Carbohydrate-Based Small-Molecule Scaffolds for the Construction of Universal Pharmacophore Mapping Libraries Michael J. Sofia,* Rachael Hunter, Tin Yau Chan, ² Andrew Vaughan, Richard Dulina, Huiming Wang, and David Gange Transcell Technologies Inc., 8 Cedar Brook Drive, Cranbury, New Jersey 08512 Received February 2, 1998 Combinatorial chemistry occupies a prominent position in the modern drug discovery process. 1 Because of its ability to generate large numbers of structurally diverse molecules, combinatorial chemistry has been able to reduce the drug discovery timeline by meeting the compound needs of high throughput screening programs. Continued success will rely heavily on the development of new chemical platforms for constructing useful combinatorial molecular diversity. By rapidly defining novel three-dimensional functional group relationships, i.e., pharmacophores, the ideal combinatorial chemical platform will allow access to broad diversity space, thus facilitating the identification of tight binding ligands against a wide variety of biomolecular targets. Monosaccharides possess a unique set of characteristics, which makes them particularly attractive as platforms around which to design primary screening libraries. Hex- oses are enantiomerically pure and conformationally rigid. They provide a defined three-dimensional spatial arrange- ment of substituents, are highly functionalized, and there- fore, provide high intrinsic combinatorial density. The unique characteristics of monosaccharides were first recog- nized by Hirschmann, Nicolaou, and Smith in their success- ful use of -D-glucose as a -turn mimetic in the design of nonpeptide somatostatin mimetics and were later exploited by others. 2 The discovery that hexose derivatives also bind with high affinity to several pharmacologically important receptors suggests that, as priviledged platforms, monosac- charide systems are valuable for generating combinatorial libraries. However, readily accessible carbohydrate-based combinatorial platforms have yet to be described. In this report, we describe the first effective solid-phase chemical method for the preparation of carbohydrate-based universal pharmacophore mapping libraries as a new strat- egy for identifying novel receptor ligands. To investigate the potential of carbohydrates for the preparation of universal pharmacophore mapping libraries, two monosaccharide scaffolds 1 and 2 were prepared as outlined in Schemes 1 and 2. Three sites of diversification were incorporated into each scaffold to provide the minimal requirements needed for pharmacophoric chiral molecular recognition. The desired three-point motif was achieved by a scaffold design that incorporated a carboxylic acid moiety, a free hydroxyl group, and a protected amino group. This functional group triad afforded the chemoselectivity neces- sary for rapid combinatorial solid-phase synthesis, allowing us to maximize molecular diversity while minimizing the number of solid-phase synthetic steps. Chemical diversity was introduced at the three combina- torial sites on each scaffold using the solid-phase chemistry exemplified in Schemes 3-5. To minimize the number of solid-phase chemistry steps, the first diversification step occurred by attaching the scaffold to the solid support through a prelinked diversity element. Consequently, each glycocarboxylic acid was linked to the free amine of an amino acid functionalized carboxytrityl Tentagel resin, 5 furnishing the scaffold functionalized resins 12 and 13. In Schemes 4 and 5, isopropyl isocyanate, 2,4-dimethoxybenzoic acid, and 4-nitrobenzoic acid were used to demonstrate the efficiency of the solid-phase chemistry strategy. Carbamate formation 6 at the free hydroxyl site followed by amide formation at the deprotected amine site produced the desired resin-linked trifunctionalized scaffolds. For scaffold 2, an additional step was required to remove the acetate protecting group at C-2. All products were cleaved from the solid support with 10% * To whom correspondence should be addressed. E-mail: sofia@ transcell.com. ² Current address: Schering-Plough Research Institute, Kenilworth, NJ. (1) Gallop, M. A.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gordon, E. M. J. Med. Chem. 1994, 37, 1233-1251. (b) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Fodor, S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385-1400. (2) Hirschmann, R.; Nicolaou, K. C.; Pietranico, S.; Leahy, E. M.; Salvino, J.; Arison, B.; Cichy, M. A.; Spoors, P. G.; Shakespear, W. C.; Sprengeler, P. A.; Hamley, P.; Smith, A. B., III; Reisine, T.; Raynor, K.; Maechler, L.; Donaldson, C.; Vale, W.; Freidinger, R. M.; Cascieri, M. R.; Strader, C. D. J. Am. Chem. Soc. 1993, 115, 12550-12568. (b) Hirschmann, R,; Wenqing, Y.; Cascieri, M. A.; Strader, C. D.; Maechler, L.; Cichy-Knight, M. A.; Hynes, J., Jr.; van Rijn, R. D.; Sprengeler, P. A.; Smith, A. B., III. J. Med. Chem. 1996, 39, 2441-2448. (c) von Roedern, E. R.; Lohof, E.; Hessler, G.; Hoffmann, M.; Kessler, H. J. Am. Chem. Soc. 1996, 118, 10156-10167. (d) Wessel, H. P.; Banner, D.; Gubernator, K.; Hilpert, K.; Muller, K.; Tschopp, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 751-752. (e) Ramamoorthy, P. S.; Gervay, J. J. Org. Chem. 1997, 62, 7801-7805. (3) Davis, N. J.; Flitsch, S. L. Tetrahedron Lett. 1993, 34, 1181-1185. (4) Baer, H. H. Methods Carbohydr. Chem. 1972, 6, 245-249. (5) NovasynTGT resin is a Tentagel-based resin that has been amino functionalized and derivatized with a 4-carboxytrityl linker. It is available from Novabiochem. (6) Duggan, M. E.; Imagire, J. S. Synthesis 1989, 131-132. Scheme 1 a a Reagents and conditions: (a) Na2CO3, BnOCOCl, H2O, 4 °C; (b) CH3OH, HCl-dioxane, 60 °C; (c) (CH3O)2C(CH3)2, p-TsOH, DMF, rt; (d) NaH, CH3I, THF, rt; (e) p-TsOH, Amberlite, rt; (f) TEMPO 3 , NaOCl, n-Bu4NCl, KBr, NaHCO3, NaCl, H2O, 0 °C; (g) 10% Pd-C, H2 (40 psi), EtOAc; (h) Fmoc-Cl, NaHCO3, DIPEA, dioxane-H2O, rt. DIPEA ) N,N-diisopropylethylamine; TEMPO ) 2,2,6,6-tetramethyl-1-piperidi- nyloxy. 2802 J. Org. Chem. 1998, 63, 2802-2803 S0022-3263(98)00164-9 CCC: $15.00 © 1998 American Chemical Society Published on Web 04/16/1998