~) Pergamon Bioorganic & Medicinal Chemistry Letters, Vol. 7, No. 21, pp. 2729-2734, 1997 © 1997 Elsevier Science Ltd All rights reserved. Printed in Great Britain PII: S0960-894X(97)10077-4 0960-894X/97 $17.00 + 0.00 DESIGN AND SYNTHESIS OF SIALYL Le x MIMETICS BASED ON CARBOCYCLIC SCAFFOLDS DERIVED FROM (-) QUINIC ACID Stephen Hanessian,* Gurijala V. Reddy, Hoan K. Huynh, Jingwen Pan, and Silvana Pedatella Department of Chemistry, Universitd de Montrdal, P.O.Box 6128, Succ. Centre-ville, Montreal, (Quebec), H3C 3J7, CANADA Beat Ernst and Hartmuth C. Kolb Novartis Pharma Ltd, Basel, Switzerland Abstract: The synthesis of sialyl Lewisx mimetic anologs in which the D-glucosamine, D-galactose, and sialic acid residues are replaced individually with appropriate glycomimetics is described. A computational model for predicting bioactive conformations was tested. © 1997ElsevierScienceLtd. Sialyl Lewis x (sLe x) 1 (Figure 1) is the terminal tetrasaccharide structural unit of the physiological selectin ligands that are present on the surface of leukocytes. 1 This unique structure is responsible for the initial interaction of leukocytes with the surface of blood vessels at sites of inflammation or injury. 2 Much effort has been focused in recent years to antagonize this interaction which is a prerequisite for the inflammatory response to take place. In an effort to obtain simpler and more effective analogs, numerous potential sLe x mimetics have been synthesized. 3 Figure 1 Ha OH ~02H .OH ~/CH o./-- -o o;c-o. HO OH J X H30'''I'''~ 0''7 1. Sialyl Le OH~'~ "-/-~OH He HO i QH ~ 02FI OH HO ?H .o Co .- J 2 H30~H 0 OH HO H O 2 ~ O ~ ~ .OH HO? H OH OH O ~ OH OH O~ H O o: I H30~HO OH G-~u OH HO 3 4 H3 , um OH 5 HO HO In previous studies directed at probing the functional and structural requirements for activity of sLe x, we utilized pentaerythritol as an anchoring subunit for the attachment of (~-L-fucosyl and o~-sialylresidues. 4 These sugar residues are essential for effective recognition by the E-selectins, although carboxylic acid derivatives appear to replace the sialic acid part.5, 6 The N-acetyl-D-glucosamine residue in 1 has shown no preponderant contribution towards the binding process, apparently acting as a scaffold to provide a spacially suitable arrangement for the molecule as a whole. 7 It is also known that the D-galactosyl residue is subject to considerable functional manipulations. 8 2729