Novel reverse-turn mimics inhibit farnesyl transferase (original) (raw)
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Preparation of a clinically investigated ras farnesyl transferase inhibitor
Journal of Heterocyclic Chemistry, 2003
The synthesis of ras farnesyl-protein transferase inhibitor 1 is described on a multi-kilogram scale. Retrosynthetic analysis reveals chloromethylimidazole 2 and a piperazinone 3 as viable precursors. The 1,5disubstituted imidazole system was regioselectively assembled via an improved Marckwald imidazole synthesis. A new imidazole dethionation procedure has been developed to convert the Marckwald mercaptoimidazole product to the desired imidazole. This methodology was found to be tolerant of a variety of functional groups providing good to excellent yields of 1,5-disubstituted imidazoles. A new Mitsunobu cyclization strategy was developed to prepare the arylpiperazinone fragment 3.
Farnesyl Diphosphate-Based Inhibitors of Ras Farnesyl Protein Transferase
Journal of Medicinal Chemistry, 1995
The rational design, synthesis, and biological activity of farnesyl diphosphate (FPP)-based inhibitors of the enzyme Ras farnesyl protein transferase (FPT) is described. Compound 3, wherein a ,&carboxylic phosphonic acid type pyrophosphate (PPI surrogate is connected to the hydrophobic farnesyl group by a n amide linker, was found to be a potent (150(FPT) = 75 nM) and selective inhibitor of FPT, as evidenced by its inferior activity against squalene synthetase (15dSS) = 516 pM) and mevalonate kinase (150(MK) = '200 pM). A systematic structureactivity relationship study involving modifications of the farnesyl group, the amide linker, and the PP surrogate of 3 was undertaken. Both the carboxylic and phosphonic acid groups of the P-carboxylic phosphonic acid PP surrogate are essential for activity, since deletion of either group results in 50-2600-fold loss in activity (6-9, 1 5 0 = 4.6-220 pM). The farnesyl group also displays very stringent requirements and does not tolerate one carbon homologation (12, 1 5 0 = 17.7 pM), substitution by a dodecyl fragment (14,150 = 9 pM), or introduction of a n extra methyl group at the allylic position (18,150 = 55 ,LAM). Modifications around the amide linker group of 3 were more forgiving, as evidenced by the activity ofN-methyl analog (21,150 = 0.53 pM), the one carbon atom shorter farnesoic acid-derived retroamide analog (32,150 = 250 nM), and the exact retroamide analog (49, 1 5 0 = 50 nM). FPP analogs such as 3, 32, and 49 are novel, potent, selective, small-sized, nonpeptidic inhibitors of FPT that may find utility as antitumor agents.
Hydroxamic Acid-Based Bisubstrate Analog Inhibitors of Ras Farnesyl Protein Transferase
Journal of Medicinal Chemistry, 1996
The rational design, synthesis, and activity of novel, hydroxamic acid-based, collective bisubstrate analog inhibitors of farnesyl protein transferase (FPT) is described. This class of compounds differ structurally from the conventional FPT inhibitors by being non-sulfhydryl and by being bisubstrate based rather than peptide or FPP derived inhibitors. Whereas replacement of the sulfhydryl group of tetrapeptide CVLS (I 50) 1 µM) by an N-methylhydroxamic acid had a deleterious effect (10, I 50 > 360 µM), moderate inhibition was realized with 16 (I 50) 42.5 µM), a bisubstrate analog involving anchorage of farnesyl and tripeptide groups by a hydroxamic acid-embedded linker. Starting from 16, a 1 order of magnitude improvement in in vitro potency was obtained by optimization of the linker (20, I 50) 4.35 µM). An additional 13-fold enhancement was achieved by substituting the tripeptide moiety VLS in 20 by VVM (23, I 50) 0.33 µM). The dependence of these inhibitors on their peptide and farnesyl subunits is suggestive of their bisubstrate nature. Compound 23 (I 50) 0.33 µM) is 2 orders of magnitude better in activity compared to the initial lead 16 (I 50) 42.5 µM) and is effective in blocking prenylation of protein in whole cells including p21 ras .
