Farnesylation inhibitors agents

Introduction Cyclooxygenase-2 Antiangiogenesis Agents Signal Transduction Inhibitors Ras Farnesylation Inhibitors Cell Cycle Inhibitors Promotors of Apoptosis Conclusions References... 

Fig. 1 Heterocycles bearing a 2-pyridone moiety with wide range of medicinal applications. Amrinone WIN 40680 1 is a cardiotonic agent for the treatment of heart failure. ZAR-NESTRA 2 is a selective farnesyl protein inhibitor and NP048 3 is a pilicide with novel antibacterial properties. The 2-pyridones 4, 5 and 6 are schematic representations of the three categories of 2-pyridones that wiU be covered in this chapter i.e., substituted 2-pyridones 4, 2-quinolones 5 and other ring-fused 2-pyridones 6...

The protein Ras, an important intracellular signal transducer, is crucially involved in the development of tumor growth. The farnesylation of Ras, catalyzed by the enzyme Ras-farnesyl-transferase, is essential to its proper functioning in the normal and in the transformed state. Therefore, the inhibition of Ras lipidation has become a promising target for the development of new classes of anti-tumor agents. This review focuses on the different classes of Ras-farnesyl-transferase inhibitors and compares their biological properties and modes of action in vitro as well as in vivo. 

To function, Ras must be attached to the plasma membrane. Translocation from the cytoplasm to membrane requires a series of posttranslational modifications that begin with farnesylation of the cysteine residue, the fourth amino acid residue from the C terminus of the protein, by famesyl protein transferase (FPTase) (64). Attachment of the hydrophobic 15-carbon lipid farnesyl group allows Ras molecule insertion into the plasma membrane and is crucial for Ras signaling activity and transformation properties. As farnesylation is required for oncogenic Ras function, FPTase inhibitors (FTIs) are obvious candidate antineoplastic agents. Several drugs that inhibit Ras farnesylation are at various stages of clinical development (65). 

Synthesis of a Selective, Non-Peptide, Non-Sulfhydryl Farnesyl Protein Transfer Inhibitor (Antitumor Agent)... 

Schering Plough demonstrated the kinetic resolution of a secondary amine (24) via enzyme-catalyzed acylation of a pendant piperidine (Scheme 7.13) [32]. The compound 27 is a selective, non-peptide, non-sulfhydryl farnesyl protein transfer inhibitor undergoing clinical trials as a antitumor agent for the treatment of solid tumors. The racemic substrate (24) does not contain a chiral center but exists as a pair of enantiomers due to atropisomerism about the exocylic double bond. The lipase Toyobo LIP-300 (lipoprotein lipase from Ps. aeruginosa) catalyzed the isobu-tylation of the (+) enantiomer (26), with MTBE as solvent and 2,2,2-trifluoroethyl isobutyrate as acyl donor [32]. The acylation of racemic 24 yielded (+) 26 at 97% and (-) 25 at 96.3% after 24h with an E >200. The undesired enantiomer (25)... 

FARNESYL TRANSFERASE INHIBITORS DESIGN OF A NEW CLASS OF CANCER CHEMOTHERAPEUTIC AGENTS... 

Manne, V., et al. (1995). Ras farnesylation as a target for novel antitumor agents potent and selective farnesyl diphosphate analog inhibitors of farnesyltransferase. Drug Dev Res 34 121-137. 

Travis, J. (1993). Novel anticancer agents move closer to reality. Science 260, 1877 1878. (Inhibitors of protein farnesylation.)... 

Stemerick, D.M.. Farnesyl protein transferase inhibitors as anticancer agents, Merrell Dow Pharmaceuticals, Int. Patent Appl. WO 9419357, 1994 Chem. Abstr, 121, 301073, 1994. 

Compounds of type 135 and 141 have been synthesised as inhibitors of PFT, an enzyme that catalyses the transfer of the farnesyl group from farne-syl pyrophosphate to the cysteine SH in the protozoan parasite Trypanosoma brucei, the causative agent of African sleeping sickness. The parent compound 140 (Ar = (2,4,6-trimethylphenyl) is the most active (ED50 10 xM) [44, 45]. This class of compounds has been tested also on mammalian PFTase and some of them showed inhibitory activity. In particular, none of the dihydro derivatives affects the enzyme in a concentration-dependent manner. 

More classical approaches to the 2-benzazepine system, in particular the 2-benzazepinone 23, have been reported by Le Digueiher et al. The first was based on (5)-phenylalanine carboxamide 20 via the protected acetoxy compound 21 and acid-catalysed cyclization to 22 A-alkylation and carbamate deprotection then afforded 23. The second, more general route, was based on N-Boc aminomalonate 25 and 2,2 -dibromo-o-xylene, and then steps via 26 and 27. Yields were fair to moderate. The benzazepinone 23 was converted into the N-substituted derivatives 24, which were potent and specific farnesyl transferase inhibitors such compounds are of interest as potential anti-tumour agents <04BMCL767>. 

The chaetomellic acids A and B (43 and 44), isolated from Chaetomella acutiseta found in seeds of peas, are potent and highly specific famesyl-mimic inhibitors of ras farnesyl-protein transferase. Farnesylation by this enzyme is the first and obligatory step for the post-translational modification of ras. The modified ras protein appears to be involved in tumorigenesis (approximately 25% of tumours) and there is evidence that inhibitors of the transferase have the potential to be antitumorigenic agents. These metabolites can be considered to be assembled by condensation of a palmitoyl and oleic acid chain C2 with pyruvate or oxaloacetate (Scheme 2) [38, 39]. Two syntheses have been reported for chaetomallic acid A [39, 40], one of which is patterned on the probable biogenesis [39]. 

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