Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1989-08-18
1991-08-27
Brown, Johnnie R.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 28, 536 29, C07H 1900, C07H 1920
Patent
active
050434373
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the art of molecular biology and, more specifically, to novel 5'-phosphonates of 3'-azido-2',3'-dideoxynucleosides which are selective inhibitors of the reproduction of the virus of human immunodeficiency in a culture of human lymphocytes.
BACKGROUND OF THE INVENTION
Known in the art are various compounds inhibiting the reproduction of the virus of human immune deficiency. The most effective among the known compounds is 3'-azido-3'-dideoxythymidine (AZT) (Mitsuya, et al, Proc. Natl. Acad. Sci., U.S.A., 1985, 82, 7096-7100; M. A. Fischl, et al, New England J. Medicine, 1987, 317, 185-191; and D. D. Richman, et al, New England J. Medicine, 1987, 317, 192-197), incorporated herein by reference.
The molecular mechanism of the effect of AZT comprises its diffusion inside cells infected with the virus of human immune deficiency. Thereafter, it is subjected to triphosphorylation and specifically blocks the synthesis of a DNA catalyzed by a reverse transcriptase which is coded by the virus of human immune deficiency. However, AZT inhibits reproduction of the virus of human immune deficiency not in all types of human cells which is apparently associated with different degrees of conversion of AZT into AZT 5'-triphosphate (AZTTP). AZT is a toxic substance which mainly affects hemopoiesis and the activity of the central nervous system.
Other 3'-azido-2',3'-dideoxynucleosides with bases: cytosine (AzC), adenine (AzA) and guanine (AzG) also exhibit an inhibiting activity in reproduction of the virus of human immune deficiency, though less clearly pronounced as compared to AZT.
SUMMARY OF THE INVENTION
The present invention is directed to novel compounds exhibiting a selective inhibition of the reproduction of the virus of human immune deficiency and which possess low toxicity.
The present compounds are 5'-phosphonates of 3'-azido-2',3'-dideoxynucleosides having the formula ##STR2##
These compounds are capable of inhibiting the reproduction of the human immune deficiency virus and are less toxic as compared to the prior art compounds.
DETAILED DESCRIPTION OF THE INVENTION
The compounds according to the present invention are white amorphous powders, readily soluble in water, sparingly soluble in ethanol and insoluble in other organic solvents.
The purity and structure of the compounds according to the present invention were proven by chromatography, UV- and NMR-spectroscopy.
The compounds according to the present invention selectively inhibit the virus of human immune deficiency in vitro in a culture of human lymph cytes H9/IIIB MT4.
As the source of the virus of human immune deficiency use was made of grafted lymphoblastoidal lines of human cells producing said virus (H9/IIIB and MT4), the production of the virus by the cells was controlled in an immunofluorescence reaction and by means of electron microscopy. Cells were cultured in RPMI 1640 with a 15% inactivated serum of cow embryos with 300 .mu.g/ml of glutamine, 100 .mu.g/ml of gentamycin, 10 mM of HEPES-buffer and grown as a suspension. The cultured liquid was collected by centrifugation at 5,000 r.p.m. for 10 minutes and lymphocytes of the peripheral blood of healthy donors were used for infecting at the rate of 1 ml of a supernatant of a cultured liquid containing the virus of human immune deficiency per every 10.sup.6 lymphocytes of human peripheral blood isolated from the harinized blood of healthy donors in a phycoll-isopane gradient. The cells were cultures in RPMI 1640 with a 15% inactivated serum of cow embryos, 300 .mu.g/ml of glutamine, 100 .mu. g/ml of gentamycin, 100 mM of HEPES-buffer and incubated for 48 hours at 37.degree. C. in a humidified CO.sub.2 atmosphere in the presence of phytohemagglutinin at the concentration of 100 .mu.g/ml. A further culturing of lymphocytes after the incorporation of the virus was effected for 6 days in the presence of a 10% natural human lymphocytic interleukin-2.
The determination of an antigenic effect (immunoenzymatic analysis) of the material was car
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Bibilashvili Robert S.
Bukrinskaya, administrator by Alisa G.
Dergach, administrator by Dmitry J.
Dyatkina Natalya B.
Galegov Georgy A.
Brown Johnnie R.
Kunz Gary L.
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