The assignee for this patent application is Universite de
Reporters obtained the following quote from the background information supplied by the inventors: "Cyclitols in general, and inositols in particular, exhibit a wide distribution in biological systems, suggesting their importance in biological functions. As a class, cyclitols encompass all polyhydroxylated isocyclic molecules. Inositols refer specifically to the polyhydroxylated cyclohexane derivatives. Inositol has a number of known conformational isomers (i.e. cis-inositol, epi-inositol, allo-inositol, myo-inositol, muco-inositol, neo-inositol, scyllo-inositol, and chiro-inositol), with myo-inositol being the most naturally abundant and well characterized of the conformational isomers. Some polyphosphorylated and pyrophosphate derivatives of inositols are known to possess biological activity. This activity spans from functioning as key secondary messengers in important cell-signaling pathways to the ability to function as allosteric effectors of hemoglobin.
"For instance, inositol 1,4,5-trisphosphate is a soluble secondary messenger responsible for the generation of highly organized Ca.sup.2+ signals in a variety of cell types. These Ca.sup.2+ signals are known to function in the control of many cellular responses, including cell growth, fertilization, smooth muscle contraction and secretion (1). In addition, inositol 1,3,4,5 tetrakisphosphate has been shown to mobilize Ca.sup.2+ from internal stores through interactions with the inositol 1,4,5 trisphosphate receptor (2), and studies have implicated inositol 1,3,4,5 tetrakisphospohate in the regulation of Ca.sup.2+ influx across the plasma membrane (3-8, 29). Inositol 1,4 bisphosphate has been reported to exert allosteric activation of muscle-type 6-phosphofructo-1-kinase (9). It has been show that inositol 4,5 bisphosphate and inositol 1,4,5 trisphosphate, but not inositol 1,3,4,5 tetrakisphosphate selectively inibit Ca.sup.2+-ATPase of rat heart sarcolemma (10) and of human erythrocyte membrane (11). Inositol 1,3,4,6 tetrakisphosphate-activated Ca.sup.2+ mobilization has been observed in microinjected Xenopus oocytes (12) and in permeablized human neuroblastoma cells (13).
"Further, inositol hexaphosphate, including its trispyrophosphate derivatives, have been shown to function as allosteric effectors of hemoglobin (Nicolau et al. U.S. Pat. No. 7,084,115). Hemoglobin is a tetrameric protein which delivers oxygen via an allosteric mechanism. In blood, hemoglobin is in equilibrium between two allosteric structures. In the 'T' (for tense) state, hemoglobin is deoxygenated. In the 'R' (for relaxed) state, hemoglobin is oxygenated. An oxygen equilibrium curve can be scanned to observe the affinity and degree of cooperatively (allosteric action) of hemoglobin. In the scan, the Y-axis plots the percent of hemoglobin oxygenation and the X-axis plots the partial pressure of oxygen in millimeters of mercury (mmHg). If a horizontal line is drawn from the 50% oxygen saturation point to the scanned curve and a vertical line is drawn from the intersection point of the horizontal line with the curve to the partial pressure X-axis, a value commonly known as P.sub.50 is determined (i.e. this is the pressure in mmHg when the scanned hemoglobin sample is 50% saturated with oxygen). Under physiological conditions (i.e. 37.degree. C., pH=7.4, and partial carbon dioxide pressure of 40 mm Hg), the P.sub.50 value for normal adult hemoglobin (HbA) is around 26.5 mmHg. If a lower than normal P.sub.50 value is obtained for the hemoglobin being tested, the scanned curve is considered to be 'left-shifted' and the presence of high-oxygen affinity hemoglobin is indicated. Conversely, if a higher than normal P.sub.50 value is obtained for the hemoglobin being tested, the scanned curve is considered to be 'right-shifted,' indicating the presence of low oxygen-affinity hemoglobin.
"The oxygen release capacity of mammalian red blood cells can be enhanced by introducing allosteric effectors like inositol hexakisphosphate and inositol trispyrophosphate, thereby decreasing the affinity of hemoglobin for oxygen and improving the oxygen economy of the blood. This phenomenon suggests various medical applications for treating individuals suffering from hypoxia related diseases or other conditions associated with inadequate function of the lungs or circulatory system.
"For instance, the role of VEGF in the regulation of angiogenesis has been the object of intense investigation (14-19). Whereas VEGF represents a critical, rate-limiting step in physiological angiogenesis, it is also important in pathological angiogenesis, such as that associated with tumor growth (20). VEGF also is known as vascular permeability factor, based on its ability to induce vascular leakage (21) Several solid tumors produce ample amounts of VEGF, which stimulates proliferation and migration of endothelial cells, thereby inducing neovascularization (21). VEGF expression has been shown to significantly affect the prognosis of different kinds of human cancer. Oxygen tension in the tumor has a key role in regulating the expression of the VEGF gene. VEGF mRNA expression is induced by exposure to low oxygen tension under a variety of pathophysiological circumstances (21). Growing tumors are characterized by hypoxia, which induces expression of VEGF also and may be a predictive factor for the occurrence of metastatic disease. Therefore, the ability to increase the oxygen tension in tumor may help inhibit angiogenesis and growth of the tumor. Similar applications also can be envisioned for other angiogenesis related diseases such as hemangioma, rheumatoid arthritis, ulcerative colitis and Crohn's disease.
