Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Patent
1999-05-25
2000-02-22
Krass, Frederick
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
514642, 514666, 514671, 514676, 514702, 514704, A61K 3113
Patent
active
060281146
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to the use of aminothiol ester derivatives in the preparation of a pharmaceutical composition for increasing the inhibition of apoptosis due to the presence of the bc1.sub.2 gene in transformed cells.
There are two types of mechanism involved in cell death. The first, of a conventional type, is called necrosis. Morphologically, necrosis is characterized by swelling of the mitochondria and of the cytoplasma and by nuclear impairment, followed by the destruction of the cell and its autolysis, this being accompanied by an inflammation phenomenon. Necrosis occurs in a passive and incidental manner. Tissue necrosis is generally due to a physical trauma of cells or a chemical poison, for example.
The other form of cell death is called apoptosis [Kerr, J. F. R. and Wyllie, A. H., Br. J. Cancer, 265, 239 (1972)]; however, unlike necrosis, apoptosis does not cause an inflammation phenomenon. It has been described that apoptosis can occur under different physiological conditions. It is a highly selective form of cellular suicide which is characterized by easily observable morphological and biochemical phenomena. Thus, condensation of chromatin associated or otherwise with an endonuclease activity, the formation of apoptotic bodies and fragmentation of deoxyribonucleic acid (DNA) by the activation of endonucleases into DNA fragments of 180-200 base pairs (these fragments can be observed by agarose gel electrophoresis), have been observed in particular.
Apoptosis may be considered as a programmed cell death involved in tissue development, differentiation and renewal. It is also considered that the differentiation, growth and maturation of cells are closely linked to apoptosis and that substances capable of playing a role in the differentiation, growth and maturation of cells are also linked to the phenomenon of apoptosis.
There has already been described in patent application WO 96-20701 filed by the applicant a compound chosen from methional, malondialdehyde and any factor increasing the intracellular level of methional or of malondialdehyde for use as medicament, this medicament being more particularly intended to increase the phenomenon of programmed cell death (apoptosis) and thus making it possible to treat numerous diseases, more particularly diseases linked to cell hyperproliferation, such as in the case of cancer, autoimmune diseases or allergies. However, the addition of exogenous methional to cells in culture inhibits the growth of transformed cells just as much as that of normal cells.
In order to try to increase the level of endogenous methional in transformed cells, but not in normal cells, its metabolism was studied.
Thus, in the metabolism of methional, it is known that 4-methylthio-2-oxobutanoic acid can be metabolized in vivo by the branched chain oxoacid-dehydrogenase complex present in the mitochondria of cells of the liver, heart and skeletal muscle via methional to give methylthiopropionylCoA [cf. Wu, G. & Yeaman, S. J. (1989) Biochem. J. 257, 281-284; Haussinger, D., Stehle, T. & Gerok, W. (1985) J. Biol. Chem. 366, 527-536; Jones, S. M. A. & Yeaman, S. J. (1986) Biochem. J. 237, 621-623]. It has also been described that methylthio-2-oxobutanoic acid can be metabolized in vivo by transamination into methionine [cf. Ogier, G., Chantepie, J., Deshayes, C., Chantegrel, B., Charlot, C., Doutheau, A. & Quash, G. (1993) Biochem. Pharmacol. 45, 1631-1644]. Methional can also possibly be reduced or oxidized respectively into methionol by an aldehyde reductase or into methylthiopropionic acid by an aldehyde dehydrogenase. Finally, methional, in combination with the HO* radical, can give malondialdehyde and methane thiol by a .beta.-hydroxylation reaction [Quash, G., Roch, A. M., Chantepie, J., Michal, Y., Fournet, G., and Dumontet, C. (1995) Biochem. J. 305, 1017-1025].
In the text which follows, the following abbreviations may be used: complex whose cofactor is thiamine pyrophosphate (TPP); complex whose cofactor is thioctic acid (TA);
It has also been described that inhibit
REFERENCES:
patent: 5744499 (1998-04-01), Quash et al.
Galderma Research & Development S.N.C.
Krass Frederick
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