Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1993-06-22
2001-02-06
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S673000, C514S674000, C546S186000, C564S511000, C564S512000
Reexamination Certificate
active
06184232
ABSTRACT:
BACKGROUND OF THE INVENTION
Research leading to the completion of the invention was supported, in part, by Grant No. 2-U01-CA37606 awarded by the National Institutes of Health (NIH). The United States Government has certain rights in and to the invention claimed herein.
FIELD OF THE INVENTION
The present invention relates to analogs of biologically active, naturally occurring polyamines having a wide variety of therapeutic properties, as well as pharmaceutical compositions containing the analogs and their use in methods of therapeutic treatment.
DISCUSSION OF THE PRIOR ART
In recent years, a great deal of attention has been focussed on the polyamines, e.g., spermidine, norspermidine, homospermidine, 1,4-diaminobutane (putrescine) and spermine. These studies have been largely directed at the biological properties of the polyamines probably because of the role they play in proliferative processes. It was shown early on that the polyamine levels in dividing cells, e.g., cancer cells, are much higher than in resting cells. See Janne et al,
A. Biochim. Biophys. Acta., Vol.
473, page 241 (1978); Fillingame et al,
Proc. Natl. Acad. Sci. U.S.A., Vol.
72, page 4042 (1975); Metcalf et al,
J. Am. Chem. Soc., Vol.
100, page 2551 (1978); Flink et al,
Nature
(London), Vol. 253, page 62 (1975); and Pegg et al, Polyamine Metabolism and Function,
Am. J. Cell. Physiol
., Vol. 243, pages 212-221 (1982).
Several lines of evidence indicate that polyamines, particularly spermidine, are required for cell proliferation: (i) they are found in greater amounts in growing than in non-growing tissues; (ii) prokaryotic and eukaryotic mutants deficient in polyamine biosynthesis are auxotrophic for polyamines; and (iii) inhibitors specific for polyamine biosynthesis also inhibit cell growth. Despite this evidence, the precise biological role of polyamines in cell proliferation is uncertain. It has been suggested that polyamines, by virtue of their charged nature under physiological conditions and their conformational flexibility, might serve to stabilize macromolecules such as nucleic acids by anion neutralization. See Dkystra et al.
Science
, Vol. 149, page 48 (1965); Russell et al,
Polyamines as Biochemical Markers of Normal and Malignant Growth
(Raven, N.Y., 1978); Hirschfield et al,
J. Bacteriol
., Vol. 101, page 725 (1970); Hafner et al,
J. Biol. Chem
., Vol. 254, page 12419 (1979); Cohn et al,
J. Bacteriol
., Vol. 134, page 208 (1978); Pohjatipelto et al,
Nature
(London), Vol. 293, page 475 (1981); Mamont et al,
Biochem. Biophys. Res. Commun.
., Vol. 81, page 58 (1978); Bloomfield et al,
Polyamines in Biology and Medicine
(D. R. Morris and L. J. Morton, eds., Dekker, N.Y., 1981), pages 183-205; Gosule et al,
Nature
, Vol. 259, page 333 (1976); Gabbay et al,
Ann. N.Y. Acad. Sci
., Vol. 171, page 810 (1970); Suwalsky et al,
J. Mol. Biol
., Vol. 42, page 363 (1969); and Liquori et al,
J. Mol. Biol
., Vol. 24, page 113 (1968).
However, regardless of the reason for increased polyamine levels, the phenomenon can be and has been exploited in chemotherapy. See Sjoerdsma et al,
Butterworths Int. Med. Rev.: Clin. Pharmacol. Thera
., Vol. 35, page 287 (1984);
Israel et al,
J. Med. Chem
., Vol. 16, page 1 (1973); Morris et al,
Polyamines in Biology and Medicine
, Dekker, New York, page 223 (1981); and Wang et al,
Biochem. Biophys. Res. Commun.
., Vol. 94, page 85 (1980).