"In addition, it is known that medial temporal oxygen metabolism is markedly affected in patients with mild-to-moderate Alzheimer's disease. It also is known that mean oxygen metabolism in the medial temporal, as well as in the parietal and lateral temporal cortices, is significantly lower in patients with Alzheimer's disease than in control groups without Alzheimer's disease (22). Thus, one potential means of treating patients with Alzheimer's disease is to increase oxygen across the blood brain barrier using an allosteric effector.
"Allosteric effectors also may help in the treatment of a variety of diseases associated with various forms of dementia. Because the brain relies on a network of vessels to bring it oxygen-bearing blood, if the oxygen supply to the brain fails, brain cells are likely to die which can cause symptoms of vascular dementia. These symptoms can occur either suddenly following a stroke, or over time though a series of small strokes. Thus, one potential means for treating patients with vascular diseases associated with various forms of dementia is to increase the oxygen available to affected areas such as across the blood brain barrier.
"Moreover, treatment of an individual with an allosteric effector may have beneficial effects for both the treatment of stroke and the condition of osteoporosis that can sometime follow. Although, stroke and the bone-thinning disease, osteoporosis, are usually thought of as two distinct health problems, it has been found there is a connection between the two. Patients who survive strokes are significantly more likely to suffer from osteoporosis, a disease that puts them at high risk for bone fractures. Often the fractures occur on the side of the body that has been paralyzed from the stroke. It is known that a stroke occurs when the supply of blood and oxygen to the brain ceases or is greatly reduced. If a portion of the brain loses its supply of nutrient-rich blood and oxygen, the bodily functions controlled by that part of the brain (vision, speaking, walking, etc.) are impaired. Annually, more than 500,000 people in
"Therefore, the ability to readily synthesize polyphosphorylated and pyrophosphate derivatives of cyclitols will be a valuable tool for uncovering new allosteric effectors suitable for the potential therapeutic uses mentioned above. In addition, given the diversity of cell types and cell functions that rely on Ca.sup.2+ signaling and the role of cyclitols in conducting those signals, the ability to readily synthesize polyphosphate and pyrophosphate derivatives, will provide an invaluable tool in better elucidating the function of these complex signaling pathways. It also will be useful for determining any therapeutic activity these derivatives may have including the ability to function as prodrugs. The biological activity of myo-inositol has been fairly well characterized. However, there are a number of confoiniational isomers of inositol of which biological functions are either not known or are poorly understood. Therefore, the ability to readily synthesize polyphosphorylated and pyrophosphate derivatives of these conformational isomers of inositol also will potentially unlock a number of useful and heretofore unknown biological activities."
In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "The present invention is directed to compounds and compositions comprising polyphosphorylated and pyrophosphate derivatives of cyclitols, in particular inositols, and methods for their synthesis. In addition, the present invention is directed to the use of these compositions as allosteric effectors of hemoglobin, cell-signaling molecule analogs and as therapeutic agents in treating diseases caused by hypoxia or other conditions associated with inadequate function of the lungs or circulatory system.
"In one embodiment, the present invention is a compound that is a hexakisphophate derivative of inositol. More specifically, the triethylammonium salts of hexakisphosphate derivatives of cis-inositol, epi-inositol, allo-inositol, muco-inositol, neo-inositol, scyllo-inositol, (+) chiro-inositol, or (-) chiro-inositol In another embodiment, the compound is a polyphosphorylated inositol derivative containing one or more free hydroxyl or hydroxyl derivative groups, such as an alkoxy and acyloxy groups.
"In another embodiment, the present invention is a compound that is a pyrophosphate derivative of inositol. The inositol derivative may be a monopyrophosphate, bispyrophosphate, or trispyrophosphate derivative. In another embodiment, the compounds are trisphosphorimide derivatives or tristhiopyrophosphate derivatives of inositol.
"In another embodiment, the present invention comprises the corresponding salts of the polyphosphorylated and pyrophosphate derivatives of inositol. The salt complex may be formed with an alkali metal cation, alkaline metal cation, ammonium cation, or organic cation.
"In another embodiment, the present invention comprises pharmaceutical compositions comprising the polyphosphorylated and/or pyrophosphate derivatives of inositol.
"In yet another embodiment, the present invention is directed to the use of polyphosphorylated and pyrophosphate inositols in a method of reducing the affinity of hemoglobin for the blood.
"In another embodiment the compounds and compositions of the present invention are used as therapeutic agents for treating disease caused by hypoxia or other conditions associated with inadequate function of the lungs or circulatory system.
"In another embodiment of the invention, the compounds and compositions of the present invention may be used as analogs of naturally occurring inositol cell signaling compounds or prodrugs thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
"FIG. 1 depicts the different conformational isomers of inositol.
"FIG. 2 depicts known and suggested pathways of inositol metabolism."
For more information, see this patent application: Lehn, Jean-Marie; Pothukanuri, Srinivasu; Koumbis, Alexandros; Duarte, Carolina; Nicolau, Claude. Cyclitols and Their Derivatives and Their Therapeutic Applications. Filed
Keywords for this news article include: VEGF, Stroke, Dementia, Cyclitols, Chalcogens, Hemoglobins, Tauopathies, Hydrocarbons, Therapeutics,
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