Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ketone doai
Reexamination Certificate
1998-12-16
2001-01-30
Travers, Russell (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ketone doai
C514S675000, C514S763000
Reexamination Certificate
active
06180681
ABSTRACT:
The present application is the national stage filing of and claims priority to International Application No. PCT/EP97/03185 filed Jun. 18, 1997 and Italian Application Ser. No. RM96A000430.
FIELD OF THE INVENTION
The present invention relates to 2-cyclopenten-1-one as an inducer of HSP70. In particular the invention relates to 2-cyclopenten-1-one and its pharmaceutically acceptable derivatives as inducers of HSP70 with antiviral activity.
BACKGROUND
As known, prostaglandins (PGs) are a class of naturally occurring cyclic 20-carbon fatty acids that are syntetized by various kinds of eukaryotic cells in response to external stimuli and play an important role in the physiological response to cell proliferation and differentiation. Since their discovery, they were shown to function as microenvironmental hormones and intracellular signal mediators and to control a large number of physiological and pathological processes, including cell proliferation and differentiation, immune response, inflammation, cytoprotection and the febrile response.
In particular, the type A and J PGs, which posses a cyclopentenonic structure, are strong inhibitors of virus replication (“Stress Proteins: Induction and Function” Schlesinger MJ, Garaci E., Santoro M. G. ed.s, Springer-Verlag, Heidelberg-Berlin, 27-44, 1990).
Stress proteins, also called Heat Shock Proteins (HSPs) (Proc. Natl. Acad. Sci. USA 86, 8407-8411, 1989) are a family of polypeptides synthetized by eukaryotic and prokariotyc cells in response to a heat shock or other kinds of environmental stress. The HSPs are encoded by a cellular subgroup of genes, identified as stress genes.
The cytoprotective role of the stress proteins has been described in numerous pathologies, among which ischemia (M.S. Marber et al., J. Clin. Invest. 93, March 1994, 1087-1094).
The authors have shown that some cyclopentenonic prostaglandins (PGA e PGJ) induce the synthesis of heat shock protein HSP70 in human cells through the activation of the heat shock transcription factor HSF (C. Amici et al., Proc. Natl. Sci. USA vol. 89, 6227-6231, 7 1992) It is also known that, in the pathogenesis of the viral infection, the stress proteins HSP interfere at various levels with the virus replication, and in particular a cytoprotective role of the HSP70 protein has been characterized in some experimental models of acute infection (M. G. Santoro, Experientia, Vol. 50, 1039-1047, 1994). The possibility to selectively activate some “heat shock” (hs) genes and to manipulate the cellular stress response to the host advantage is suggested by recent studies which demonstrate that prostaglandins are able to induce HSP70 synthesis in a non-stress situation and to protect the host cell during virus infection (M. G. Santoro, Experientia, Vol. 50, 1039-1047, 1994).
The authors have recently shown that the induction of HSP70 synthesis is one of the molecular mechanisms used by cyclopentenonic prostaglandins to cause a selective and reversible block of the protein synthesis in infection models with single strand negatively polarized RNA viruses (C. Amici et al., J. Virol. 68, 6890-6899, 1994).
In Biol. Pharm. Bull. 18(12)1784-1786 (1995) it is described the cytoprotective activity of the isolated functional groups of several sesquiterpene lactones. Among others 2-cyclopenten-1-one is tested to verify its capability to prevent the formation of gastric lesions induced by various necrotizing agents such as EtOH.
In Antiviral Research 26 (1995) 83-96 it is described the antiviral activity of prostaglandins and a mechanism of action is hypothesized correlating inhibition of VSV RNA polymerase in vitro by prostaglandins with different structures to inhibition of VSV replication in infected cells.
SUMMARY OF THE INVENTION
It has now been found that 2-cyclopenten-1-one, the structure constituting the center nucleus of PGA and PGJ, turns out to have an activity which is analogous to PGA and PGJ, that is, it is able to induce the synthesis of HSP70 protein, even though it does not contain the corresponding acid function and aliphatic lateral chains. Therefore it seems that the lateral chains, which are present in the PGA and PGJ, 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 therefore an object of the present invention the 2-cyclopenten-1-one as inducer of HSP70.
Another object of the invention is the 2-cyclopenten-1-one as inducer of HSP70 with antiviral activity. Another object of the invention are the 2-cyclopenten-1-one pharmaceutically acceptable derivatives as inducers of HSP70 with antiviral activity.
Further objects of the invention are pharmaceutic compositions comprising 2-cyclopenten-1-one and/or its pharmaceutically acceptable derivatives to make medicaments with antiviral activity. In particular antiviral activity against single strand negatively polarized RNA viruses and DNA viruses. Further objects of the invention will be evident from the following detailed description of the invention.
REFERENCES:
Amici et al, J of Virology, vol. 68 (11) pp 6890-99, 1994.
Fukushima et al 98 CA 47110, 1982.
Rossi et al 126 CA: 112777, 1996.
Hungale et al 117CA: 27063, 1991.
Lee et al 89 CA 99740, 1978.
Halazy et al 118 CA 169497, 1992.
Biological & Pharmaceutical Bulletin, 1995, 18 (12): 1784-1786, “Gastric Cytoprotective Activity of 2-Cyclopenten-1-one and Related Compounds”, Alejandra O. Marla et al.
Antiviral Research, 1995, 26(1): 83-96; “Antiviral Effect of Cyclopentenone Prostaglandins on Vesicular Stomatitis Virus Replication”, Judy Parker et al.
Journal of Biological Chemistry, 1996, 271(50): 32192-32196; “2-Cyclopenten-1-one, a New Inducer of Heat Shock Protein 70 with Antiviral Activity”, Antonio Rossi et al.
Experientia, 1994, 50(11-12): 1039-1047; “Heat Shock Proteins and Virus Replication: hsp70s as mediators of the Antiviral Effects of Prostaglandins”, M. G. Santoro.
Proc. Nat'l., Acad. Sci. USA, vol. 89, pp. 6227-6231, Jul. 1992 Biochemistry.
J. Clin. Invest., The American Society for Clinical Investigation, Inc., vol. 93, Mar. 1994, pp. 1087-1094.
Proc. Nat'l. Acad. Sci. USA, vol. 86, pp. 8407-8471, Nov. 1989, Cell Biology.
Stress Proteins, Schlesinger, Santoto, Garaci (Eds.) (1990), 3, Induction of HSP70 by Prostaglandins.
Journal of Virology, Nov. 1994, pp. 6890-6899, 1994, American Society for Microbiology, vol. 68, No. 11.
Experientia 50, 1994, Birkahuser Verlag, CH-4010 Basel/Switzerland, pp. 1039-1047.
Amici Carla
Elia Giuliano
Garaci Enrico
Rossi Antonio
Santoro Maria Gabriella
Consiglio Nazionale Delle Ricerche
Hedman, Gibson & Costigan, P.C.
Travers Russell
LandOfFree
2-cyclopenten-1-one as an inducer of HSP70 does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 2-cyclopenten-1-one as an inducer of HSP70, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 2-cyclopenten-1-one as an inducer of HSP70 will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2532909