Helianthrone derivatives as anti-cancer agents

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 ...

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.

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