Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Patent
1997-03-04
2000-05-02
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
514675, A61K 3122, A61K 3112
Patent
active
06057366&
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention relates to a method of treatment of cancer in mammals and in particular humans as well as a method of inhibition or prevention of lactation in mammals using compounds which may be obtained from avocado plants.
PRIOR ARTS
It is well known that avocado plant (ie Persea americana) leaves are toxic and this has recently been reported in Craigmill et al., Vet. Hum Toxicol 26 (5) October 1984 which demonstrated that the leaves of a Guatemalan variety avocado are toxic to dairy goats even after storage for two weeks at 4.degree. C. This was also demonstrated in an article entitled "The Toxicity of Avocado (Persea americana) Leaves for the Lactating Mammary Gland of the Goat" at the Proceedings of the Third International Symposium of Poisonous Plants pp 623-625 (1989). Reference is made in the 4th International Symposium on Poisonous Plants in 1993 to a presentation by Sani et al., to a toxin obtained from avocado leaves which was responsible for demonstrated toxicity for the heat and lactating mammary gland of the mouse.
It has also been demonstrated that three long chain C17 aliphatic compounds (ie. 4-keto-2-hydroxy-1-acetate, a 1,2-dihydroxy-4 acetoxy compound and a 1,4-dihydroxy-2-acetoxy compound, each with a terminal acetylenic bond, which were isolated from immature avocado seed, flesh and skin appeared to be the main constituents of an unpleasant bitter type flavour. This has been reported in Brown, J Agr Food Chem 20 No 4 (1972) 753-757.
Reference is also made to the isolation of a compound 1-acetoxy-2-hydroxy-4-oxo-heneicosa-12,15-diene from avocado plants in the following references 367-374; (1990); (1991);
The above compound from the reference (i) above was isolated from avocado leaves and inhibited the growth of silkworm larvae.
The remainder of the abovementioned references [ie. (ii) to (xiii)] are concerned with the above compound which when isolated from avocado fruit peel or whole fruits exhibits antifungal activity in relation to the fungus Colletotrichum gloeosporioides which infects avocado and causes anthracnose in ripe fruit. The levels of the compound in avocado fruit may be decreased by degradation of the compound which is catalysed by the enzyme avocado lipoxygenase. The activity of the enzyme may increase during ripening of the fruit owing to the decline of an inhibitor of the enzyme (ie. epicatechin). The above literature also shows that the above phenomena suggest that this is why infection by the fungus is latent in unripe fruit.
Surprisingly it has now been discovered that the compounds described herein in formula (1) herein have anti-cancer activity and that such activity is particularly relevant in regard to breast cancer or cancer which may effect the mammary gland.
It has also been surprisingly discovered that these compounds inhibit or prevent lactation in mammals.
SUMMARY OF THE INVENTION
It is therefore an object of the invention to provide a method of treatment of mammals suffering from cancer and in particular breast cancer as well as a method of inhibition or prevention of lactation in mammals by administering of the compounds of formula (1) herein to such mammals and in particular humans.
It is a further object of the invention to provide anti-cancer or anti-lactation compositions which may contain the above compounds.
In the above compounds of formulae (1) R may refer to a side chain of 4 to 20 carbons and more preferably 17 carbons which may tolerate a minor degree of unsaturation (e.g. (1, 2 or 3 unsaturated bonds) as well as a minor degree of branching. Preferred compounds have the formulae 1(a) and 1(b) as shown in FIG. 1.
The chemical Abstracts Index name of the active compound that was isolated from avocado leaves as discussed above is (+)-(Z,Z)-1-acetyloxy-2-hydroxy-12,15-heneicosadien-4-one. An alternative name which is used in the aforementioned prior art is cis,cis-1-acetoxy-2-hydroxy-4-oxoheneicosa-12,15 diene.
The naturally occurring compound is the (+) or R isomer. Both the (.+-.) racemate and the (-) or S isomer ha
REFERENCES:
Chang, C et al.; "Isolation and Structure Elucidation of Growth Inhibitors for Silkworm Larvae from Avocado Leaves" Agr Biol Chem, 39(5), 1975, pp. 1167-1168.
Prusky, D et al.; "Possible Involvement of an Antifungal Diene in the Latency of Colletotrichum gloeosporioides on Unripe Avocado Fruits"; Phytophathology, 72(12), 1982, pp. 1578-1582.
Bull, Steven D et al.; "Synthesis of the Avocado Antigungal, (z,Z)-2-Hydroxy-4-oxohenicasa-12, 15-dien-1-yl Acetate", Aust J Chem. 47, 1994; pp. 1661-1672.
Craigmill, Arthur L, et al, et al.; "The Toxicity of Avocado (Persea americana) Leaves for the Lactating Mammary Gland of the Goat"; Poisonous plants: Proceedings of the third international Symposium; 1st Edition Iowa State Univeristy Press; 1992; pp. 623-625.
Craigmill, Arthur L, et al.; "Toxicity of Avocado (Persea Americana (Guatamalan var) Leaves: Review and Preliminary Report"; Vet Hum Toxicol 26(5) Oct. 1984; pp. 381-383.
"The Toxicity of Avocado (Persea Americana) Leaves for the Lactating Mammary Gland of the Goat" at the Proceedings of the Third International Symposium of Poisonous Plants, 1989, 623-625.
"The Toxicity of Avocado Leaves for the Heart and Lactating Mammary Gland in the Mouse" by Sani, et al. presented at the 4th International Symposium on Poisonous Plants in 1993.
Brown, Brian I., 1972, J. Agric. Food Chem. 20 753-757.
Prusky, et al., 1983, Physiological Plant Pathology 22 189-198.
Prusky, et al., 1985, Physiological Plant Pathology 27 267-279.
Prusky, Dov, 1988, Plant Disease 72(5) 381-384.
Prusky, et al., J. Phytophathology 123 (2) 140-146.
Karni, et al., 1989, Physiological and Molecular Plant pathology 35 367-374.
Sivanathan, et al.,1989, J. Phytopathology 125(5) 97-109.
Prusky, et al., 1990, Physiological and Molecular Plant Pathology 37425-435.
Prusky, et al., 1991, Physiololgical and Molecular Plant Pathology 39 325-334.
Plumbley, et al., 1993, Plant Pathology 42 116-120.
Prusky, et al., 1991, Plant Pathology 40 45-52.
Prusky, et al., 1991, Phytopathology 131(4) 319-327.
Carman Raymond Maurice
MacLeod John Keith
Ng Jack Chakmeng
Oelrichs Peter Brenchley
Schaeffeler Lothar
Goldberg Jerome D.
The Australian National University
The University of Queensland
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