Farnesyl-protein transferase inhibitors

Details Farnesyl-protein transferase inhibitors Farnesyl-protein transferase inhibitors

2000-04-18

2002-08-06

Solola, T. A. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S139000, C549S299000, C549S305000, C562S408000

Reexamination Certificate

active

06429203

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to farnesyl-protein transferase inhibitors.
Ras proteins transduce extracellular signals to the nucleus and are part of a large superfamily of GTP-binding proteins that are active when bound to GTP and inactive when bound to GDP. After stimulation by receptor activation, Ras protein binds GTP and transmits a proliferative signal to the nucleus. Hydrolysis of GTP to GDP by a GTPase returns Ras to an inactive state. There are three human ras genes, Harvey (H), Kirsten (K) and N-ras, that each encode a 21 kDa Ras protein. Two splice variants of K-ras, K-4A and K-4B, also exist. Approximately 30% of all human cancers harbor ras mutations that typically impair GTP-ase activity, rendering Ras protein locked in a GTP-bound or active state. Kelloff, G. J. et al., (1997),
Cancer Epidemiol. Biomarkers Prev
., 6(4):267-282.
Ras proteins are initially synthesized as cytoplasmic, soluble proteins. Post-translational modifications serve to attach Ras protein to the plasma membrane. The amino acid sequences of Ras proteins all end in CAAX, where C is cysteine, A is an aliphatic amino acid and X is another amino acid. The first post-translational modification of Ras protein is attachment of a lipophilic 15-carbon farnesyl moiety (farnesyl pyrophosphate, FPP) to the cysteine residue of the CAAX moiety through a farnesyl-protein transferase (FPT) catalyzed reaction. Subsequently, the AAX tripeptide is proteolytically cleaved and the farnesylated cysteine is converted to its methyl ester. Additional lipid modifications of upstream residues further stabilize the association of Ras protein with the plasma membrane. Lemer, E. C. et al., (1997),
Anticancer Drug Des
., 12:229-238. A related enzyme, geranylgeranyltransferase (GGT) can transfer a 20-carbon geranylgeranyl moiety to the cysteine residue of the CAAX moiety when X is leucine.
It has been shown that inhibition of FPT blocks the anchorage-independent growth of fibroblasts transformed with ras mutants and results in other morphological changes and down-regulation of Ras-protein activated signalling cascades. Omer, Ch. A. et al., (1997),
BioFactors
, 6:359-366.
A number of farnesylation inhibitors have been developed. One class of inhibitors includes FPP competitive inhibitors that bind to FPT at the FPP binding site. Compounds of this group include synthetic analogs of FPP such as (&agr;-hydroxyfarnesyl)phosphonic acid, amide analogs, hydroxamate analogs, pivolyloxymethyl ester analogs and difluorinated &bgr;-ketophosphonic acid, as well as natural products such as actinoplanic acids, chaetomellic acids, manumycin, perillyl alcohol, d-limonene and metabolites, RPR113228 and zaragozic acid. Many of these compounds are selective for GGT rather than FPT and are inactive in whole cells. Perillyl alcohol and d-limonene have chemopreventive activity and reduce tumor size in animals.
A second class of inhibitors includes CAAX tetrapeptides that can serve as substrates and/or competitive inhibitors of FPT. Structure activity analysis has indicated that nonfarnesylated tetrapeptides containing an aromatic amino acid at the A
2
position of CA
1
A
2
X and a positive charge on the cysteine amino group are the most potent. Tetrapeptides have limited use in vivo since they are inactive in whole cells. A variety of peptidomimetics that are highly selective for FPT and are potent FPT inhibitors have also been synthesized. In most of these compounds, the peptide backbone was modified to increase stability. To increase membrane penetration, the C-terminal carboxylate was masked in certain compounds using an ester prodrug strategy. Many of these compounds inhibit H-Ras processing in cells and also suppress growth of tumors in animals. For a review of peptidomimetics, see Qian, Y. et al., (1997),
Biopolymers
, 43:25-41.
There are additional FPT inhibitors including barceloneic acid, cylindrol A, fusidienol, patulin, preussomerins and streptonigrins that have been identified from natural products. The mechanism of action of these compounds is unknown. Kelloff, G. J. et al, 1997, supra.
SUMMARY OF THE INVENTION
The invention provides novel phosphosesquiterpenes that function as farnesyl-protein transferase inhibitors. The phosphorylated compounds can be used as effective chemotherapeutic agents with fewer side effects than typically follow from use of other chemotherapeutic agents.
In one aspect, the invention features a substantially pure preparation of a phosphosesquiterpene. The phosphosesquiterpene is a phosphorylation product of a sesquiterpene lactone selected from the group consisting of ambrosanolides, psilostachyanolides, cadinanolides, eremanolides, xanthanolides, guaianolides, germacranolides, elamanolides and eudesmanolides.
The phosphosesquiterpene can be a phosphorylation product of the sesquiterpene lactone having formula A.
In formula A, C
1
is further bonded to hydrogen, hydroxy, short chain alkanoyloxy, or C
2
or C
10
via a double bond or an oxy linkage. C
2
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, hydroxy, oxo, short chain alkanoyloxy, and C
1
or C
3
via a double bond or an oxy linkage. C
3
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, oxo, and C
2
or C
4
via a double bond or an oxy linkage. C
4
is further bonded to hydrogen, hydroxy, short chain alkanoyloxy, or C
3
, C
5
, or C
15
via an oxy linkage or a double bond. C
5
is further bonded to hydrogen, hydroxy, short chain alkanoyloxy, or C
4
via an oxy linkage or a double bond. C
6
is further bonded to hydrogen and C
7
is further bonded to hydrogen or C
11
via a double bond. C
8
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, hydroxy, and short chain alkanoyloxy. C
9
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, and C
10
via a double bond. C
10
is further bonded to hydrogen, hydroxy, short chain alkanoyloxy, C
1
, or C
14
via an oxy linkage, or C
1
, C
9
, or C
14
via a double bond. C
11
is further bonded to hydrogen, hydroxy, hydroxymethyl, or C
7
or C
13
via a double bond. C
13
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, an optionally substituted alkylamino salt, and C
11
via a double bond. C
14
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen and C
10
via an oxy linkage or a double bond. C
15
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen and C
4
via an oxy linkage or a double bond.
The phosphosesquiterpene can be a phosphorylation product of the sesquiterpene lactone having formula B.
In formula B, C
1
is further bonded to hydrogen, hydroxy, short chain alkanoyloxy, or C
2
or C
10
via a double bond or an oxy linkage. C
2
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, hydroxy, oxo, short chain alkanoyloxy, and C
1
or C
3
via a double bond or an oxy linkage. C
3
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, oxo, and C
2
or C
4
via a double bond or an oxy linkage. C
4
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, hydroxy, short chain alkanoyloxy, and C
3
via an oxy linkage or a double bond. C
6
is further bonded to at least one of the following substituents independently selected from the group consisting of hydrogen, hydroxy, and short chain alkanoyloxy. C
7
is further bonded to hydrogen or C
11
via a double bond and C
8
is further bonded to hydrogen. C
9
is further bonded to at least one of the following s

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