Farnesyl esters

Fig. 14 Water-soluble CCVJ, hydrophobic CCVJ farnesyl ester (FCVJ) for cell membrane applications [88], and hydrophilic CCVJ triethyleneglycol ester (CCVJ-TEG) [89]...

Hydrolysis of the pyrophosphate ester group converts farnesyl pyrophosphate to the corresponding alcohol farnesol (see Figure 26 6 for the structure of farnesol)... 

C2]-Squalene, 80, has been produced71 in the reaction sequence shown in equation 31 which involves alkylation of 3-13C-ethyl acetoacetate with geranyl bromide, followed by hydrolysis, decarboxylation and treatment with triethyl phosphonoacetate and then reduction of the ester 82 with LiAlHr, bromination with CBr4/PPh3 and coupling the farnesyl bromide with Cul/Li-pyrrolidine. Epoxidation of 80 has been effected by... 

E-0710 (IMF), the farnesil esters of indometacin145, 169 and 170, prodrugs showing anti-inflammatory activity with diminished gastro-intensinal irritation, have been synthesized146 according to two schemes shown in equations 59 and 60. 14C-IMF- 169 has been obtained by esterification of commercially available 14C-IND, 171, with farnesyl... 

The Ras proteins are synthesized as biologically inactive, cytosolic precursor proteins. They are then modified by several post-translational processing steps at the carboxyl terminal end and thereby converted into biologically active proteins localized at the plasma membrane. The cysteine of the C-terminal CAAX sequence (C is cysteine, A is generally an aliphatic amino acid, and X is methionine, serine, alanine, or glutamine) is first enzymatically S-farnesylated the AAX part is then cleaved off by a specific protease, and the free C-terminal cysteine is finally converted into a methyl ester (Scheme 1). 

The less polar methyl ester 2 as prodrug showed better results in vivo and inhibits both farnesylation of the Ras protein and growth of Ras-transformed cells, whilst proliferation of Raf- or Mos-transformed cells was not influenced. Growth of human pancreatic adenocarcinoma cells with mutated K-Ras, c-Myc and p53 genes was inhibited by application of 2. If the compound is administered over a period of 5 days to mice with implanted Ras-dependent tumors, tumor growth can be reduced by up to 66% compared to untreated mice, whereas application of the antitumor antibiotic doxorubicin only resulted in 33% reduction under the same conditions. It is particularly noteworthy that treatment with the /1-turn mimetic - in contrast to treatment with doxorubicin - was without any visible side effects, such as weight loss. 

The central unit of these peptidomimetics imitates a /1-turn and brings the NH2-terminus of the cysteine analogue and the CO OH terminus of the methionine in spatial proximity these can then complex the Zn2+ ion which is essential for activity of the FTase [26]. The free acid 7 inhibits the enzyme with an IC50 value of 1 nmol/1, whilst in intact cells the methyl ester 8, despite its weaker in vitro activity, is significantly more potent because it can penetrate the plasma membrane better due to its lower polarity. This property can be used to convert the morphology of H-Ras-transformed cells back to the normal form and to inhibit growth of these cells, whereas the substance shows no effect on Src-transformed and untransformed rat fibroblasts. The inhibitor therefore acts selectively on transformed cells and does not influence growth of normal cells. This result is noteworthy because farnesylation of the wild type H-Ras protein... 

In normal cells, the GDP/GTP-binding proteins, after protein synthesis, move to the cell membrane to which they become hooked by a hydrophobic farnesyl group. The y-subunit is anchored in the membrane by a post-translational modification of the C-terminal CAAX sequence (C - cystein, AA - aliphatic amino acids, X - methionine). This protein is first enzymatically farnesylated by a specific farnesyltransferase, then the AAX part is cleaved by specific proteases and finally the cystein residue is converted to a methyl ester. 

Acid- and base-sensitive lipidated peptides can be selectively deprotected by enzymatic hydrolysis of choline esters.[13al Choline esters of simple peptides, but also of sensitive peptide conjugates like phos-phorylated and glycosylated peptides,1141 nucleopep-tides1151 and lipidated peptides,113,1631 can be cleaved with acetyl choline esterase (AChE) and butyryl choline esterase (BChE) under virtually neutral conditions with complete chemoselectivity. Acid-labile farnesyl groups and base-sensitive thioesters are not attacked. 

