Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2000-05-31
2003-11-11
Kumar, Shailendra (Department: 1621)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C549S065000, C549S560000, C564S083000, C564S084000, C564S215000, C514S269000, C514S270000, C514S290000, C514S299000, C514S354000, C514S361000, C514S378000, C514S445000, C514S468000, C514S478000, C514S520000, C514S561000, C514S602000, C514S616000, C514S629000, C514S673000, C514S674000, C544S300000, C546S101000, C546S152000, C548S127000, C548S248000, C548S537000, C558S411000
Reexamination Certificate
active
06646149
ABSTRACT:
FIELD OF THE INVENTION
The invention in the field of chemistry and biochemistry relates to the synthesis and use of novel polyamine transport (PAT) inhibitor compounds with pharmacological or agricultural uses and as probes for biochemical assays or for purification of selected polyamine binding targets. As drugs, these compounds are used to treat disorders of undesired cell proliferation, primarily cancer, alone or combined with other agents such as polyamine synthesis inhibitors.
The invention also relates to the synthesis and use of such novel polyamine compounds as part of combinatorial libraries. These libraries are used to discover compositions that inhibit PAT and/or that bind to a cellular polyamine transporter (PATr). Various members of these libraries or compounds discovered through use of the libraries have utility as drugs, agricultural chemicals, and as probes.
BACKGROUND OF THE INVENTION
Decades of research on the myriad of biological activities that the polyamines, putrescine, spermidine and spermine play in cellular processes have shown the profound role they play in life (Cohen, S. S., “A Guide to the Polyamines” 1998, Oxford University Press, New York). As polycations at physiological pH, they bind tightly to and strongly modulate the biological activities of all of the anionic cellular components. Specific and strong interactions have been associated with DNA and RNA together with their associated chromatin proteins (Tabor, H. et al. 1,4-Diaminobutrane (putrescine), spermidine, and spermine.
Ann Rev. Biochem
. 1976, 45, 285-306; Matthews, H. R. Polyamines, chromatin structure and transcription.
BioEssays
, 1993, 15, 561-566). Spermine has been shown to function directly as a free radical scavenger that protects DNA from insults by reactive oxygen species (Ha, H. C. et al.
Proc. Natl. Acad. Sci. USA
, 1998, 95, 11140-11145). Specific interactions of multicationic polyamines with microtubules has been recently shown (Wolff, J. Promotion of Microtubule Assembly by Oligocations: Cooperativity between Charged Groups.
Biochemistry
, 1998, 37, 10722-10729; Webb, H. K. et al.,
J. Med. Chem
. 1999, in press). Allosteric regulation of membrane-bound enzymes including acetylcholinesterase has been shown (Kossorotow, A. et al. Regulatory effects of polyamines on membrane-bound acetylcholinesterase.
Biochem. J
. 1974, 144, 21-27). Polyamines have a direct influence on many neurotransmitter receptors and ion channels (Carter, C. The Neuropharmacology of Polyamines, 1994, Academic Press, San Diego, Calif.; Williams, K. Interaction of polyamines with ion channels,
Biochem. J
., 1997, 325, 289-297). Specific polyamine binding sites have also been demonstrated for the NMDA receptor complex (Ransom, R. W. et al. Cooperative modulation of [
3
H]MK-801 Binding to the N-Methyl-D-Aspartate Receptor-Ion Channel Complex by L-Glutamate, Glycine, and Polyamines.
J. Neurochem
. 1988, 51, 830-836; Williams, K. et al. Minireview: Modulation of the NMDA receptor by polyamines.
Life Sci
. 1991, 48, 469-498).
Many stimuli involved in both normal and neoplastic growth activate the polyamine biosynthetic pathway. A great number of multidisciplinary studies have shown that the intracellular concentrations of the polyamines is highly regulated at many steps in their biosynthesis, catabolism and transport. The fact that cells contain such complex apparatus for the tight control of the levels of these molecules shows that only a very narrow concentration range is tolerated. Ornithine decarboxylase (ODC), the rate-limiting enzyme in polyamine biosynthesis, catalyzes the production of putrescine from its precursor ornithine. This enzyme, with a very short biological half-life, is one of the most inducible mammalian enzymes known (Russell, D. et al. Amine synthesis in rapidly growing tissues: ornithine decarboxylase activity in regenerating rat liver, chick embryo, and various tumors.
