Chalcones and esters thereof with antiproliferative activity in

Details Chalcones and esters thereof with antiproliferative activity in Chalcones and esters thereof with antiproliferative activity in

1997-06-12

1998-09-15

Geist, Gary

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

Organic compounds

Carboxylic acid esters

560138, 554229, 554228, 554224, C07C 6702, C07C 5300

Patent

active

058081372

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to the use of chalcone compounds or the esters thereof with straight or branched aliphatic acids, saturated and unsaturated containing up to 22 carbon atoms, in the therapy and prevention of uterus, ovary and breast tumours, as well as the formulations containing them.


BACKGROUND ART

Recently, some flavonoids proved to have anticancer activity (Cancer Research 48, 5754, 1988) and chemopreventive activity in some tumours (J. Nat. Prod. 53, 23, 1990). In particular quercetin, a flavonoid almost ubiquitous in plants, has shown some inhibiting activity on the proliferation of human leukemia cells (Br. J. of Haematology 75, 489, 1990) and on other cell lines (Br. J. Cancer 62, 942, 1990--Int. J. Cancer 46, 1112, 1990--Cancer Chemother. Pharmacol. 28, 255, 1991--Gynecologic Oncology 45, 13, 1991, 1992) besides a synergistic activity with the conventional chemotherapeutics. Although the mechanism of such an inhibiting action on proliferation is unknown, it is likely to be related to the interaction of this flavonoid with the estrogen receptors of type II (J. Steroid Biochem. 30, 71, 1988). These sites have first been described by Clark (J. Biol. Chem. 253, 7630, 1978) in 1978 in the rat uterus while displaying the same steroid and tissue specificity are distinct from the "true" estrogen receptors (ER) since they are present in a higher concentration than ER and have a lower apparent affinity dissociation constant (KD: 10-20 nM) for estradiol than ER (KD: 0.2-1 nM).


SUMMARY OF THE INVENTION

Now it has surprisingly been found that the chalcone-structure compounds isocordoin, 4-hydroxyderricin, 2-hydroxyderricin, 3-hydroxyderricin, 2',4'-dihydroxychalcone, 4,2',4'-trihydroxychalcone and cordoin have a remarkable affinity to estrogen receptors of type II, extremely higher than that of the known products, together with a marked antiproliferative activity on uterus, ovary and breast tumour cell lines.


DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The structures of the compounds cited above are as follows:


______________________________________ ##STR1## R.sub.1 R.sub.2 R.sub.3 R.sub.4 R.sub.5 ______________________________________ S1 Isocordoin H H Prenyl H H S2 4-hydroxyderricin Me OH Prenyl H H S3 2-hydroxyderricin Me H Prenyl OH H S4 3-hydroxyderricin Me H Prenyl H OH S5 2',4'- H H H H H dihydroxychalcone S6 4,2',4'- H OH H H H trihydroxychalcone S7 Cordoin Prenyl H H H H ______________________________________
Other chalcones strictly related to the former as far as the chemical structure is concerned, such as 4-hydroxycordoin and dihydrocordoin, whose structures are reported below, show no affinity to the above mentioned receptors.


______________________________________ ##STR2## Chalcones R.sub.1 R.sub.2 R.sub.3 ______________________________________ S8 4-hydroxycordoin prenyl OH H S9 Dihydrocordoin prenyl H H ______________________________________
Therefore the invention, in a first aspect, provides the use of the compounds of formula (I) for the preparation of medicaments with anticancer activity, in particular for the treatment of tumours expressing estrogen receptors of type II.
The invention, according to a further aspect, also provides the esters of the compounds of formula (I) with straight or branched aliphatic acids, saturated or unsaturated, containing up to 22 carbon atoms. Particularly preferred are the esters with acetic, butyric, palmitic or ximeninic acids.
The esters of the invention can be administered by the oral route and they are likely to behave as pro-drugs for chalcones I.
Finally, the invention provides pharmaceutical compositions containing compounds I or the esters thereof as active ingredients, in admixture with suitable excipients.
Compounds (I) can be prepared according to conventional methods reported by II Farmaco, 30, 449-55, 1975; II Farmaco, 32, 261-69, 1977; Il Farmaco, 30, 326-42, 1975.
The affinity of compounds I to the estrogen receptors of type II and the anti

REFERENCES:
patent: 3928421 (1975-12-01), Kyogoku et al.
patent: 5106871 (1992-04-01), Komazawa et al.
patent: 5234951 (1993-08-01), Komazawa et al.
IL Farmaco vol. 30, pp. 326-342, 1975 New Prenylated Chalcones From Lonchocanpus Neuroscapha Benth. de Lima et al.
IL Farmaco vol. 30, pp. 449-455, 1975 Synthesis of The Prenylated Chalcones From Corda Piaca. Lupi et al.
IL Farmaco vol. 32, pp. 261-269, 1977 Synthetic Analogs of Natural Prenylated and Chromene Chalcones. Lupi et al.
R. De Vincenzo et al., "Effect of synthetic and naturally occurring chalcones on ovarian cancer cell growth: structure-activity relationships", Anti-Cancer Drug Des., vol. 10, No. 4 (1995) pp. 481-490.

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