Isoprenoid analog compounds and methods of making and use...

Details Isoprenoid analog compounds and methods of making and use... Isoprenoid analog compounds and methods of making and use...

2002-04-03

2004-04-27

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C558S152000, C558S155000

Reexamination Certificate

active

06727234

ABSTRACT:

BACKGROUND OF THE INVENTION
Prenylation of proteins is a common form of post-translational processing found in many biological systems. For example, at least 300 human proteins are prenylated and many of these proteins play critical roles in essential signal transduction pathways. Mevalonic acid derivatives, known collectively as isoprenoids, are known to be central to mammalian metabolism, but the smaller intermediates in this pathway were viewed primarily as precursors to larger compounds such as steroids and dolichols. Not until 1989 was the presence of prenylated cysteines demonstrated in mammalian cells. The number of prenylated proteins continues to grow, with sequences for at least 300 prenylated proteins now recognized in humans corresponding to about 1% of the total cellular protein by mass. These include all of the known monomeric and trimeric G proteins, proteins which play central roles in a variety of signal transduction processes that regulate cell growth. Therefore, inhibition or modification of protein prenylation processes is a promising area for the development of new therapeutic agents and treatment methods, for example, anticancer agents and cancer treatments. Additionally, diagnosis or treatment regimes directed toward inhibition or modification of protein prenylation processes can be improved and refined with the help of enhanced means and methods of detecting changes in vivo or in vitro in the prenylation process.
Goody reported the preparation of detectable terpenoid analog compounds as substrates for GGPTase II in vitro. (
Angew. Chem., Int. Ed. Eng
., 1999, 38, 509-512; See also J. Davisson, et al.
J. Org. Chem
. 1986, 51, 4768-4779.) However, potential biologic and chemical instability considerations of these compounds may limit their utility, for example, in in vivo experiments where intracellular esterases can cleave the anthranilic ester linkage to the component parts thereby liberating a fluorescent anthranilic acid.
Other publications of interest are listed in the references section below.
U.S. Pat. Nos. 5,998,204 and 6,197,928 are of general interest and relate to fluorescent protein sensors for detection of analytes, for example, localization sequences for prenylation or for insertion into a plasma membrane (CaaX) CAAX [(SEQ ID NO:51][).
Thus, there is a continuing need for compounds which can inhibit the prenylation process, and have improved stability, improved spectral detectability, or both.
SUMMARY OF THE INVENTION
The present invention provides analog compounds of key intermediates of isoprenoid biosynthesis and metabolism. These analogs can be prepared through chemical synthesis and can function as alternate substrates for enzymes involved in post-translation processing in either in vitro or in vivo. The compounds of the invention can be potent prenylation process inhibitor compounds which can also have improved stability, improved spectral detectability, or both. The compounds of the invention are also useful as probes for studying the prenylation process and related processes.
The invention provides a compound of formula I:
wherein:
X is independently —NR
a
—, O, or S;
R
1
is a detectable group;
R
2
is independently
OH,
(C
1
-C
10
)alkanoyloxy,
—O—P(═O)(—OR
a
)
2
,
—O—P(═O)(—OR
a
)—O—P(═O)(—OR
a
)
2
,
—CH
2
—O—P(═O)(—OR
a
)
2
,
—CH
2
—O—P(═O)(—OR
a
)—O—P(═O)(—OR
a
)
2
,
—CH
2
—P(═O)(—OR
a
)
2
,
—CH{—P(═O)(—OR
a
)
2
}
2
,
—CH
2
—P(═O)(—OR
a
)—O—P(═O)(—OR
a
)
2
,
—CH═CH{—P(═O)(—OR
a
)
2
}, or
—CH═C{—P(═O)(—OR
a
)
2
}
2
;
each R
a
is independently hydrogen, (C
1
-C
10
)alkyl, (C
1
-C
10
)alkanoyl, (C
1
-C
10
)alkanoyloxy, (C
1
-C
10
)alkoxycarbonyl, or —CH
2
—O—(C
1
-C
10
)alkanoyl;
n is independently 1, 2, or 3;
or a pharmaceutically acceptable salt thereof.
The invention also provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable diluent or carrier.
The invention also provides a method of treating cancer, comprising administering to a mammal afflicted with cancer, an amount of a compound of the invention effective to treat the cancer.
The invention also provides a method of inhibiting a prenylation transferase or synthase enzyme comprising contacting the enzyme in vivo or in vitro with an effective amount of a compound of the invention.
The invention also provides a method of accessing the metabolic status of an enzyme, such as a prenylation transferase enzyme, comprising:
contacting the enzyme with an effective amount of a mixture of a farnesol analog compound of the invention and a geraniol or geranylgeraniol analog compound of the invention, and as described herein; and
measuring the relative ratio, or levels, of farnesylation to geranylgeranylation of the farnesol and geraniol or geranylgeraniol analog compounds accomplished by the enzyme, and wherein the ratio correlates with the metabolic status of the enzyme.
The invention also provides a compound of the invention for use in medical therapy or diagnosis, for example, treating cancer.
The invention also provides for the use of a compound of the invention for the manufacture of a medicament useful for the treatment of cancer.
The invention also provides for the use of a compound of the invention for the manufacture of a medicament useful for inhibiting prenylation transferase or synthase enzymes in a mammal.
The invention also provides processes and intermediates disclosed herein that are useful for preparing compounds of the invention. Some compounds of the formula I are useful as intermediates in preparing other compounds of formula I.


