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Honokiol derivatives for the treatment of proliferative disorders

A technology of honokiol and its compound, which is applied in the field of honokiol derivatives for the treatment of proliferative disorders, and can solve the problems of limited therapeutic effect and side effects of cancer and related diseases

Inactive Publication Date: 2008-07-16
杰克·L·阿比瑟 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Current therapies for cancer and related diseases have limited efficacy and have multiple serious unintended side effects

Method used

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  • Honokiol derivatives for the treatment of proliferative disorders
  • Honokiol derivatives for the treatment of proliferative disorders
  • Honokiol derivatives for the treatment of proliferative disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0408] Example 1: MAPKK Screening

[0409] Figure 12 shows the effect of inhibition of MAPKK by dominant negative MAPKK gene or PD98059, a chemical inhibitor of endothelial cell morphology. MS1 represents endothelial cells containing only the SV40 large T antigen; SVR represents MS1 cells transformed with ras; SVR+PD98059 represents SVR cells treated with PD98059 (5 μg / ml); SVRA221a represents the dominant negative A221 allele stably expressing MAPKK genetic cells. The morphology of SVR and SVRbag4 cells is consistent. The original is magnified 40 times. This figure illustrates the differential response of SVR cells to MAP kinase inhibition, which can be used in visualized high-throughput screening to discover inhibitors of MAP kinase and related inhibitors (see also, LaMontagne et al., (2000) Am.J. Pathol.157, 1937-1945).

Embodiment 2

[0410] Example 2: Intracellular Effects of Honokiol

[0411]Figure 13 illustrates the effect of honokiol and magnolol on apoptosis. Light-colored bars represent SVR cells treated with magnolol, and black bars represent SVR cells treated with honokiol. Control strips represent cells immediately after treatment and are compared to 18 and 48 hours of treatment. This figure shows that honokiol is more effective than magnolol in inducing apoptosis.

[0412] Figure 14 depicts the effect of honokiol on the phosphorylation of different intracellular proteins. A shows that honokiol inhibits the phosphorylation of AKT, p44 / 42MAPK and Src. SVR cells were incubated with 20 (75 μM), 30 (112.5 μM), 40 (150 μM) or 45 μg / ml (169 μM) honokiol for 1 hour. SVR cells were also incubated with 50 μM LY294002 (LY) or 50 μM U0126 (U0) for 2 hours. Cells were lysed and subjected to Western blot analysis using antibodies specific for phosphorylated (P-AKT, P-MAPK, and P-Src) or non-phosphorylated ...

Embodiment 3

[0414] Example 3: Effect of honokiol on multiple myeloma cells

[0415] Materials and methods

[0416] Cells: Dexamethasone (Dex)-sensitive MM.1S (wild-type p53) and Dex-resistant MM.1R, RPMI 8226-Dox40 (doxorubicin-resistant) and RPMI 8226-LR5 (L-phenylalanine nitrogen Mustard (melphalan) resistant) human multiple myeloma (MM) cell line. RPMI-8226 and U266 cells were obtained from the American Type Culture Collection (Rockville, MD). SU-DHL-4 cells were also used. Fresh peripheral blood mononuclear cells (PBMNCs) were obtained from informed and consented healthy subjects. PBMNCs were isolated from heparinized peripheral blood by Ficoll Hipaque density sedimentation. BM samples were obtained from informed and consented patients with MM. Monocytes were isolated by FicollHipaque density sedimentation. Cells were cultured at 37°C in RPMI 1640 containing 10% fetal bovine serum (FBS; Sigma, St Louis, MO), 2 μM L-glutamine, 100 U / mL penicillin, and 100 μg / mL streptomycin ( ...

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Abstract

The present invention provides novel honokiol derivatives, as well as pharmaceutical compositions containing the honokiol derivatives. These compounds and pharmaceutical compositions can be used in the prevention and / or treatment of cancer. In particular, honokiol derivatives, pharmaceutical compositions comprising the derivatives, and methods for their use in the treatment of myeloma are provided.

Description

[0001] This application claims priority to US Provisional Application US No. 60 / 655,346, filed February 23, 2005, which is hereby incorporated by reference in its entirety. technical field [0002] The application describes honokiol-related compounds and compositions for use in the treatment of disorders associated with angiogenesis, cell proliferation, tumor growth and tumorigenicity, such as the treatment of myeloma. Background technique [0003] Cancer is an abnormal growth of cells. Cancer cells replicate rapidly despite spatial constraints, sharing nutrients with other cells, or signals from the body to stop replicating. Cancer cells often have a different shape than healthy cells, do not function normally, and are able to spread to many areas of the body. Abnormal growths of tissue called tumors are clusters of cells that grow and divide uncontrollably. Tumors can be benign (noncancerous) or malignant (cancerous). Benign tumors tend to grow slowly and not spread. M...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C41/00C07C43/20C07C43/02
CPCC07D321/10C07C39/225C07C39/205C07C43/215C07C211/53C07C39/15C07C43/23A61P19/10A61P29/00A61P35/00A61P35/02A61P35/04A61P43/00
Inventor 杰克·L·阿比瑟弗兰克·安布勒德
Owner 杰克·L·阿比瑟
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