Novel lipophilic n-substituted norcantharimide derivatives and uses thereof

Active Publication Date: 2016-05-26
VETERANS GEN HOSPITAL TAIPEI +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Benefits of technology

The present patent is based on the discovery of two N-substituted norcantharimide derivatives that can slow down the growth of cancer cells. These compounds have potential to be used as therapeutic agents for treating various cancers such as leukemia, hepatic cancer, bladder cancer, colon cancer, kidney cancer, ovarian cancer, cervical cancer, endometrial carcinoma, prostate cancer, pancreatic cancer, lung cancer, breast cancer, melanoma, or squamous cell carcinoma (SCC). The patent describes a pharmaceutical composition containing these compounds and a method of treating cancer by administering the composition to a patient. The compounds can be used alone or in combination with other agents such as chemotherapy.

Problems solved by technology

However, it was also found to be poisonous to the kidney and liver.

Method used

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  • Novel lipophilic n-substituted norcantharimide derivatives and uses thereof
  • Novel lipophilic n-substituted norcantharimide derivatives and uses thereof
  • Novel lipophilic n-substituted norcantharimide derivatives and uses thereof

Examples

Experimental program
Comparison scheme
Effect test

example 2

Anti-Proliferative Activity of the Compounds of this Invention

[0092]Effects of the compounds of formula (I) of this disclosure, specifically, NOC15 and NC 15, on HepG2 cells (liver carcinoma), BFTC905 (bladder carcinoma), HT29 (colon carcinoma), SW480 (colon carcinoma) and HL60 (leukemia) were assessed by cell viability analysis in accordance with procedures described above, in which compound 2, and other known anti-cancer agents including 5-FU, cisplatin and doxorubicin were respectively used as positive controls. Results are summarized in Table 1.

TABLE 1Growth Inhibition On Various Cancer Cell LinesIC50 (μM) (Mean ± SD)CompoundHepG2BFTC905HT-29SW480HL-60Compound 242.0 ± 1.818.9 ± 0.319.5 + 0.249.1 + 8.4NDCompound 9 8.3 ± 1.311.3 ± 1.0 9.7 ± 1.718.5 ± 2.339.0 ± 1.1(NOC15)Compound16.4 ± 1.2 9.3 ± 0.614.8 ± 1.933.1 ± 1.079.8 ± 1.118 (NC15)5-FU40.2 ± 7.6NDND32.7 ± 8.3NDCisplatin36.1 ± 3.1—a24.1 ± 0.140.7 ± 1.2NDDoxorubicin 0.3 ± 0.0—a 1.7 ± 0.2 0.5 ± 0.114.3 ± 0.9aNot tested.ND indica...

example 3

Anti-Proliferative Activities of NOC15 and NC15 on Human Hepatic Cancer

3.1 Cell Viability Analysis

[0094]In this example, effects of NOC15 or NC15 on HepG2 cells were assessed by cell viability analysis in accordance with procedures described above, in which compound 2 was used as a positive control. Results are summarized in Table 2.

TABLE 2Growth Inhibition On Hepatic Cancer CellsIC50 (μM) (Mean ± SD)Compound24 hrs48 hrs72 hrsCompound 248.0 ± 0.7 42.0 ± 1.8  22.8 ± 0.6  Compound 9 10.7 ± 0.2*** 8.3 ± 1.3*** 8.2 ± 0.6***(NOC15)Compound 1819.43 ± 2.1**16.4 ± 1.2***12.8 ± 2.5***(NC15)**p ****P

[0095]It is evident from Table 2, NOC15 and NC 15 were respectively at least 3 to 4 times more potent than compound 2, in which same level of inhibition in terms of the reduction in cell number was achieved at 1 / 3 to 1 / 4 of the dose of compound 2.

3.2 Nuclear Morphological Changes

[0096]To further investigate the role of apoptosis in the cytotoxicity of NOC15 and NC15, HepG2 cells were incubated wi...

example 4

Anti-Proliferative Activities of NOC15 on Leukemia

4.1 Cell Viability Analysis

[0101]In this example, a model of phorbol 12-myristate 13-acetate plus ionomycin (PMAI) activated leukemia Jurkat T cells model was employed to investigate the effects of the NOC15 on human leukemia cells (Jurkat T cells) and human lymphoblast cells (NHL).

[0102]As depicted in FIG. 4A, compound 2 alone did not possess significant cytotoxicity to normal lymphatic cells, but was toxic to leukemia cancer Jukat T cells. Further, the percentage of viable cells increased slightly if cells were pre-treated with phorbol 12-myristate 13-acetate (PMA), an agent that is known to protect cells from apoptosis. Similar results were also observed in NOC15 treated cells (FIG. 4B). The finding confirmed that both compound 2 and NOC15 suppressed cell growth via interfering the mitogen-activated protein kinase pathway.

4.2 Cell Cycle Distribution Analysis

[0103]Cell cycle distribution was determined by flow cytometry as describe...

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Abstract

Novel N-substituted norcantharimide derivatives are disclosed herein. The novel N-substituted norcantharimide derivatives are useful as lead compounds for manufacturing a medicament or a pharmaceutical composition for treating cancer, particularly for treating leukemia.

Description

BACKGROUND OF THE INVENTION[0001]1. Field of the Invention[0002]The present disclosure relates to novel synthetic compounds of N-substituted norcantharimide derivatives, and their uses for manufacturing a medicament or a pharmaceutical composition for treating cancer.[0003]2. Description of Related Art[0004]Cantharidin, one of the active compounds isolated from Mylabris, is a potent serine / threonine protein phosphatase 1 (PP1) and phosphatase 2A (PP2A) inhibitor, and has been shown to possess anti-cancer properties both in vitro and in vivo. However, it was also found to be poisonous to the kidney and liver. Research in the past has tried to identify analogues and / or derivatives of cantharidin that exhibit anti-cancer activity without significant cytotoxicity towards normal tissues, and norcantharidin and norcantharimide have thus been produced. Norcantharidin, which is the de-methylated form of cantharidin, is found to possess less nephrotoxicity, yet the demethylation also results...

Claims

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Application Information

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IPC IPC(8): C07D491/18
CPCC07D491/18
Inventor KUO, CHENG-DENGCHEN, YU-JENWU, JIN-YILIAO, HUI-FEN
Owner VETERANS GEN HOSPITAL TAIPEI
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