Because of the role the natural polyamines play in proliferation, a great deal of effort has been invested in the development of polyamine analogs as anti-proliferatives [
Cancer Res
., Vol. 49, “The role of methylene backbone in the anti-proliferative activity of polyamine analogues on L1210 cells,” Bergeron et al, pages 2959-2964 (1989);
J. Med. Chem
., Vol. 31, “Synthetic polyamine analogues as antineoplastics,” Bergeron et al, pages 1183-1190 (1988); Polyamines in
Biochemical and Clinical Research
, “Regulation of polyamine biosynthetic activity by spermidine and spermine—a novel antiproliferative strategy,” Porter et al, pages 677-690 (1988);
Cancer Res
., Vol. 49, “Major increases in spermidine/spermine-N
1
-acetyl transferase activity by spermine analogues and their relationship to polyamine depletion and growth inhibition in L1210 cells,” Basu et al, pages 6226-6231 (1989);
Biochem. J
., Vol. 267, “Induction of spermidine/spermine N
1
-acetyltransferase activity in Chinese-hamster ovary cells by N
1
,N
11
-bis(ethyl)norspermine and related compounds,” Pegg et al, pages 331-338 (1990);
Biochem. J
., Vol. 268, “Combined regulation of ornithine and S-adenosylmethionine decarboxylases by spermine and the spermine analogue N
1
,N
12
-bis-(ethyl)spermine,” Porter et al, pages 207-212 (1990);
Cancer Res
., Vol. 50, “Effect of N
1
,N
14
-bis(ethyl)-homospermine on the growth of U-87 MG and SF-126 on human brain tumor cells,” Basu et al, pages 3137-3140 (1990); and
Biochem. Biophys. Res. Commun
., Vol. 152, “The effect of structural changes in a polyamine backbone on its DNA binding properties,” Stewart, pages 1441-1446 (1988)]. These efforts have included the design of new synthetic methods [
J. Org. Chem
., Vol. 45, “Synthesis of N
4
-acylated N
1
,N
8
-bis(acyl)spermidines: An approach to the synthesis of siderophores,” Bergeron et al, pages 1589-1592 (1980);
Synthesis
, “Reagents for the selective acylation of spermidine, homospermidine and bis-[3-amino-propyl]amine,” Bergeron et al, pages 732-733 (1981);
Synthesis
, “Reagents for the selective secondary functionalization of linear triamines,” Bergeron et al, pages 689-692 (1982);
Synthesis
, “Amines and polyamines from nitrites,” Bergeron et al, pages 782-785 (1984);
J. Org. Chem
., Vol. 49, “Reagents for the stepwise functionalization of spermidine, homospermidine and bis-[3-aminopropyl]amine,” Bergeron et al, page 2997 (1984);
Accts. Chem. Res
., Vol. 19, “Methods for the selective modification of spermidine and its homologues,” Bergeron, pages 105-113 (1986);
Bioorg. Chem
., Vol. 14, “Hexahydropyrimidines as masked spermidine vectors in drug delivery,” Bergeron et al, pages 345-355 (1986);
J. Org. Chem
., Vol. 53, “Reagents for the stepwise functionalization of spermine,” Bergeron et al, pages 3108-3111 (1988);
J. Org. Chem
., Vol. 52, “Total synthesis of (±)-15-Deoxyspergualin,” Bergeron et al, pages 1700-1703 (1987);
J. Org. Chem
., Vol. 56, “The total synthesis of Alcaligin,” Bergeron et al, pages 586-593 (1991); and
CRC Handbook on Microbial Iron Chelates
, “Synthesis of catecholamide and hydroxamate siderophores,” Bergeron et al, pages 271-307 (1991)] for the production of these analogs, as well as extensive biochemical studies focussed on the mechanism by which these compounds act [
Cancer Res
., Vol. 46, “A comparison and characterization of growth inhibition by &agr;-Difluoromethylornithine (DFMO), and inhibitor of ornithine decarboxylase and N
1
,N
8
-bis(ethyl)spermidine (BES), an apparent regulator of the enzyme,” Porter et al, pages 6279-6285 (1986);
Cancer Res
., Vol. 47, “Relative abilities of bis(ethyl) derivatives of putrescine, spermidine and spermine to regulate polyamine biosynthesis and inhibit L1210 leukemia cell growth,” Porter et al, pages 2821-2825 (1987);
Cancer Res
., Vol. 49, “Correlation between the effects of polyamine analogues on DNA conformation and cell growth,” Basu et al, pages 5591-5597 (1989);
Cancer Res
., Vol. 49, “Differential response to treatment with the bis(ethyl)polyamine analogues between human small cell lung carcinoma and undifferentiated large cell lung carcinoma in culture,” Casero et al, pages 639-643 (1988);
Mol. Pharm
., Vol. 39, “Selective cellular depletion of mitochondrial DNA by the polyamine analog, N
1
,N
12
-bis(ethyl)spermine, and its relationship to polyamine structure and function,” Vertino et al, pages 487-494 (1991);
Biochem. and Biophys. Res. Comm
., Vol. 157, “Modulation of polyamine biosynthesis and transport by oncogene transfection,” Chang et al, pages 264-270 (1988); and
Biopolymers
, Vol. 26, “Structural determinants
Clarke Dennis P.
Lambkin Deborah C.
Miles & Stockbride
University of Florida
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