Helianthrone derivatives as anti-cancer agents

a technology of helianthrone and derivatives, applied in the field of polycyclic dianthraquinones, can solve problems such as severe side effects, and achieve the effects of preventing metastatic growth, preventing incurable metastases, and stimulating the growth of micrometastases

Inactive Publication Date: 2005-02-17
YEDA RES & DEV CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

Hypericin and helianthrone and derivatives of both are now disclosed to interfere with the process of tumor angiogenesis. This discovery renders these compounds useful as treatment modalities in cancer patients undergoing surgical removal of primary tumors to prevent the growth of incurable metastases. Surgery has been established to stimulate the growth of micrometastases that were maintained dormant by growth factor inhibitors secreted from the primary tumors. These compounds may prevent metastatic growth by interfering with the production or activity of vascular endothelial growth factor (VEGF) or other angiogenic factors. VEGF, a potent enhancer of vascular permeability, is known to exert in vivo a key role in pathological neovascularization associated with many diseases including tumor neovascularization, rheumatoid arthritis, and diabetic retinopathy.

Problems solved by technology

Unfortunately, hypericin is active in only half of the cases and, in addition, may cause severe side effects, such as prolonged post-treatment sensitivity to light, a condition medically known as hypericism.

Method used

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  • Helianthrone derivatives as anti-cancer agents
  • Helianthrone derivatives as anti-cancer agents
  • Helianthrone derivatives as anti-cancer agents

Examples

Experimental program
Comparison scheme
Effect test

example 1

Killing of Malignant Tumor Cells in Culture by Dimethyl-TMH and TMH in the Dark

Three human malignant cell lines were evaluated to sensitivity to dimethyl TMH in vitro. Human U251 glioblastoma, U87MG glioblastoma and LAN5 neuroblastoma cells were plated (2×105 per well) in 96-well flat bottom microculture plates, treated with dimethyl-TMH and hypericin at dose ranges of 0 (control), 0.1 -20 μM in complete darkness for a period of 72 hours. The medium was aspirated, the adherent monolayer was washed with phosphate-buffered saline, and cell viability was monitored by the MTT assay.

FIGS. 1, 2 and 3 show the results for the U251 glioblastoma, LAN5 neuroblastoma and U87MG glioblastoma cells, respectively, comparison of the cytotoxic activity with hypericin being shown in FIGS. 1 and 3. Cell viability was lost in all three after exposure to dimethyl-TMH for at least 72 hours, as measured in MTT viability assays. Loss of cell viability following treatment with dimethyl-TMH in the dark of...

example 2

Light-Dependent, Photodynamic Effects of Dimethyl-TMH on Normal Primary Human Peripheral Blood Lymphocytes

Human peripheral blood lymphocytes (PBL) are non-proliferating cells in the absence of mitogenic stimuli. The effects of different doses of dimethyl-TMH on PBL were examined in the presence or absence of irradiation with polychromatic white light. PBL (post-mitotic) were plated (2×105 cells / well) in two separate round bottom 96-well plates (in triplicates). Dimethyl-TMH was added to the cultures. One plate was kept in the dark, and the other was exposed to polychromatic white light at a fluence rate of 8 mW / cm2 for 30 min (a total of 14.4 J / cm2). Both plates were then cultured at 37° C., 5% CO2 for 72 hours and cell viability was assayed by the MTT assay. The results, in FIG. 5, show that dimethyl-TMH had no effect on PBL viability in the absence of light irradiation, however, photosensitization with light caused cell death with an LD50 of approximately 0.65 μM dimethyl TMH, i...

example 3

Determination of the Cell Cycle Phases in which Dimethyl-TMH Arrests Malignant Tumor Cells Growth and Proliferation in the Dark

Cell cycle and DNA content analyses were conducted in U251 human glioblastoma cells after treatment with 5 μg / ml (10 μM) dimethyl-TMH for 24, 48 and 72 hours, and on LAN5 neuroblastoma cells after 48 hours. The cells were then stained with propidium iodide, washed with PBS and analyzed in a fluorescence activated cell sorter (FACS). A computer program arranged the DNA-related fluorescence as follows: the minimal amount of fluorescence is considered to be one whole set of cellular DNA related to the resting G1 phase. A double amount of fluorescence is considered to be G2 phase, in which the whole genome is duplicated following complete DNA synthesis, and the in-between amounts are considered to be the DNA synthetic S-phase, in which the total DNA synthesis is not yet completed.

The results, shown in FIGS. 6-7, reveal that administration of 10 μM dimethyl-T...

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Abstract

Hypericin and helianthrone derivatives of general formula (I)
wherein the dotted line between positions 11 and 12 represent an optional C11-C12 bond; R is independently selected from the group consisting of hydroxy, C1-C10 alkoxy, NH—C1-C10 alkyl, and NH-hydroxy(C1-C10)alkyl; R′ is independently selected from the group consisting of hydroxy and C1-C10 alkoxy; R″ is independently selected from the group consisting of hydrogen, hydroxy, C1-C10 alkoxy, NH—C1-C10 alkyl, and NH-hydroxy(C1-C10)alkyl; and R1, R2, R3, R4, R5 and R6 are independently selected from the group consisting of hydrogen, hydroxy, chloro, bromo, C1-C10 alkyl, C1-C10 alkoxy, and C1-C10 alkoxycarbonyl, provided that R″ is not hydrogen when there is a C11-C12 bond and when there is a C11-C12 bond and both R′ are hydroxy, both R″ groups are not hydroxy. These compounds and pharmaceutical compositions containing them as active agents are useful as inhibitors of angiogenesis and can be used to prevent formation of metastases and restenosis and for the treatment of angiogenesis-associated ophthalmologic disorders. In addition, the helianthrone derivatives of formula (I) can be used for the treatment of tumors in the absence of light irradiation.

Description

FIELD OF THE INVENTION The present invention relates to the therapeutic use of polycyclic dianthraquinones such as hyperycins and helianthrones as inhibitors of angiogenesis and to the use of some of them, particularly of 1,3,4,6-tetrahydroxy-helianthrone and derivatives thereof, as anti-cancer agents in the absence of light irradiation. BACKGROUND OF THE INVENTION The discovery of the signal transduction pathways that activate cell proliferation in response to interactions between growth factors and corresponding cellular receptors, triggered an extensive search for inhibitors that can interfere with this cascade in malignancies where malignant cells undergo uncontrolled proliferation. The chemical signals in this cascade have been identified as phosphorylation of proteins either on tyrosine residues, catalyzed by a group of enzymes collectively termed protein tyrosine kinases (PTK), or on senne / threonine residues by protein kinases A, B, and C. Protein kinase C (PKC) is also an ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/122A61K31/136A61K31/235
CPCA61K31/122A61K31/235A61K31/136A61P27/02A61P35/00A61P35/04A61P9/10
Inventor MAZUR, YEHUDALAVIE, GAD
Owner YEDA RES & DEV CO LTD
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