Famesyl transferase inhibitor

Nagasu T, Yoshimatsu K, Rowell C, et al. Inhibition of human tumor xenograft growth by treatment with the famesyl transferase inhibitor B956. Cancer Res 1995 55 5310-5314. 

An example of the signal-transduction protein-targeted inhibitor design which illustrates both peptide scaffold- and nonpeptide template-based approaches is that for the Ras famesyl transferase inhibitor discovery. Such compounds show potential as new therapeutic agents for Ras-related carcinogenesis [81]. Substrate sequences for famesyl transferase have the consensus Cy s-A A, - A A2-Met motif (AA refers to Val or lie). Both substrate-based... 

Gamer, R. C., Goris, I., Laenen, A. A., Vanhoutte, E., Meuldermans, W., Gregory, S., Gamer, J. V., Leong, D., Whattam, M., Calam, A., and Snel, C. A. (2002). Evaluation of accelerator mass spectrometry in a human mass balance and pharmacokinetic study—Experience with 14C-labeled (R)-6-[amino(4-chlorophenyl)(l-methyl-l //-imidazol-5-yl)methyl -4-(3-chlorophenyl)- l-methyl-2(17/ i-quinolinone (R115777), a famesyl transferase inhibitor. Drug Metab. Dispos. 30 823-830. 

Parallel liquid synthesis has been applied to the synthesis of a range of N,N -disubstituted 3-aminoazepin-2-ones 7 (e.g. R = w-BrC6H4) starting from 6. These compounds were required for SAR studies as specific famesyl transferase inhibitors <03BMC3193>. 

N-aryl-2-piperazmones are of great interest as famesyl-transferase inhibitors, and both N-aryl-2-piperazinones and N-aryl-2,5-piperazinediones are synthetic precursors of N-arylpiperazines which are key elements in monoamine receptor-active drugs. Lange et al. enhanced the Goldberg reaction with microwaves for synthesis of N-arylpiperazinones, N-arylpiperazinediones, and N-aryl-3,4-dihydroquinolines [88]. Microwave irradiation greatly accelerates the reaction when NMP is used as solvent. 

Adjei AA et al. A Phase I trial of the famesyl transferase inhibitor SCH66336 Evidence for biological and chnical activity. Cancer Res 2000 60 1871-1877. 

Perola E, Xu K, Kollmeyer TM, Kaufmann SH, Prendeigast FG, Pang Y-P (2000) Successful virtual screening of a chemical database for famesyl transferase inhibitor leads. J Med Chem 43(3) 401-408... 

Mizoroki-Heck cyclization of 198 was part of the studies towards the total synthesis of taxol (224) (see Scheme 5.38) by Danishefsky and coworkers [84] (198 199, Scheme 5.35). The strained seven-membered ring is formed in the presence of the hydroxyketone moiety in 52% yield and unconsumed 198 was re-isolated quantitatively. Danishefsky and coworkers [85] employed the high-yielding Mizoroki-Heck reaction of200 to assemble the bridged carbon skeleton in 201, an intermediate en route to the synthesis of CP-225,917 (202) and related CP-263,114 (not shown), which are squalene synthetase and famesyl transferase inhibitors (200 201). 

Singh, R. Chen, I.-W. Jin, L. Silva Ehpe, M.V. Arison, B.H. Lin, J.H. Wong, B.K. Pharmacokinetics and metabolism of RAS famesyl transferase inhibitor in rats and dogs In vitro-in vivo correlation. Drug Metab. Dispos. 2001,29, 1578-1587. 

Mazieres J, Pradines A, Favre G (2004) Perspectives on famesyl transferase inhibitors in canccu therapy. Cancer Lett 206 159... 

Appels, N.M., van Maanen, M.J., Rosing, H., Schellens, J.H. and Beijnen, J.H., Quantitative analysis of the famesyl transferase inhibitor lonafamib (Sarasartrade mark, SCH66336) in human plasma using high-performance liquid chromatography coupled with tandem mass spectrometry. Rapid Common. Mass Spectrom., 19(15), 2187-2192 (2005). 

NO (nM concentxation) has been reported to activate Ras post-translational modification via S-nitrosylation of critical cysllS residue which stimulates guanine nucleotide exchange (Gallo et al. 1998). We have reported that NO (60 nM) treatment of MDA-MB-231 cells led to Ras-mediated increase in PI-3 kinase/Akt and Raf/MEK/ERK signal transduction pathways which was independent of cGMP. It was shown that pre-treatment of the cells by famesyl transferase inhibitors (FTIs), which block the post-translational modification of Ras protein, decreased the basal levels of pERKl/2, pAKT, and cyclin D1 to induce cytostasis (Pervin et al. 2007). 

Mori, D., Kimura, Y, Kitamura, S., Sakagami, Y., Yoshioka, Y., Shintani, T., Okamoto, T, and Ojika, M. (2007) Spongolactams, famesyl transferase inhibitors from a marine sponge isolation through an LC/MS-guided assay, structures, and semisynfhesis. J. Org. Chem., 71, 7191-7198. 

---