Farnesyltransferase inhibitors versus Ras inhibitors
Current Opinion in Chemical Biology, 1997
Over the past few years, the idea that farnesyl-protein transferase (FPTase) inhibitors might be effective antiproliferativelantitumor agents has been realized in studies of cultured cells and in rodent models of cancer. Most of the studies with FPTase inhibitors have focused on inhibiting the growth of ras-transformed cells in vitro or the growth of ras-dependent tumors in mice. More recently, it has been recognized that the antiproliferative effect of FPTase inhibitors may extend beyond ras-driven tumors. It now seems likely that the ability of FPTase inhibitors to reverse the malignant phenotype results, at least in part, from inhibiting the farnesylation of proteins other than Ras. Addresses Boyartchuk VL, Ashby MN, Rine J: Modulation of Ras and afactor function by carboxyl-terminal proteolysis. Science 1997, 275:1796-l 600. First molecular characterization of a CaaX protease. Genetic inhibition of the protease inhibited Ras function in yeast but was not toxic to the yeast. This work should lead to the cloning of mammalian CaaX protease, which is a potential target for the development of inhibitors with anti-Ras activity. 9. Clarke S: Protein isoprenylation and methylation at carboxylterminal cysteine residues. Annu Rev Biochem 1992, 61:355-386. 10. Dudler T, Gelb MH: Palmitoylation of Ha-Ras facilitates membrane binding, activation of downstream effecters. and meiotic maturation in Xenopus oocytes. J Biol Chem 1996, 271 :11541-l 1547. Farnesyltransferase inhibitors versus Ras inhibitors Gibbs et a/. 203 22. James GL, Goldstein JL, Brown MS: Polylysine and CVIM sequences of K-RasB dictate specificity of prenylation and confer resistance to benzodiazepine peptidomimetic in vitro. J Biol Chem 1995, 270:6221-6226. 23. Rowell CA, Kowalczyk JJ, Lewis MD, Garcia AM: Direct . . demonstration of geranylgeranylation and farnesylation of Ki-Ras in Go. J Biol Chem 1997, 272:14093-l 4097. Please see annotation I1 5.01.
Drug Development Research, 1995
Protein prenylation is increasingly recognized as an important mechanism by which functional association of proteins to membranes is mediated. Ras proteins, regulators of cell proliferation and differentiation, are among the proteins that undergo farnesylation, one of the two prenylation modifications known. Since ras proteins are activated into hyperactive oncogenic versions in a wide variety of human cancers, agents that down modulate ras activity could be antineoplastic. Therefore, inhibitors of farnesyltransferase have the potential to be of therapeutic value as anticancer agents due to their ability to block ras processing and hence its function. We describe the identification of two farnesyl pyrophosphate (FPP) analogs that are potent and selective inhibitors of farnesyltransferase. While showing no toxicity to untransformed cells, a pivaloyloxymethyl ester of one of these inhibitors blocked ras mediated transformation of NIH 3T3 cells. In addition, both the ester and its parent acid inhibited ras farnesylation as measured by incorporation of labeled mevalonate into ras proteins in whole cells. Thus, this is the first report of an FPP analog to show biological activity by inhibiting ras processing in whole cells. © 1995 Wiley-Liss, Inc.
The Journal of Organic Chemistry, 2000
The posttranslational addition of a farnesyl moiety to the Ras oncoprotein is essential for its membrane localization and is required for both its biological activity and ability to induce malignant transformation. We describe the design and synthesis of a farnesyl pyrophosphate (FPP) analogue, 8-anilinogeranyl pyrophosphate 3 (AGPP), in which the ω-terminal isoprene unit of the farnesyl group has been replaced with an aniline functionality. The key steps in the synthesis are the reductive amination of the R, -unsaturated aldehyde 5 to form the lipid analogue 6, and the subsequent conversion of the allylic alcohol 7 to the chloride 8 via Ph 3 PCl 2 followed by displacement with [(n-Bu) 4 N] 3 HP 2 O 7 to give AGPP (3). AGPP is a substrate for protein farnesyltransferase (FTase) and is transferred to Ras by FTase with the same kinetics as the natural substrate, FPP. AGPP is highly selective, showing little inhibitory activity against either geranylgeranyl-protein transferase type I (GGTase I) (K i ) 0.06 µM, IC 50 ) 20 µM) or squalene synthase (IC 50 ) 1000 µM). AGPP is the first efficiently transferable analogue of FPP to be modified at the ω-terminus that provides a platform from which additional analogues can be made to probe the biological function of protein farnesylation. AGPP is the first example of a class of compounds that are alternate substrates for protein isoprenylation that are not inhibitors of squalene synthase.
Potent, non-thiol inhibitors of farnesyltransferase
Bioorganic & Medicinal Chemistry Letters, 1998
The structure-activity relationship of a series of non-thiol CaaX analogs, which are inhibitors of farnesyltransferase, is described. These inhibitors contain a substituted phenyl group at the N terminus, which may occupy a novel binding domain on the Ras protein.