Helianthrone derivatives as anti-cancer agents

Details Helianthrone derivatives as anti-cancer agents Helianthrone derivatives as anti-cancer agents

2000-01-31

2001-05-08

Dees, Jose′ G. (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C564S301000, C564S305000, C564S308000, C568S303000, C568S306000, C568S326000

Reexamination Certificate

active

06229048

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to the therapeutic use of helianthrones, particularly of 1,3,4,6-tetrahydroxy-helianthrone and derivatives thereof as anti-cancer agents both in the presence and in the absence of light irradiation. In conjunction with light irradiation, these compounds are photosensitizers useful in photodynamic therapy (PDT). The present invention also provides some novel 1,3,4,6-tetrahydroxy-helianthrone derivatives.
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 serine/threonine residues by protein kinases A, B, and C. Protein kinase C (PKC) is also an important cellular signal transducer that contains a catalytic domain which phosphorylates substrates and a regulatory domain which controls its activity. Polyhydroxylated flavones such as genistein and quercetin were identified as inhibitors of the phosphorylation kinases (Losiewicz et al, 1994).
Perylene quinones are a unique group of kinase inhibitors (Diwu et al, 1994). The first of these compounds to be thoroughly evaluated was hypericin, a potent photodynamic agent initially discovered by the present inventors to be virucidal to retroviruses (Lavie et al, 1989; Meruelo et al, 1988), and subsequently to all lipid-enveloped viruses (Tang et al, 1990). Additional studies identified hypericin as a potent and irreversible light-dependent inhibitor of protein kinase C (PKC), particularly when PKC is translocated to the cell membrane following cell activation, this PKC inhibitory activity of hypericin being possibly related to its antiretroviral activity (Takahashi et al, 1989).
Hypericin is able to act within biological systems in the dark, possibly because of a low red/ox potential, and this appears to enable electron scavenging from physiological transfer reactions (Lavie et al, 1994). The unique combination of properties of hypericin prompted its current clinical evaluation in phase II clinical trials as an anti-tumor agent in the treatment of malignant glioma (Couldwell et al, 1994). This neoplasia relies on PKC signaling for cell proliferation. Hypericin is also a potent photosensitizer capable of generating singlet oxygen and free radicals (Hadjur et al, 1994). These properties also render it useful in photodynamic therapy (PDT) of superficial tumors accessible to light irradiation.
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. It would be desirable to provide additional photosensitizing agents and cell proliferation signal transduction inhibitors which can elicit their cytotoxic effect with greater efficiency as compared with existing agents and, potentially, with lower and less severe side effects.
SUMMARY OF THE INVENTION
The present invention is based on the surprising findings that some helianthrone derivatives are capable, at micromolar concentrations, of inhibiting transduction of signals for cell proliferation and cell progression through the cell replication cycle, indicating that they can be used as antineoplastic agents for the treatment of cancer.
The present invention thus provides a method for inhibiting transduction of cell proliferation signals comprising administering to a patient in need thereof an effective amount of a compound of the general formula (I):
wherein R is selected from the group consisting of hydroxy, C
1
-C
10
alkoxy, NH-C
1
-C
10
alkyl, and NH-hydroxy(C
1
-C
10
) alkyl; R′ is selected from the group consisting of hydroxy and C
1
-C
10
alkoxy; and R
1
, R
2
, R
3
, R
4
, R
5
and R
6
are independently selected from the group consisting of hydrogen, hydroxy, chloro, bromo, C
1
-C
10
alkyl, C
1-C
10
alkoxy, and C
1
-C
10
alkoxycarbonyl.
In one embodiment, the treatment with the compound of formula (I) is carried out in the absence of light irradiation.
In another embodiment, the treatment of solid tumors, particularly superficial solid tumors accessible to light irradiation, with the compound of formula (I), is followed by light irradiation. Thus, in accordance with this embodiment of the invention, there is provided a method of photodynamic therapy (PDT) of tumors consisting of injecting to a patient an appropriate amount of a compound of formula (I) above, followed by local irradiation.
The present invention further provides pharmaceutical compositions comprising a compound of formula (I) and a pharmaceutically acceptable carrier.
The present invention still further provides novel compound of formula (I), excepting the compound wherein R and R′ are hydroxy and R
1
to R
6
are each hydrogen.
The compound of formula (I) wherein R and R′ are hydroxy and R
1
to R
6
are each hydrogen, namely 1,3,4,6-tetrahydroxy-helianthrone, was synthesized by Rodewald et al (1977) using 1,3-dihydroxy-anthrone as the starting material. The structure assigned to the resulting compound by the authors of said publication was mistaken, and found by the present inventors to be 1,3,4,6-tetrahydroxy-helianthrone.


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Rodewaldet et al, “Synthesis of hypericin and related meso-nuphthodianthrones by alkaline dimerization of hydroxyanthraquinones”,Angew Chem Int Ed Engl89(1):46-47 (1977).
Weiner et al, “EPR Studies of Hypericin. Photogeneration of Free Radicals and Superoxide”,J Chem Soc Perkin Trans2:1439-1442 (1992).

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