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Pharmaceutical composition

A compound and thermostatic animal technology, which is applied in the direction of drug combination, pharmaceutical formula, antineoplastic drugs, etc., can solve the problems of not indicating PDH complexes, regulating the activity of PDH complexes, etc., and achieve the effect of minimizing side effects

Inactive Publication Date: 2011-05-11
罗伯特・绍尔 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, although these patents describe the general use of the structures of these lipoic acid derivatives, there is no indication in any of these patents that these derivatives are useful for modulating the structure and / or expression levels of the PDH complex, and / or modulating the PDH complex active

Method used

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Examples

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Embodiment 1

[0187] Chemical synthesis of thioctan

[0188] Lipoic acid derivatives (ie thioctan) CPI-613 and CPI-157 were synthesized using 6,8-dimercaptooctanoic acid as a starting material by using modified methods described in US 6,331,559B1 and US 6,951,887B2. Thioctan CPI-045 was synthesized as described in US 6,331,559B1.

[0189] The structural analysis of these three thioctans is as follows. Multiple independent syntheses of CPI-613 and CPI-157 are indistinguishable in their anticancer properties. In allogeneic transplantation ( Figure 7 ) and ATP measurements ( Figure 9 ) of CPI-613 used in the purity of more than 99%. All other preparations were greater than 98% pure.

[0190] CPI-613: 6,8-dibenzylsulfanyl octanoic acid: white crystalline solid, melting point 65-66°C (documentation 1 67.5-69°); 1 H-NMR (250MHz, CDCl 3 ): δ7.15-7.4(m, 10H), 3.66(s, 2H), 3.64(s, 2H), 2.52-2.62(m, 1H), 2.50(t, J=7.6Hz, 2H), 2.29( t, J=7.6Hz, 2H), 1.2-1.8(m, 8H); 13 C-NMR (62.9MHz, CDCl3...

Embodiment 2

[0194] Method for determining the anticancer efficacy of THIOCTAN

[0195]Cells: Human tumor cell lines were obtained from ATCC and propagated according to ATCC recommendations. Human mammary epithelial cells (HMEC), small airway epithelial cells (SAEC) and normal human epidermal keratinocytes (NHEK) primary cells were obtained from LONZA Walkersville, Inc (Walkersville, MD). Each cell line was maintained and propagated in the appropriate medium developed by the supplier and purchased from the supplier according to the supplier's instructions. The experiments reported here used normal cells at passages 3 to 6.

[0196] Tumor Growth Inhibition Study: Human BxPC-3 or AsPC-1 pancreatic tumor cells or H460 NSCLC were transplanted subcutaneously (SC) into CD1-Nu / Nu female mice. About 8-12 days later, the mice were injected intraperitoneally (IP) according to the dosage and schedule shown in the legend. Drug or vehicle was injected approximately 2 ml per 25 gm body weight. Drug ...

Embodiment 3

[0217] Thioctan interferes with mitochondrial membrane potential and Ca +2 intake

[0218] Substrate effect of Thioctan on ATP synthesis inhibition ( Figure 9 ) showed that the drug interferes with the TCA cycle in the mitochondrial matrix. If so, we would expect the mitochondrial membrane potential 1 May decrease at lethal threshold doses and above. Using the potential-sensitive dye TMRE, we observed the desired effect. ( Figure 13 ) With the initiation of drug treatment, the mitochondrial membrane potential decreased rapidly. The kinetics of the decrease in membrane potential closely resemble the loss of ATP synthesis in the presence of mitochondrial substrates. ( Figure 9 )

[0219] ATP reduction in mitochondria is known to trigger the uptake of Ca released from cytoplasmic reserves, including the endoplasmic reticulum +2 Equilibrium homeostatic response to uptake. Moreover, it is believed that this Ca +2 Input to the mitochondrial matrix requires the mitochon...

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Abstract

A pharmaceutically-acceptable modulator of the regulation or perturbation of the structure, expression, and / or activity of at least one enzyme and / or enzyme complex, or subunit thereof, such as via the altered mitochondrial energy metabolism of the pyruvate dehydrogenase (PDH) complex of warm-blooded animals, including humans, and methods of use thereof, comprises an effective amount of at least one lipoic acid derivative and at least one pharmaceutically-acceptable carrier thereof to affect the complex's phosphorylation state. By increasing PDH kinase activity and / or decreasing PDH phosphatase activity, the modulator prevents the detoxification anaerobic glycolytic toxic metabolites through inhibition of the activity of the PDH complex's El a subunit, obliging increased mitochondrial oxidative phosphorylation activity. As cells characterized by hyperproliferation, such as tumor cells, cannot also generate acetyl-CoA and NADH because of the modulator's additional action in inhibiting the action of the PDH complex's E2 subunit, the mitochondrial membrane polarization is lost, facilitating cell death.

Description

Field of Invention [0001] The present invention relates to therapeutic and diagnostic compositions, more particularly pharmaceutical compositions, and methods of use thereof, which exhibit selective uptake into cells characterized by hyperproliferation, including cancer cells, and which regulate the structure of enzymes, Modulation or interference of expression and / or activity to facilitate detection and treatment or destruction of these cells. More particularly, these agents target and interfere with the activity or modulation of altered mitochondrial energy metabolism observed at sites such as the modified pyruvate dehydrogenase (PDH) complex associated with most cancers. Background of the Invention [0002] Mitochondria are the major control centers of energy production and cellular life-and-death processes in eukaryotes. Although there are various mechanisms for communicating with the rest of the cell, reversible phosphorylation is an important way to regulate mitochond...

Claims

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Application Information

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IPC IPC(8): A61K31/385A61K31/19
CPCA61K31/19A61K31/385A61P35/00A61P43/00
Inventor 罗伯特·绍尔罗伯特·罗德里格斯保罗·宾厄姆拉克玛尔·W·波特尤苏珊娜·扎卡尔
Owner 罗伯特・绍尔
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