135304-07-3

Usage

Uses

Used in Pharmaceutical Industry:
N-Acetyl-S-trans,trans-farnesyl-L-cysteine is used as a research compound for the pharmaceutical industry. Its primary application is to inhibit the methylation of endogenous isoprenylated proteins, which can be beneficial in studying the effects and roles of these proteins in various biological processes and potential therapeutic interventions.
Used in Biochemical Research:
In the field of biochemical research, N-Acetyl-S-trans,trans-farnesyl-L-cysteine is used as a tool to investigate the function and regulation of isoprenylated protein methyltransferase. By inhibiting the methylation process, researchers can gain insights into the consequences of altered methylation patterns on protein function and cellular signaling pathways.
Used in Drug Development:
N-Acetyl-S-trans,trans-farnesyl-L-cysteine may also be utilized in drug development efforts, particularly in the design of novel therapeutics targeting the isoprenylation and methylation of proteins. Its inhibitory properties could be harnessed to develop drugs that modulate protein function, potentially leading to treatments for diseases associated with abnormal protein methylation.
Overall, N-Acetyl-S-trans,trans-farnesyl-L-cysteine is a versatile compound with applications in various scientific and medical fields, primarily due to its ability to inhibit the methylation of isoprenylated proteins.

References

1) Volker?et al.?(1991),?Effects of farnesylcyteine analogs on protein carboxyl methylation and signal transduction; J. Biol. Chem.?266?21515 2) Xu?et al.?(1996),?Inhibition of capacitative Ca2+ entry into cells by farnesyl analogs; Mol. Pharmacol.?50?1495 3) Rosado and Sage (2000),?Farnesylcyteine analogues inhibit store-regulated Ca2+ entry in human platelets: evidence for involvement of small GTP-binding proteins and actin cytoskeleton; Biochem. J.?347?183 4) Gordon?et al.?(2008),?Topical N-acetyl-S-farnesyl-L-cysteine inhibits mouse skin inflammation, and unlike dexamethasone, its effects are restricted to the application site; J. Invest. Dermatol.?128?643 5) Adhami?et al.?(2012),?N-acetyl-S-farnesyl-L-cysteine suppresses chemokine production by human dermal microvascular endothelial cells;?Exp. Dermatol.?21?700

InChI:InChI=1/C20H33NO3S/c1-15(2)8-6-9-16(3)10-7-11-17(4)12-13-25-14-19(20(23)24)21-18(5)22/h8,10,12,19H,6-7,9,11,13-14H2,1-5H3,(H,21,22)(H,23,24)/b16-10+,17-12+/t19-/m0/s1

Synthetic route

N-acetylcystein (616-91-1) + farnesyl bromide (24163-93-7, 24163-94-8, 56881-57-3, 6874-67-5, 28290-41-7) → N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3)

Conditions	Yield
With ammonia In methanol for 16h;	99%
With ammonia In methanol Alkylation;

N-acetyl cysteine (S-farnesyl) methyl ester (135304-08-4) → N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3)

Conditions	Yield
With lithium hydroxide In methanol; water for 24h;	84%

trans,trans-farnesyl-L-cysteine (68000-92-0) + acetic anhydride (108-24-7) → N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3)

Conditions	Yield
With sodium hydroxide at 0 - 20℃;	52%

Farnesol (106-28-5) → N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: polymer supported PPh3; CBr4 / CH2Cl2 / 5 h 2: 70 percent / zinc acetate; TFA / dimethylformamide; acetonitrile; H2O / 24 h 3: 84 percent / LiOH / methanol; H2O / 24 h View Scheme

farnesyl bromide (24163-93-7, 24163-94-8, 56881-57-3, 6874-67-5, 28290-41-7) → N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 70 percent / zinc acetate; TFA / dimethylformamide; acetonitrile; H2O / 24 h 2: 84 percent / LiOH / methanol; H2O / 24 h View Scheme

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → titanium (R)-2-acetamido-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)propanoate

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With sodium hydroxide In water Stage #2: With titanium tetrachloride In tetrahydrofuran at 20℃;	91%