In females of the genus Agriotes, several esters of acyclic terpenes have been identified as pheromone components. Typical examples are geranyl 3-methyl-butyrate 95, the first pheromone identified from an Agriotis species [193] or ( , )-farnesyl butyrate 96, which together with geranyl butyrate is the major component of the sex pheromone of A. brevis [194]. In A. lineatus, the activity... 

Afterward, the peptide chain was elongated following the standard Fmoc-based protocol. Before cleavage of the peptide the incorporated Mmt-protected cysteine was deprotected using 1% TFA. Under these very mild conditions the farnesyl moiety was not harmed. Palmitoylation could he achieved using an excess of palmitoyl chloride. Cleavage with copper acetate and methanol as a nucleophile gave the farnesylated and palmitoylated N-Ras sequence with the C-terminal methyl ester 78. ... 

S-Farnesylated cysteine methyl ester represents in most of the cases the C-terminal residue of the synthetic model peptides. The choice whether to use this amino acid derivative or related larger fragments for the final coupling step, strongly depends upon the peptide sequence. 

Lipo-amino acid derivatives are readily obtained in good yields by direct alkylation of amino acids esters with the related alkyl halides, e.g. farnesyl bromide, under careful control of the reaction conditions to avoid exhaustive alkylation of the amino group. 128 Alternatively, peptoid chemistry is applied for N-alkylation of glycine ester via reaction of alkyl amines, e.g. hexadecylamine, with ethyl bromoacetate. 36,98 ... 

Other components are acyclic aliphatic esters and terpenes, such as farnesol and farnesyl acetate [237-239a]. Ambrette seed oil is one of the most expensive essential oils and, thus, is used mainly in fine fragrances and in alcoholic beverages. FCT 1975 (13) p.705 [8015-62-1], [84455-19-6]. 

Sexual conjugation in yeast is also induced by pheromones (mating factors).325-327 Yeast cells of mating type a synthesize the 12-residue mating factor a which contains a C-terminal cysteine methyl ester S-alkylated with a frans,frans-farnesyl group (Table 30-5). Cells of type a synthesize a 13-residue factor ol 327a Cells are attracted to the pheromone produced by cells of the opposite type. The tremerogens, sex hormones of certain basidiomycetes, have related structures (Table 30-5)328... 

Stimmel, J. B., Deschenes, R. J., Volker, C., Stock, J., and Clarke, S. (1990) Evidence for an S-farnesyl cysteine methyl ester at the carboxyl terminus of the Saccharomyces RAS 2 protein, Biochemistry 29, 9651-9659. 

Troutman, J.M., Chehade, K.A.H., Kiegiel, K., Andres, D.A., and Spielmann, H.P. (2004). Synthesis of acyloxymethyl ester prodrugs of the transferable protein farnesyl transferase substrate farnesyl methylenediphosphonate. Bioorg Med Chem Lett 14 4979 982. 

Gaon, I., Turek, T.C., Weller, V.A., Edelstein, R.L., Singh, S.K., and Distefano, M.D. (1996). Photoactive analogs of farnesyl pyrophosphate containing benzoylbenzoate esters synthesis and application to photoaffinity labeling of yeast protein farnesyltransferase. J Org Chem 61 7738-7745. 

Icmt catalyzes the methyl esterification of the prenylated cysteine residue after Reel has proteolyzed the -CaaX-containing proteins. The first step in identification of the minimal substrate for Icmt was through identification of AFC (Figure 9.2) as described above. Interestingly, farnesylcys-teine (FC), which is devoid of the acetyl substitution, was not a substrate but did possess some activity as an inhibitor [51], suggesting that the free amine of FC requires modification for catalytic turnover. Alterations in the stereochemistry about the FC backbone also appeared to be detrimental to substrate activity. The stereoisomer, d-AFC, was not a substrate for Icmt but was a modest mixed-type inhibitor of the enzyme. AFC-methyl ester (AFC-Me) was also reported to be a mixed-type inhibitor with respect to both l-AFC and -adenosylmethionine (SAM), the methyl donor, with Ki values of 41 and 73 pM, respectively [52,53] The farnesyl homocysteine homolog of AFC is not a substrate for the enzyme however, the racemic DL-homocysteine farnesyl derivative is in fact a weak inhibitor [40]. Similar to the results with racemic prenylcysteine, these data demonstrate that the linker between the carboxylate and thioether moieties is critical for substrate activity. 

---