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WO1994012464A1 - Role protecteur des polyamines lors de modifications des macromolecules des couches sous-epitheliales - Google Patents

Role protecteur des polyamines lors de modifications des macromolecules des couches sous-epitheliales Download PDF

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Publication number
WO1994012464A1
WO1994012464A1 PCT/US1993/011769 US9311769W WO9412464A1 WO 1994012464 A1 WO1994012464 A1 WO 1994012464A1 US 9311769 W US9311769 W US 9311769W WO 9412464 A1 WO9412464 A1 WO 9412464A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
glucosylation
putrescine
polyamines
acid addition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1993/011769
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English (en)
Inventor
Aristidis S. Charonis
Leo T. Furcht
Evangelo Canellakis
Photini-Effie C. Tsilibary
Christina Zioudrou
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Individual
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Individual
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Filing date
Publication date
Application filed by Individual filed Critical Individual
Priority to AU57394/94A priority Critical patent/AU5739494A/en
Publication of WO1994012464A1 publication Critical patent/WO1994012464A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/09—Diamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/14—Amines containing amino groups bound to at least two aminoalkyl groups, e.g. diethylenetriamines

Definitions

  • This invention relates to polyamine compositions useful in preventing diabetic complications caused by nonenzymatic glucosylation, cross-linking and oxidative damage and tissue changes like cross-linking and oxidative alterations that a contributors to the aging process.
  • Basement membranes are multifunctional specializations of the extracellular matrix. They are found either at the basal surface of various cell types that exhibit polarity (epithelial, mesothelial, endothelial cells) or surround various oth cell types (muscle cells, adipose cells, Schwann cells). Various biologically significa roles have been ascribed to basement membranes: compartmentalization of tissues, contribution in cell anchorage and in the maintenance of cell polarity, control of cell migration, involvement in invasion of normal and malignant cells, and as a permeability barrier to macromolecules [Vracko, R (1974) Am. J. Pathol. 77:314-388 Timpl, R. and Dziadek, M. (1986) Inl. Rev.
  • microangiopathy In diabetes, hyperglycemia affects many metabolic pathways and each o these changes may contribute to the development of diabetic complications.
  • the basis of many diabetic complications is microangiopathy, and microangiopathy is characterized by morphological and physiological changes in the basement membrane underlying endothelial cells of the microvasculature.
  • Glucose has the ability to attach chemically to proteins without the participation of enzymes. This reaction occurs normally but at very slow rates when compared to hyperglycemic conditions, and is known as Maillard reaction or nonenzymatic glucosylation [Day, J.F., et al. (1979) J. Biol. Chem. 254:595-597; Brownlee, M., et al. (1984) Ann. Intern. Med. 101:527-537].
  • the site of nonenzymatic glucosylation is either at the N-terminal amino acid or at the epsilon amino group of lysine residues, which is by far the more common site.
  • nonenzymatically glucosylated proteins may exhibit altered physiochemical properties. For example, hemoglobin has lower affinity for oxygen [McDonald, M.J., et al. (1979) J. Biol. Chem. 254:702-707] albumin has decreased ability for bilirubin [Shaklai, N., et al. (1984) J. Biol. Chem. 259:3812-3817], lens crystallins may aggregate and cause opalescence [Monnier, V.M. et al. (1979) J. Exp. Med. 150: 1098- 1107].
  • nonenzymatic glucosylation of domain NC 1 of type IV collagen leads to defective association between this domain and binding sites along the length of its triple helical portion and therefore it interferes with its ability to polymerize [Tsilibary, E.C., et al. (1988) J. Biol. Chem. 263:4302-4308].
  • nonenzymatic glucosylation may lead to structural changes that may affect important functions. In the case of the basement membrane macromolecules, it may affect their assembly process and therefore their supramolecular organization.
  • crosslinks both intra- and inter-molecular in nature, has been postulated as one major parameter in the process of aging. This process is considered very complicated and the development of crosslinks can be due to nonenzymatic as well as enzymatic mechanisms, the nature of which is largely unknown.
  • Glucose and monosaccharides in general can reduce molecular oxygen and yield H 2 O 2 and free radical intermediates [Thornalley, P. et al. (1984) Biochim. Biophys. Acta 797:276-287]. These compounds can lead to fragmentation of proteins [Hunt, J.V., et al. (1988) Biochem. J. 250:87-93]. This process is catalyzed by Cu ++ and can be inhibited by metal chelating agents.
  • Polyamines including putrescine, may act to minimize d e oxidative damage to proteins, by acting as a reducing agent.
  • the polyamines of the invention are useful in preventing glucose-induced changes in macromolecules.