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → silver (R)-2-acetamido-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)propanoate

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With sodium hydroxide In water at 20℃; for 0.166667h; Stage #2: With silver nitrate In water for 1h;	84%

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → C20H35N3O2S (1160502-59-9)

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine In dichloromethane for 0.5h; Stage #2: With hydrazine In tetrahydrofuran; dichloromethane at 20℃; for 3h;	80%

D-(+)-glucosamine hydrochloride (66-84-2) + N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → glucosamine (R)-2-amino-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)propanoate

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With sodium hydroxide In ethanol; water Stage #2: D-(+)-glucosamine hydrochloride In ethanol; water for 0.5h;	76%

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) + phenylhydrazine (100-63-0) → C26H39N3O2S (1160502-64-6)

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With triethylamine; HATU In tetrahydrofuran for 0.5h; Stage #2: phenylhydrazine In tetrahydrofuran	73%

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → zinc (R)-2-acetamido-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)propanoate

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With sodium hydroxide In water at 20℃; for 0.166667h; Stage #2: With zinc(II) chloride In water for 1h;	67%

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) + methylhydrazine (60-34-4) → C21H37N3O2S (1160502-63-5)

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With triethylamine; HATU In tetrahydrofuran for 0.5h; Stage #2: methylhydrazine In tetrahydrofuran	65%

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → strontium (R)-2-acetamido-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)propanoate

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With sodium hydroxide In water Stage #2: With strontium chloride In water	57%

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → C20H34N2O3S (1160502-62-4)

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine In dichloromethane for 0.5h; Stage #2: With hydroxylamine In tetrahydrofuran; dichloromethane; water at 20℃; for 3h;	45%

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) + acetic acid hydrazide (1068-57-1) → C22H37N3O3S (1160502-65-7)

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With triethylamine; HATU In tetrahydrofuran for 0.5h; Stage #2: acetic acid hydrazide In tetrahydrofuran	35%

nicotinamide hydrochloride (25334-23-0) + N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → nicotinamide (R)-2-acetamido-3-((2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienylthio)propanoate (1239578-25-6)

Conditions	Yield
Stage #1: N-acetyl-S-trans,trans-farnesyl-L-cysteine With sodium hydroxide In water Stage #2: nicotinamide hydrochloride In ethanol for 1h;	35%

(R)-Phenylglycinol (56613-80-0) + N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → N-acetyl-S-farnesyl-L-cysteine-(D)-α-phenylglycinolamide

Conditions	Yield
With 1-hydroxybenzotriazol-hydrate; 1-ethyl-(3-(3-dimethylamino)propyl)-carbodiimide hydrochloride In N,N-dimethyl-formamide at 0 - 20℃;

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) + isobutyl chloroformate (543-27-1) → C25H41NO5S

Conditions	Yield
With 4-methyl-morpholine In tetrahydrofuran at -15℃; Acetylation;

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → N-[(R)-3-Diazo-2-oxo-1-((2E,6E)-3,7,11-trimethyl-dodeca-2,6,10-trienylsulfanylmethyl)-propyl]-acetamide (253871-52-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: NMM / tetrahydrofuran / -15 °C 2: diethyl ether / 0 °C View Scheme

N-acetyl-S-trans,trans-farnesyl-L-cysteine (135304-07-3) → N-[(R)-3-Chloro-2-oxo-1-((2E,6E)-3,7,11-trimethyl-dodeca-2,6,10-trienylsulfanylmethyl)-propyl]-acetamide

Conditions	Yield
Multi-step reaction with 3 steps 1: NMM / tetrahydrofuran / -15 °C 2: diethyl ether / 0 °C 3: HCl / ethyl acetate / 0.17 h / 0 °C View Scheme

Upstream product

• 68000-92-0 trans,trans-farnesyl-L-cysteine 
• 108-24-7 acetic anhydride 
• 616-91-1 N-acetylcystein 
• 24163-93-7 farnesyl bromide 
• 135304-08-4 N-acetyl-S-farnesyl-L-cysteine methyl ester 
• 106-28-5 Farnesol 

