded in the ligand so as to ensure sufficient solubility. Furthermore, the imine groups of the ligand are susceptible to hydrolysis, so that the effectiveness in an aqueous environment declines relatively quickly; that is to say the residence time is too low for therapeutic applications. In addition, hydrolysis of the ligand liberates the metal and this can bring about serious toxicity problems and nonspecific cleavage of the RNA. They are also weak Lewis acids because a charge on the Eu cation is neutralised by a ligand and therefore a complex having two charges is present. In addition, the described complexes can be obtained only by procedures that are expensive in terms of synthesis.
It is known that in cells the formation of physiologically harmful polypeptides is brought about by the gene-controlled formation of mRNA. In order to combat or prevent diseases it is therefore desirable to have agents that impede the action of the mRNA. In particular, the mRNA should be destroyed by irreversible cleavage at a defined site and the information content should therefore be lost. It is also desirable by a sequence-specific cleavage of RNA chains to provide fragments that can be used for the more rapid synthesis of oligonucleotides in the "antisense field" for diagnostic purposes (biosensors) or for the treatment of diseases by affecting metabolic processes in the cell.
It has now been found that oligonucleotides the sequence of which is complementary to a target RNA and to which a terpyridine-lanthanide complex is bonded are highly effective and it is possible to achieve sequence-specific cleavages in a target RNA.
The present invention relates to compounds of formula I ##STR1## wherein R.sub.1 is H or a substituent and R.sub.5 is a monovalent functional group or the functional group being bonded to the pyridine ring directly or via a group Z and the group Z being a radical selected from the group consisting of C.sub.1 -C.sub.20 alkylene, C.sub.2 -C.sub.12 alkenylene, C.sub.2 -C.sub.12 alkynylene, C.sub.5 -C.sub.8 cycloalkylene, C.sub.6 -C.sub.12 arylene and C.sub.7 -C.sub.12 aralkylene, which radical is uninterrupted or interrupt
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Hall Jonathan
Haner Robert
Husken Dieter
Moser Heinz
Pieles Uwe
Dees Jos,e G.
Hartley Michael G.
McCormack Myra H.
Novartis Finance Corporation
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