  • the compositions may be used beneficially to treat a variety of diseases or aging in which damage is associated wid glucose-induced macromolecule changes.
  • the compositions are useful whenever protein damage is to be minimized, and therefore includes applications to retard food spoilage.
  • FIG. 1 shows crosslink formation using gel electrophoresis with separate gel lanes for each sample.
  • Polyamines are low molecular weight aliphatic nitrogenous bases.
  • the three common polyamines are: putrescine with the formula NH 2 (CH 2 ) 4 NH 2 ; spermidine widi the formula NH 2 (CH 2 ) 3 NH(CH 2 ) 4 NH 2 ; and spermine with the formula NH 2 (CH 2 ) 3 NH(CH 2 ) 4 NH(CH 2 ) 3 NH 2 .
  • other less common polyamines exist, mainly in plants and microorganisms, the above described polyamines are present in every living organism and often their intracellular concentration reaches millimolar amounts [Morgan, D.M.L. (1987) Essays in Biochem. 23:82-115].
  • Some of the less common polyamines include me diamines such as 1,3-diaminopropane and cadaverine; triamines such as norspermidine, aminopropylcadaverine and homospermidine; tetra-amines such as norspermine, thermospermine and canavalmine; and penta-amines including caldopentamine and homocaldopentamine.
  • putrescine the simplest member of this group.
  • the pK of the amino group of putrescine is 8.71; the pKs of the amino and imino groups of spermine and spermidine exhibit on the average much higher values, therefore they should be considered stronger bases. If these values are crucial for the phenomena studied below, it is believed that the action of spermine and spermidine will be even more dramatic than the one of putrescine.
  • compositions may also be useful with substitutions in place of one or more hydrogen atoms. It has been found, however, that introduction of a carboxyl group will very markedly lower the usefulness of the compound.
  • laminin one basement membrane glycoprotein, laminin.
  • me source of laminin was the matrix of the Engelbreth-Holm-Swarm tumor, grown subcutaneous in mice [Orkin, R.W., et al (1977) J. Exp. Med. 145:204-220].
  • Laminin was extracted and purified following well-established techniques [Charonis, A.S., et al. (1985) J. Cell Biol. 100:1848-1853].
  • Laminin, at a concentration of 500 /xg/ml was incubated in die presence or absence of 0.5M glucose, and in die absence or presence of increasing putrescine concentrations (5 mM, 50 mM, 500 mM). Samples were incubated for 21 days at 37 °C in me dark witii occasional shaking. At the end of d e incubation period aliquots from each sample were dialyzed in phosphate buffered saline to remove all me small molecular weight components, their protein concentration was determined, and equal amounts of protein were analyzed by gel electrophoresis. In mis experiment, highly crosslinked material is not able to enter the running gel and is observed as a band at the bottom of die stacking gel.
  • Example 3 Effect of putrescine on protein degradation
  • me intacmess of laminin after incubation in the absence (lane a of Figure 1) or the presence of putrescine (lane c of Figure 1) was measured densitometrically.
  • the results are presented in Figure 2.
  • the top panel is lane a and the bottom panel is lane c.
  • Both Figure 1 and Figure 2 show mat the presence of putrescine allowed for a better preservation of laminin A and B chains.
  • Diabetics or others wishing to decrease nonenzymatic glucosylation, reduce crosslink formation of advanced glucosylation end-products or reduce oxidative damage to proteins may be treated with compounds of me invention.
  • the treatment involves introduction of a polyamine of me invention into the individual at an effective amount. This may be given one or more times daily, and may involve dosages d at would provide an effective amount of polyamine in the blood of up to 500 mM.
  • This therapy may be used to decrease nonenzymatic glucosylation, reduce crosslink formation of advanced glucosylation end-products or reduce oxidative damage to proteins associated with aging, diabetes or even food spoilage.
  • me compounds may be formulated for topical, oral or parenteral administration wim the usual carriers or diluents.
  • compositions of the invention may be converted to hydrochloride salts from bicarbonate salts to improve solubility for intraperitoneal injection.
  • Other pharmaceutically acceptable acid addition salts of the compositions of the invention may be formulated. These salts include derivation from organic and inorganic acids such as sulfuric, phosphoric, p-toluenesulfonic, hydrochloric, hydrobromic, sulfamic, citric, lactic, maleic, benzoic, ascorbic and related acids.
  • the composition may be formulated as a liquid for intravenous, intraperitoneal or oral administration.
  • Topical usages as an anti-aging formulation may be useful, in which case the compositions may be compounded as ointments or cremes.
  • the expected dosage may be as high as 10 g/day for humans, and more typically up to 0.1 g/kg of body weight. Even higher dosages may be beneficial and are not expected to cause any deleterious side effects.
  • the inventors best estimate on e upper useful range of application is given to satisfy die disclosure requirements and does not necessarily represent absolute limits.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