Downstream Products

• 1160502-64-6 C₂₆H₃₉N₃O₂S 

Relevant academic research and scientific papers

Structure-activity studies on the retinal rod outer segment isoprenylated protein methyltransferase

Structure-activity studies were performed on the retinal rod outer segment isoprenylated protein methyltransferase that transfers a methyl group from S-adenosylmethionine (AdoMet) to the carboxyl group of isoprenylated (farnesylated or geranylgeranylated) cysteine residues. This methyltransferase enzyme has been shown to methylate N-acetyl-S-farnesyl-L-cysteine (L-AFC, 1) and S-(farnesyl-3-thio)propionic acid (FTP, 2). It is shown here that the enzyme does not enzymatically process D-AFC (8), although D-AFC (8) is a mixed-type inhibitor of the enzyme. Small modifications in the FTP (2) structural series generally lead to inactive substrates. For example, neither the cis- nor the trans-acrylate derivatives of FTP (2) are substrates of the enzyme, but both are inhibitors of it. Alkyl substitutions at the 3-position of FTP (2), moreover, lead to inhibitors of the methyltransferase. Substituents at the 2-position of FTP (2), as in 2-methyl-S-(farnesyl-3-thio)propionic acid (MFTP, 28) or S-farnesyl-2-(thiomethyl)acrylic acid (FTMA, 31), produce active substrates. Modifications at the carboxyl moiety produce neither substrates nor inhibitors of the enzyme. The conclusion from this and earlier studies is that the methyltransferase is selective for an isoprenylated thiopropionate moiety. Small deviations from this minimally essential structure lead to the abolition of substrate activity.

An improved method for cysteine alkylation

An improved method for the synthesis of S-alkylated cysteine derivatives with branched alkyl chains is reported. These compounds can be obtained in good yield and high purity by refluxing the cysteine thiol with the appropriate alkyl bromide in a solution of sodium ethoxide in ethanol.

A photoactivatable prenylated cysteine designed to study isoprenoid recognition

Protein prenylation, involving the alkylation of a specific C-terminal cysteine with a C15 or C20 isoprenoid unit, is an essential posttranslational modification required by most GTP-binding proteins for normal biological activity. Despite the ubiquitous nature of this modification and numerous efforts aimed at inhibiting prenylating enzymes for therapeutic purposes, the function of prenylation remains unclear. To explore the role the isoprenoid plays in mediating protein-protein recognition, we have synthesized a photoactivatable, isoprenoid-containing cysteine analogue (2) designed to act as a mimic of the C-terminus of prenylated proteins. Photolysis experiments with 2 and RhoGDI (GDI), a protein which interacts with prenylated Rho proteins, suggest that the GDI is in direct contact with the isoprenoid moiety. These results, obtained using purified GDI as well as Escherichia coli (E. coli) crude extract containing GDI, suggest that this analogue will be an effective and versatile tool for the investigation of putative isoprenoid binding sites in a variety of systems. Incorporation of this analogue into peptides or proteins should allow for even more specific interactions between the photoactivatable isoprenoid and any number of isoprenoid binding proteins.

Cysteine chloromethyl and diazomethyl ketone derivatives with potent anti-leukemic activity

A series of cysteine diazomethyl- and chloromethyl ketone derivatives has been synthesized and evaluated against human B-lineage (Nalm-6) and T-lineage (Molt-3) acute lymphoblastic leukemia cell lines. The chloromethyl ketone compounds showed potent cytotoxicity against these cell lines, with IC50 values in the low micromolar range. The best compounds were N-acetyl-S-dodecyl-Cys chloromethyl ketone (IC50 = 2.0 μM against Nalm-6, 2.3 μM against Molt-3) and N-acetyl-S-trans,trans-farnesyl-Cys chloromethyl ketone (IC50 = 3.0 μM against Nalm-6 and 1.4 μM against Molt-3). (C) Elsevier Science Ltd. All rights reserved.