Modulation of cell fates and activities by phthalazinediones

a technology of phthalazinedione and cell fate, which is applied in the direction of drug compositions, immunological disorders, metabolism disorders, etc., can solve the problems of defective protein products that function abnormally or not at all, defective proteins that could disrupt certain cellular processes, and leave the cell's redox system depleted and unstabl

Inactive Publication Date: 2007-06-21
BACH PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Current medical treatments generally focus on the disease and strive to eliminate the inciting agent or the symptoms, often injuring healthy tissue in the process.
For example, a genetic mutation may produce defective protein products that function abnormally or not at all.
These defective proteins could disrupt certain cellular processes, including redox reactions.
The external stress could trigger defensive responses that leave the cell's redox system depleted and unstable.
Cellular redox status may become impaired in numerous disease conditions.
When such cellular functions are impaired, the survival of the cell becomes uncertain.
Agents currently available for correcting redox imbalances are inadequate in that they are labile, quickly oxidized, or unable to translocate to the proper region of the cell.
However, toxicity and the lack of pharmacological activity of certain phthaloylhydrazides, including 2,3-dihydrophthalazine-1,4-dione and 5-amino-2,3-dihydrophthalazine-1,4-dione, were noted (U.S. Pat. Nos. 6,489,326; 5,543,410; 5,512,573).

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Uncontrolled Inflammation

[0045] In inflammatory conditions, such as acute infections, wounds, and immune responses, phthalazinediones, especially amino phthalazinediones, quickly ameliorate the painful redox-induced edematous swelling and facilitate rapid healing. Edematous inflammatory lesions in intestines, such as duodenal ulcers, ulcerative colitis, and acute vascular injury, are all suppressed to some degree by thiol redox modulators, including dihydrolipoates, reduced biopterins, amino phthalazinediones, and more slowly by glucocorticoids. Healing rates increase, with replacement of the injured epithelial cells by thiol redox-stimulated new cell growth. Thus, phthalazinediones, acting as thiol redox modulators, suppress injurious over-reactive inflammatory responses and also facilitate healing and replacement of injured cells.

example 2

Uncontrolled Proteolysis

[0046] In conditions with aberrant or uncontrolled proteolysis, as in apoptosis or necrosis, thiol redox modulators, especially thioredoxin, either upregulate or downregulate the regulatory proteases involved in processing and digesting the thiol redox dependent caspases, endonucleases, and histone deacetylases responsible for protein and DNA hydrolysis. Diamide, a phthalazinedione with activity similar to the oxidized 4-amino phthalazinedione, can activate and cross-link proteases that hydrolyze procaspase 3 to the active caspase fragments that, along with cytochrome c, initiate the apoptotic cascade in the nucleus.

[0047] Since these cross-linking agents can also oxidize essential membrane proteins, such as the adenine nucleotide translocase in mitochondria or amyloid protein fragments in brain, the result is membrane pore formation in mitochondria with increased reactive oxygen species and cell destruction (Ueda et al., J. Immunol. 161: 6689-6695, 1998). ...

example 3

Helicase Deficiencies

[0048] The XPD gene of the xeroderma pigmentosum family codes for a helicase. In XPD deficiency, DNA transcription and repair functions are impaired, resulting in multiple symptoms of early aging (De Boer et al., Science 296: 1276-1281, 2002). Wasting, loss of subcutaneous fat and muscle cells, gray brittle greasy hair with hyperplasia of sebaceous and mammary glands, severe osteoporosis, atrophic germ and stem cells, and immunoneurodegenerative and hyperplastic changes all occur prematurely in XPD-deficient mice or humans.

[0049] The failure to maintain normal numbers of cells or normal amounts of cellular thiols, at least in the brittle hair, suggests that a global thiol redox deficiency is responsible for the progressive wasting and chronic cell losses. Since amino derivative phthalazinediones with reduced thiol redox modulators, at low dosage, stimulate cell growth and maintain thiol redox status in cells, treatment with appropriate amounts of reduced thiol...

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Abstract

Phthalazinediones that function as intracellular redox modulators are useful in treating cells in various disease states where intracellular redox status is impaired. By buffering aberrant redox states, phthalazinediones enable cellular processes essential for survival and augment medical treatments. The phthalazinediones of the invention can modulate functions related to cell growth, differentiation, activity, or death, to correct aberrations and restore homeostasis, and can serve as adjunctive therapy in treating various disease conditions.

Description

[0001] This application is a divisional of application Ser. No. 11 / 199,394 filed Aug. 8, 2005, which is a continuation-in-part of application Ser. No. 10 / 283,647 filed Oct. 30, 2002, now U.S. Pat. No. 6,953,799, which are incorporated herein by reference in their entirety.BACKGROUND OF THE INVENTION [0002] Current medical treatments generally focus on the disease and strive to eliminate the inciting agent or the symptoms, often injuring healthy tissue in the process. The present invention focuses instead on the patient, to enable self-repair mechanisms by supporting the patient's body in controlling or stabilizing its cellular functions without toxic side effects. The methods and compositions of the invention comprise phthalazinedione compounds that buffer intracellular reduction and oxidation (redox) reactions and thereby modulate cellular functions of growth, differentiation, activity, and death in various disease states. [0003] In healthy cells, a balance of redox reactions maint...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K38/05A61K31/573A61K31/502A61K31/65A61K31/55A61K31/4743A61K31/385A61K45/06
CPCA61K31/19A61K31/195A61K31/385A61K31/4743A61K31/502A61K45/06A61K31/56A61K31/573A61K31/65A61K38/063A61K31/55A61K2300/00A61K31/197A61K31/519A61P17/00A61P17/18A61P19/02A61P25/00A61P25/16A61P29/00A61P3/00A61P31/00A61P31/04A61P31/06A61P31/18A61P35/00A61P35/02A61P37/00A61P9/00A61P9/10Y02A50/30A61K38/44A61N5/10
Inventor HENRY, MARK O.LYNN, WILLIAM S.
Owner BACH PHARMA
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