2-Cyclopenten-1-one as inhibitors of the NF-KB factor

Details 2-Cyclopenten-1-one as inhibitors of the NF-KB factor 2-Cyclopenten-1-one as inhibitors of the NF-KB factor

1999-06-10

2002-05-21

Padmanabhan, Sreeni (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Oxygen containing

C514S690000, C514S886000

Reexamination Certificate

active

06392100

ABSTRACT:

FIELD OF INVENTION
The present invention relates to 2-cyclopenten-1-one and its derivatives as inhibitors of the transcription factor Nuclear Factor-kappaB (NF-&kgr;B). In particular the invention relates to 2-cyclopenten-1-one and its derivatives comprising the cyclopentenone nucleus as inhibitors of the NF-&kgr;B factor with anti-inflammatory, antiproliferative, immuno-suppressive, cytoprotective and antiviral activity.
BACKGROUND OF THE INVENTION
NF-&kgr;B (Nuclear Factor-&kgr;B) is an eucariotic transcription factor of the rel family, which is normally located in the cytoplasm in an inactive complex, whose predominant form is a heterodimer composed of p50 and p65 subunits, bound to inhibitory proteins of the I&kgr;B family, usually I&kgr;B-alpha (D. Thanos and T. Maniatis, and Cell 80:529-532, 1995).
NF-&kgr;B is activated in response to different stimuli, among which phorbol esters, inflammatory cytokines, UV radiation, bacterial and viral infections. Stimulation triggers the release of NF-&kgr;B from I&kgr;B in consequence of the phosphorylation and the following degradation of the I&kgr;B-alpha protein (P. A. Baeuerle and T. Henkel, Annu. Rev.
Immunol. 12: 141-179, 1994). Once it is activated, NF-&kgr;B translocates to the nucleus where it binds to DNA at specific &kgr;B-sites and induces the transcription of a variety of genes encoding proteins involved in controlling the immune and inflammatory responses, among which a variety of interleukins, the tumor necrosis factor alpha, the NO synthase and the cyclo-oxigenase 2 (S. Grimm and P. A. Baeuerle, Biochem. J. 290: 297-308, 1993). Accordingly, NF-&kgr;B is considered an early mediator of the immune and inflammatory responses and it is involved in the control of cell proliferation and in the pathogenesis of various human diseases, among which rheumatoid arthritis (H. Beker et al., Clin. Exp. Immunol. 99: 325, 1995), ischemia (A. Salminen et al. Biochem. Biophys. Res. Comm. 212: 939, 1995), arteriosclerosis (A. S. Baldwin. Annals Rev. Immunol. 14: 649, 1996), as well as in the pathogenesis of the acquired immunodeficiency syndrome (AIDS), due to the enhanced human immunodeficiency virus (HIV-1) transcription in the presence of activated NF-&kgr;B. The increase of HIV-1 virus RNAs transcription by NF-&kgr;B is caused by the presence of &kgr;B-sites in the (LTR) (Long Terminal Repeats) sequences of the virus genome (M. J. Lenardo and D. Baltimore, Cell 58: 227-229, 1989).
It is also known that prostaglandins (PGs) are a class of naturally occurring cyclic 20-carbon fatty acids that are synthetized by various types of eukaryotic cells in response to external stimuli and play an important role in a variety of physiological responses. Since their discovery, PGs were shown to act as microenvironmental hormones and intracellular signal mediators and to control a large number of physiological and pathological processes, including cell proliferation and differentiation, the immune response, inflammation, cytoprotection and the febrile response. In particular, type A and J PGs, which possess a cyclopentenonic structure, are strong inhibitors of virus replication (“Stress Proteins: Induction and Function” Schlesinger M J, Garaci E., Santoro M. G. ed.s, Springer-Verlag, Heidelberg-Berlin, 27-44, 1990). Particularly, it has been recently demonstrated that cyclopentenonic prostaglandins inhibit HIV-1 virus replication, by blocking the viral RNAs transcription (C. Rozera et al. J. Clin. Invest. 97: 1795, 1996).
It is also known that the Heat Shock Proteins (HSPs), also called stress proteins (Proc. Natl. Acad. Sci. USA 86, 8407-8411, 1989), are a family of polypeptides synthetized by eukaryotic and prokaryotic cells in response to heat shock or other kinds of environmental stresses. The HSPs are encoded by a cellular subgroup of genes, identified as stress genes.
The authors have shown that the cyclopentenone prostaglandin PGA inhibits the activation of NF-&kgr;B in human cells by inhibiting the phosphorylation and degradation of the inhibitory I&kgr;B-alpha protein (A. Rossi, G. Elia and M. G. Santoro, Cold Spring Harbour, N.Y. 1-5 May, 1996, Abstract p. 255).
The authors have also recently shown that inhibition of NF-&kgr;B activation is one of the molecular mechanisms used by cyclopentenonic prostaglandins to cause a selective and reversible block of HIV-1 virus RNAs transcription.
SUMMARY OF THE INVENTION
It has now been found that 2-cyclopenten-1-one, the structure constituting the center nucleus of PGA, possesses an activity which is analogous to PGA, that is, it is able to inhibit NF-&kgr;B activation, even though it does not contain the corresponding acid function and aliphatic lateral chains. Therefore it is found that the lateral chains, which are present in the PGA with their substituents and double bonds, in particular the acid function, which implies the fatty acid nature of prostaglandins, can be eliminated without substantially modifying the herein above described specific activity. It is also found that the alpha, &bgr;-unsatured carbonyl group in the cyclopentenone ring is the key structure necessary for NF-&kgr;B inhibition.
Furthermore it has been found that the inhibition of NF-&kgr;B by the cyclopentenone group is related to the ability to activate the HSF transcription factor (Heat Shock Transcription Factor), which is responsible for the synthesis of HSPs (Heat Shock Proteins).
In view of the fact that NF-&kgr;B inhibition is associated with HSF activation, it is evident that molecules containing the cyclopentenone nucleus, which is active in inhibiting NF-&kgr;B, will be inducers of the HSF factor and therefore they will be inducers of heat shock proteins. It is therefore an object of the present invention the 2-cyclopenten-1-one, and its substituted derivatives comprising the cyclopentenone nucleus, as inhibitors of NF-&kgr;B, the substituents being selected among the ones which do not affect the NF-&kgr;B inhibitory activity.
Another object of the present invention is the 2-cyclopenten-1-one and its pharmacologically acceptable derivatives as inhibitors of NF-&kgr;B.
Another object of the invention is the 2-cyclopenten-1-one and its derivatives as inhibitors of NF-&kgr;B with anti-inflammatory, anti-proliferative, immuno-suppressive, cytoprotective and antiviral activity.
A further object of the invention are pharmaceutical compositions comprising 2-cyclopenten-1-one and/or its pharmaceutically acceptable derivatives to make medicaments with anti-inflammatory, anti-proliferative, immuno-suppressive, cytoprotective and antiviral activity. In particular with antiviral activity against the HIV-1 virus and viruses whose transcription is controlled by NF-&kgr;B, including herpesviruses.


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Dimitris Thanos and Tom Maniatis, NF-

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