Improved jasmonate derivatives, pharmaceutical compositions and methods of use thereof

A technology of compounds and hydrates, applied in the field of chemotherapeutic agents for the treatment of cancer, can solve problems such as the therapeutic application of derivatives that have not been described

Inactive Publication Date: 2008-12-17
SEPAL PHARMA LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, therapeutic applications of these derivatives, such as for cancer treatment, have not been previously described

Method used

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  • Improved jasmonate derivatives, pharmaceutical compositions and methods of use thereof
  • Improved jasmonate derivatives, pharmaceutical compositions and methods of use thereof
  • Improved jasmonate derivatives, pharmaceutical compositions and methods of use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0260] Example 1: Cellular Effects of Jasmonate Derivatives A1-A6, B1 and B2 on Leukemic Cells toxicity

[0261] The cytotoxicity of jasmonate derivatives A1-A6, B1 and B2 was compared with that of previously studied jasmonate, methyl jasmonate (MJ). Cytotoxicity of each compound was determined in Molt-4 (human acute lymphoblastic leukemia cell line).

[0262] experiment settings

[0263] Inoculate Molt-4 lymphoid leukemia cells (1.5x10 4 / well), and jasmonate derivatives in the concentration range of 0.1-1mM were added and cultured for 24 hours. Three parallels were performed for each experimental point. Untreated cells were used as controls. Test compounds were prepared as 100 mM stocks in dimethylsulfoxide (DMSO). Dilutions were made in medium and DMSO such that the maximum concentration of DMSO in each well was 0.5%. This DMSO concentration by itself did not affect the viability of any cell lines. Cytotoxicity and optical density were determined as described a...

Embodiment 2

[0270] Example 2: Compounds A3 and A4 selectively fight cancer cells

[0271] Experimental setup:

[0272] Molt-4 ( leukemia) cells (2.5x10 4 / ml) and normal peripheral blood lymphocytes (PBL, 2x10 5 / ml) one day. In some experiments, PBLs were preincubated with 0.8 μg / ml phytohemagglutinin (PHA) and 5 ng / ml TPA for 48 or 24 hours to induce their entry into the cell cycle. These cell proliferations are similar to those of cancer cells, making the comparison more valid. The optical density of viable cells was determined as described above.

[0273] result

[0274] Below, shown in Table 2 below are IC 20 and IC 50 Level.

[0275] Table 2

[0276]

[0277] * ~20 repetitions

[0278] ** A3 and A4, two repetitions

[0279] According to previously reported data, MJ is cytotoxic to Molt-4 cells and almost non-toxic to normal lymphocytes. Compound A3 was found to be toxic to Molt-4 cells (IC 50 =0.05mM), while the toxicity to normal lymphocytes (-PHA / TPA) was ...

Embodiment 3

[0281] Example 3 - Cytotoxicity of oligomeric jasmonate derivatives on leukemia cells

[0282] The cytotoxicity of the novel MJ derivatives C1 and C2 was tested in 3 cancer cell lines:

[0283] A) Molt-4-human acute lymphoblastic leukemia cell line

[0284] B) CT26-murine colon cancer cell line

[0285] C) MCF7-human breast cancer cell line

[0286] The new derivatives were also tested in normal lymphocytes (PBL) obtained from healthy donors. The experimental setup is listed below along with the obtained ICs for the different cell lines 50 value.

[0287] Experimental setup:

[0288] Mononuclear cells were isolated from peripheral blood of healthy donors by ficoll-hypaque density gradient centrifugation. Monocytes were allowed to attach to plastic dishes to remove macrophages. The cell density is as follows: Molt-4 (2.5×10 in 100 μL per well 4 cells), CT26 (5×10 in 100 μL per well 3 cells), MCF7 (5×10 in 100 μL per well 3 cells) and PBL (1.5×10 in 100 μL per well...

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Abstract

The present invention relates to novel jasmonate derivatives, methods for their preparation, pharmaceutical compositions including such compounds, and methods of using these compounds and compositions, especially as chemotherapeutic agents for prevention and treatment of cancers.

Description

technical field [0001] The present invention relates to the field of novel jasmonate-derived compounds, processes for their preparation, pharmaceutical compositions comprising such compounds, and methods of use of these compounds and compositions, especially as chemotherapeutic agents for the treatment of cancer, The cancer is especially a cancer in a mammal, in particular a human. Background technique [0002] Jasmonate is a family of plant stress hormones obtained from linolenic acid through stearic acid. Trace amounts of jasmonate have been found in various edible plants. Stress hormones such as the jasmonate family are produced in plants and are released during periods of stress such as extreme ultraviolet radiation, osmotic shock, heat shock and pathogen attack to initiate various cascades that culminate in an appropriate response. Examples of members of the jasmonate family are jasmonate, which is critical for intracellular signaling in response to injury, and jasmona...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D277/60A61K31/428
Inventor 马科斯·赫茨伯格艾德里安·哈瑞尔克里斯汀·曼格
Owner SEPAL PHARMA LTD
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