REFERENCES:
patent: 5574025 (1996-11-01), Anthony et al.
Adjei, A.A., et al., “A Phase I Trial of the Farnesyl Transferase Inhibitor SCH66336: Evidence for Bioligical and Clinical Activity”,Cancer Research, vol. 60, (Apr. 1, 2000), pp. 1871-1877.
Ashar, H.R., et al., “Farnesyl Transferase Inhibitors Block the Farnesylation of CENP-E and CENP-F and Alter the Association of CENP-E with the Microtubules”,The Journal of Biological Chemistry, vol. 275, No. 39, (Sep. 29, 2000), pp. 30451-30457.
Bergo, M.O., et al., “Targeted Inactivation of the Isoprenylcysteine Carboxyl Methyltransferase Gene Causes Mislocalization of K-Ras in Mammalian Cells”,The Journal of Biological Chemistry, vol. 275, No. 23, (2000), pp. 17605-17610.
Casey, P.J., et al., “Enzymatic modification of proteins with a geranylgeranyl isoprenoid”, Proc. Natl. Acad. Sci. USA, vol. 88, (Oct., 1991), pp. 8631-8635.
Cermak, D.M., et al., “2-(Acyloxy)ethylphosphonate Analogues of Prenyl Pyrophosphates: Synthesis and Biological Characterization”,Bioorganic & Medicinal Chemistry, vol. 8, (2000), 2729-2737.
Cermak, D.M., et al., “Synthesis of Nonracemic Dimethyl &agr;-(Hydroxyfarnesyl)phosphonates via Oxidation of Dimethyl Farnesylphosphonate with (Camphorsulfonyl)oxaziridines”,J. Org. Chem., vol. 64, No. 2, (1999), pp. 388-393.
Chang, Jen-Wen, A., et al., “Stereoelectronic Effects on the Conformation and Kinetics of Nucleophilic Desplacement Reactions in Epimeric Six-membered Ring Phosphonate Diesters”,Tetrahedron, vol. 43, No. 22, (1987), pp. 5187-5196.
Chehade, K.A., et al., “Design and Synthesis of a Transferable Farnesyl Pyrophosphate Analogue to Ras by Protein Farnesyltransferase”,J. Org. Chem. vol. 65, No. 10, (2000), pp. 3027-3022.
Chen, Z., et al., “Both Farnesylated and Geranylgeranylated RhoB Inhibit Malignant Transformation and Suppress Human Tumor Growth in Nude Mice”,The Journal of Biological Chemistry, vol. 275, No. 24, (Jun. 16, 2000), pp. 17974-17978.
Davisson, V.J., et al., “Phosphorylation of Isoprenoid Alcohois”,J. Org. Chem. vol. 51, No. 25 (1986), pp. 4768-4779.
Ding, C.Z., et al., “Discovery and Structure-Activity Relationships of Imidazole-Containing Tetrahydrobenzodiazepine Inhibitors of Farnesyltransferase”,J. Med. Chem., vol. 42, No. 25, (1999), pp. 5241-5253.
Du, W., et al., “Geranylgeranylated RhoB Mediates Suppression of Human Tumor Cell Growth by Farnesyltransferase Inhibitors”,Cancer Research

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