On a découvert que des polyamines, y compris la putrescine, entravent la glucosylation non enzymatique et la formation des produits finaux d'une glucosylation avancée en minimisant la formation de liaisons croisées et en agissant comme agents réducteurs qui minimisent les dommages causés aux protéines par l'oxydation. Ces polyamines sont utiles dans le traitement de diabétiques pour minimiser les dommages causés par de hautes concentrations de glucose et pour réduire le vieillissement des tissus favorisé par des liaisons croisées ou par l'oxydation.
PCT/US1993/011769 1992-12-03 1993-12-03 Role protecteur des polyamines lors de modifications des macromolecules des couches sous-epitheliales Ceased WO1994012464A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57394/94A AU5739494A (en) 1992-12-03 1993-12-03 Protective role of polyamines in modifications of basement membrane macromolecules

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US98615292A 1992-12-03 1992-12-03
US07/986,152 1992-12-03

Publications (1)

Publication Number Publication Date
WO1994012464A1 true WO1994012464A1 (fr) 1994-06-09

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AU (1) AU5739494A (fr)
WO (1) WO1994012464A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2802817A1 (fr) * 1999-12-23 2001-06-29 Centre Nat Rech Scient Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete
WO2005013932A1 (fr) * 2003-07-31 2005-02-17 Giuliani S.P.A. Utilisation de spermine et/ou de spermidine contre le vieillissement de la peau dans des compositions dietetiques, pharmaceutiques ou cosmetiques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5299224A (en) * 1976-02-13 1977-08-19 Dainippon Pharmaceut Co Ltd Remedy for hepatic deseases
US5077313A (en) * 1988-11-25 1991-12-31 Gert Lubec Process for inhibiting pathological collagen cross-linking in diabetes patients

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5299224A (en) * 1976-02-13 1977-08-19 Dainippon Pharmaceut Co Ltd Remedy for hepatic deseases
US5077313A (en) * 1988-11-25 1991-12-31 Gert Lubec Process for inhibiting pathological collagen cross-linking in diabetes patients

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 80, No. 21, issued 27 May 1974, HAYASHI, "Pharmacological and Physiological Actions of Polyamines", see page 2, column 2, abstract no. 115852y; & TAISHA, 9(11), 1026-32, (1972). *
TAISHA, Volume 9, No. 11, issued 1972, HAYASHI, "Pharmacological and Physiological Actions of Polyamines", pages 1026-32. *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2802817A1 (fr) * 1999-12-23 2001-06-29 Centre Nat Rech Scient Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete
WO2001047528A3 (fr) * 1999-12-23 2002-06-20 Centre Nat Rech Scient Nouveaux inhibiteurs de glycosidases et leurs applications pharmacologiques, notamment pour traiter le diabete
WO2005013932A1 (fr) * 2003-07-31 2005-02-17 Giuliani S.P.A. Utilisation de spermine et/ou de spermidine contre le vieillissement de la peau dans des compositions dietetiques, pharmaceutiques ou cosmetiques
CN1829496B (zh) * 2003-07-31 2011-02-09 朱利亚尼股份公司 精胺和/或亚精胺在食用、药用或美容用组合物中对抗皮肤老化的用途

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Publication number Publication date
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