Proc. Natl. Acad. Sci. USA
. 1968, 60, 1420-1427). Many biological stimuli involved in cellular growth have been shown to induce this enzyme and a distinct growth advantage is gained by induction of ODC (Alhonen-Hongisto, L. et al. Tumourigenicity, cell-surface glycoprotein changes and ornithine decarboxylase gene pattern in Ehrlich ascites-carcinoma cells.
Biochem. J
. 1985, 229, 711-715). An increase in the activity of ODC has been associated with tumor growth (Jänne, J. et al. Polyamines in rapid growth and cancer.
Biochim. Biophys. Acta
1978, 473, 241-493; Scalabrino, G. et al. Polyamines in mammalian tumors. Part I.
Adv. Cancer Res
. 1981, 35, 151-268; Scalabrino, G. et al. Polyamines in mammalian tumors. Part II.
Adv. Cancer Res
. 1982, 36, 1-102). Feedback inhibition of ODC activity is mediated by ODC-antizyme protein. Following elevation of polyamine concentrations, a polyamine-stimulated +1 frameshift of the ODC-antizyme mRNA reading frame causes elevation of this ODC-inhibiting protein (Hayashi, S. et al. Ornithine decarboxylase antizyme: a novel type of regulatory protein.
TIBS
, 1996, 21, 27-30; Matsufuji, S. et al.
EMBO Journal
, 1996, 15, 1360-1370). The ODC-antizyme protein binds to ODC with high affinity to form an inactive complex that is then tagged for degradation in an ATP-dependent fashion by the 26S proteosome (Heller, J. S. et al.
Proc. Natl. Aced. Sci. USA
. 1976, 73,1858-1862; Murakami, Y. et al. Ornithine decarboxylase is degraded by the 26S proteosome without ubiquitination.
Nature
, 1992, 360, 597-599). ODC-antizyme also represses the polyamine uptake system of cells (Suzuki, T. et al. Antizyme protects against abnormal accumulation and toxicity of polyamines in ornithine decarboxylase-overproducing cells.
Proc. Natl. Acad. Sci. USA
. 1994, 91, 8930-8934).
The polyamine catabolism pathway is important to prevent the toxic effects of excess polyamines on cells (Seiler, N. Functions of polyamine acetylation.
Can. J. Physiol. Pharmacol
. 1987, 65, 2024-2035; Seiler, N. Polyamine oxidase, properties and functions.
Progress in Brain Res
. 1995, 106, 333-344). This pathway is used by the cell to interconvert the various polyamines and to eliminate excess polyamines before they reach toxic levels. This pathway introduces no additional carbon precursors into the polyamine pool.
Polyamine transport into mammalian cells is energy and temperature dependent, saturable, carrier mediated and operates against a substantial concentration gradient (Seiler, N. et al. Polyamine transport in mammalian cells.
Int. J Biochem
. 1990, 22, 211-218; Khan, N. A.; Quemener, V. et al. Characterization of polyamine transport pathways, in
Neuropharmacology of Polyamines
(Carter, C., ed.), 1994, Academic, San Diego, pp. 37-60). Ample experimental proof exists that polyamine concentration homeostasis is mediated via this transport system. Changes in the requirements for polyamines in response to growth stimulation is reflected by increases in the transport activity. Stimulation of human fibroblasts to cell proliferation by serum or epidermal growth factor was followed by an 18-100 fold increase in the uptake of putrescine (DiPasquale, A. et al. Epidermal growth factor stimulates putrescine transport and ornithine decarboxylase activity in cultures human fibroblasts.
Exp. Cell Res
. 1978, 116, 317-323; Pohjanpelto, P. Putrescine transport is greatly increased in human fibroblasts initiated to proliferate.
J. Cell Biol
. 1976, 68, 512-520). Tumors have been shown to have an increased rate of putrescine uptake (Volkow, N. et al. Labeled putrescine as a probe in brain tumors.
Science
, 1983, 221, 673-675; Moulinoux, J-P. et al. Biological significance of circulating polyamines in oncology.
Cell. Mol. Biol
. 1991, 37, 773-783). Inhibition of polyamine biosynthesis in cells in culture by &agr;-difluoromethylornithine (DFMO), a well-studied mechanism-based inhibitor of ODC, causes a substantial depletion of intracellular putrescine and spermidine with resultant cell growth inhibition. Upon supplementing the culture media with exogenous polyamines this depletion causes transport activity
Bergstrom Donald E.
Burns Mark R.
O'Day Christine L.
Vermeulin Nicolaas M. J.
Webb Heather K.
Amernick Burton A.
Connolly Bove & Lodge & Hutz LLP
Kumar Shailendra
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