New oligo-b-(1,3)-glucan derivatives as immunostimulating agents Karine Descroix a,b,  , Vaclav Ve ˇtvic ˇka c, * , Isabelle Laurent a,b , Frank Jamois d , Jean-Claude Yvin d,à , Vincent Ferrières a,b, * a Ecole Nationale Supérieure de Chimie de Rennes, CNRS, UMR 6226, Avenue du Général Leclerc, CS 50837, 35708 Rennes Cedex 7, France b Université européenne de Bretagne, France c Department of Pathology, University of Louisville, 511 S. Floyd Street, MDR Building, Louisville, KY 40202, USA d Laboratoire Goëmar, ZAC La Madeleine, Avenue du Général Patton, 35400 Saint Malo, France article info Article history: Received 1 July 2009 Revised 26 October 2009 Accepted 27 October 2009 Available online 30 October 2009 Keywords: Carbohydrates b-(1,3)-Glucans Immunostimulation abstract Oligo-b-(1,3)-glucans were chemically modified in order to introduce a structural variation specifically on the reducing end of the oligomers. The impact of well defined structural modulations was further studied on cancer cells and murin models to evaluate their cytotoxicity and immunostimulating potential. Ó 2009 Elsevier Ltd. All rights reserved. 1. Introduction It is now well established that natural b-(1,3)-glucans, which are neither biosynthesized nor metabolized by mammals, are po- tent immunological activators. Recent studies give evidence for re- newed interest in these polysaccharides in the health domain, 1–3 particularly with those related to clinical trials where they are used as bioactive adjuvants in the treatment of patients receiving chemotherapies. 4,5 These studies notably highlight improvement of the quality of life of cancer patients—a very important criterion in oriental countries. During the last decade, the main receptors able to interact specifically with b-(1,3)-glucans were identified. Amongst them are the dectin-1, 6,7 the complement receptor of type 3 (CR3), 8–10 a scavenger and a lactosylceramide. Since these receptors are widely distributed on various immunocompetent cells, b-(1,3)-glucans impact on both the innate and the adaptive immunity. The related biological effects were recently reviewed favorably. 1,3 It was also shown that therapies based on antitumor monoclonal antibodies are enhanced by administered b-glu- cans. 11–13 However, the structure–function relationships are still objects of debate. 2,14,15 It results from biological data obtained un- til now from polysaccharides that poor correlations can be estab- lished with structural and conformational requirements, molecular weight and degree of branching. In summary, glucans have been extensively studied for their immunological and phar- macological effects. More than 10,000 papers describing the bio- logical activities of glucans exist. 16 However, many of the available data were obtained from extracted materials. As a result, neither chemical structure nor purity of actual bioactive mole- cule(s) can be rigorously specified. The absence of direct benefits of polysaccharides on health therefore dampens the development in western countries of such complementary and alternative med- icine. It is important, therefore, to evaluate the possibility of using synthetic oligosaccharides based on the structure of glucans. In this context, and in order to increase our knowledge of lam- inarine extracted from brown seaweeds, 17 we have recently initi- ated a program devoted to the chemical synthesis of well defined and pure oligo-b-(1,3)-glucans. 18 As a result, while they are not able to adopt any helical arrangements, small linear oligo-b- (1,3)-glucans possess biological activity comparable to that of the native Phycarine Ò . Consequently, compared with polysaccharides, minor chemical variations on small oligoglucans may present sig- nificant changes in interactions with the targeted receptors. These effects are expected to give a great deal of information on the respective importance of hydroxyl groups. Upon this basis, we now present a first chemical modulation that results in a new fam- ily of oligo-b-(1,3)-glucans (Fig. 1) modified on the reducing end. The designed glycosides are characterized by the presence of four or five glucopyranose entities and a mannose residue at the reduc- 0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2009.10.053 * Corresponding authors. Fax: +33 (0) 2 23 23 80 46 (V.F.). E-mail address: vincent.ferrieres@ensc-rennes.fr (V. Ferrières).   Present address: School of Chemical Sciences and Pharmacy, Norwich NR4 7TJ, UK. à Present address: AFI, 27 Avenue Franklin Roosevelt, BP 158, 35408 Saint Malo Cedex, France. Bioorganic & Medicinal Chemistry 18 (2010) 348–357 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc