BIOORGANIC & MEDICINAL CHEMISTRY Bioorganic & Medicinal Chemistry Letters 9 (1999) 623-626 LETTERS Pergamon Solid-phase synthesis of novel inhibitors of Farnesyl Transferase Amelia Moreno Barber, Ian R. Hardcastle*, Martin G. Rowlands, Bernard P. Nutley, Jonathan H. Marriott, Michael Jarman Cancer Research Campaign Laboratory, CRC Centre for Cancer Therapeutics at the Institute of Cancer Research, Cotswold Road, Sutton, Surrey SM2 5NG, UK Received 25 November 1998; accepted 19 January 1999 Abstract: A novel diphosphate mimic, the 2,3,6-trifluoro-5-hydroxy-4-nitrophenoxy group (1), has been employed as the template in the solid-phase synthesis of novel Famesyl Transferase inhibitors using the Mitsunobu reaction. The most potent inhibitor (farnesyloxy-5-hydroxy-2,3,6-trifluoro-4-nitrobenzene) displayed an IC50 of 6.3 p.M versus Famesyl Transferase. © 1999 ElsevierScience Ltd. All rightsreserved. Famesyl Transferase (FTase) catalyses the transfer of the farnesyl moiety from farnesyl diphosphate (FPP) to the Ras protein.1 This post-translational modification enables anchoring of the protein to the cell membrane which is necessary for cell transformation. 2 Mutant Ras is found in many human colon (50%) and pancreatic (90%) cancers, 3 thus inhibition of FTase is an attractive therapeutic target for new anticancer agents and has been the subject of vigorous research activity. 4'5 Recently, potent diphosphate-competitive inhibitors of Ftase have been reported. 6 Previous work carried out in our laboratories showed the ability of the 2,3,6-trifluoro-5- hydroxy-4-nitrophenoxy group to mimic the diphosphate (dpp) residue. 7 In this paper, we describe the preparation of the dpp mimic 1 and its use as a template in a solid-phase synthesis of potential FPP-related inhibitors of FTase. HO F F F 1 Chemistry The synthesis of the protected dpp mimic 4 is illustrated in Scheme 1. Pentafluoronitrobenzene reacts with nitrite ion in DMSO 8 to give the phenol 2 in 80% yield. The phenol was then protected as the allyl ether 3 (100% yield) followed by nucleophilic "E-mail:ianh@icr.ac.uk; Fax: +181 770 7899 0960-894X/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(99)00043-8