Solid-phase synthesis of Biotin-S-Farnesyl-l-Cysteine, a surrogate substrate for isoprenylcysteine Carboxylmethyltransferase (ICMT)

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 20; pp. 5671 - 5673
• Main Authors: Stevenson, Graeme I., Yong, Sarah, Fechner, Gregory A., Neve, Juliette, Lock, Aaron, Avery, Vicky M.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.10.2013; Elsevier
• Subjects: Biotin - chemistry; Biotin-S-Farnesyl-l-Cysteine (BFC); Cancer; Chemistry; Chemistry, Medicinal; Chemistry, Organic; chemotherapy; Cysteine - chemical synthesis; Cysteine - chemistry; High-Throughput Screening Assays; Isoprenylcysteine Carboxylmethyltransferase (ICMT); Kinetics; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Physical Sciences; Prenylation; Protein Methyltransferases - chemistry; Protein Methyltransferases - metabolism; Science & Technology; screening; Solid-Phase Synthesis Techniques; Substrate Specificity; Trityl Compounds - chemistry; Prenylation; Isoprenylcysteine Carboxylmethyltransferase (ICMT); S:N; HOBt; HBTU; SAH; DMF; SAM; Biotin-S-Farnesyl-l-Cysteine (BFC); CANCER-CELLS; INACTIVATION; Isoprenylcysteine; K-RAS; CARBOXYL METHYLTRANSFERASE; Carboxylmethyltransferase (ICMT); Biotin-S-Farnesyl-L-Cysteine (BFC); SMALL-MOLECULE INHIBITOR; S-adenosyl-l-methionine; O-benzotriazole-N,N,N′, N′-tetramethyluronium hexafluoro-phosphate; S-adenosyl-l-homocysteine; N,N-dimethylformamide; signal to noise; hydroxy-benzotriazole
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.08.022

Inhibition of isoprenylcysteine carboxyl methyltransferase (ICMT) is of particular interest as a potential target for the development of cancer chemotherapeutic agents. A solid-phase synthesis protocol for the preparation of BFC using 2-chlorotrityl chloride resin as a solid support has been developed to provide sufficient supply of BFC for high throughput screening (HTS) and subsequent chemistry campaigns to target inhibitors of ICMT. The BFC prepared by this method can be produced quickly on large scale and is stable when stored at −20°C as a solid, in solution, or on the resin. Inhibition of isoprenylcysteine Carboxylmethyltransferase (ICMT) is of particular interest as a potential target for the development of cancer chemotherapeutic agents. Screening for inhibitors of ICMT utilises a scintillation proximity assay (SPA) in which Biotin-S-Farnesyl-l-Cysteine (BFC) acts as a surrogate substrate. A solid-phase synthesis protocol for the preparation of BFC using 2-chlorotrityl chloride resin as a solid support has been developed to provide sufficient supply of BFC for high throughput screening (HTS) and subsequent chemistry campaigns to target inhibitors of ICMT. The BFC prepared by this method can be produced quickly on large scale and is stable when stored at −20°C as a solid, in solution, or on the resin.