RAPID SYNTHESIS OF MYCOBACTERIAL MANNAN POLYSACCHARIDE WITH ALKYNE TERMINATED LINKER
Keywords:
Adjuvant, glycan, Mycobacterium tuberculosis (Mtb), polymannan, rapid synthesisAbstract
Recently, we have found that the synthetic polysaccharides, α(1,6)polymannans, derived from the surface molecules of Mycobacterium tuberculosis (Mtb), have potent immune modulatory properties. In the quest to increase the potency of this polysaccharide, a dimerization on the reducing end of the polymer molecules, that would yield an α(1,6)polymannan dimer, is revealed here. The dimer of the polysaccharide would interact stronger with mammalian immune receptors through more multivalent bindings. Thus, we set out to synthesize the dimerized α(1,6)polymannan relying on a cross coupling of the functionalized polysaccharide at its reducing end. A conjugated α(1,6)polymannan with an alkyne linker was achieved in a single chemical transformation, using a tricyclic mannosyl orthoester as a monomer. The synthetic approach relies on regio- and stereocontrolled polymerization. The terminal alkyne of conjugated polymannan facilitates a self-cross-coupling reaction, providing a dimer of α(1,6)polymannan. The dimer of the polysaccharide may be a more potent immune modulatory agent due to the more multivalency binding with human immune receptors such as DC-SIGN and mannose receptor in human immune system. This target molecule may serve as a vaccine adjuvant by increasing immune responses toward a vaccine antigen.
References
Balaraman, K., and Kesavan, V. (2010). Efficient copper(II) acetate catalyzed homo- and heterocoupling of terminal alkynes at ambient conditions. Synthesis, 2010(20): 3461.
Batsanov, A. S., Collings, J. C., Fairlamb, I. J. S., Holland, J. P., Howard, J. A. K., Lin, Z., Marder, T. B., Parsons, A. C., Ward, R. M., and Zhu, J. (2005). Requirement for an oxidant in Pd/Cu co-catalyzed terminal alkyne homocoupling to give symmetrical 1,4-disubstituted 1,3-diynes. J. Org. Chem., 70(2): 703.
Boyarskiy, V. P., Ryabukhin, D. S., Bokach, N. A., and Vasilyev, A. V. (2016). Alkenylation of arenes and heteroarenes with alkynes. Chem. Rev., 116(10): 5894.
Bunthitsakda, W., Leelayuwapan, H., Paha, J., Kangwanrangsan, N., Chawengkirttikul, R., Ponpuak, M., Ruchirawat, S., and Boonyarattanakalin, S. (2018). Controlled rapid synthesis and in vivo immunomodulatory effects of LM α(1,6)mannan with an amine linker. Carbohydr. Polym., 195420.
Cadiot, P., and Chodkiewicz, W. (1969). Chemistry of acetylenes. In: Chemistry of acetylenes. Dekker, M., (eds). New York, p. 597.
Cahiez, G., Moyeux, A., Buendia, J., and Duplais, C. (2007). Manganese- or iron-catalyzed homocoupling of grignard reagents using atmospheric oxygen as an oxidant. J. Am. Chem. Soc, 129(45): 13788.
Chan, C. E., Götze, S., Seah, G. T., Seeberger, P. H., Tukvadze, N., Wenk, M. R., Hanson, B. J., and MacAry, P. A. (2015). The diagnostic targeting of a carbohydrate virulence factor from M.Tuberculosis. Sci. Rep., 510281.
Chinchilla, R., and Nájera, C. (2014). Chemicals from alkynes with palladium catalysts. Chem. Rev., 114(3): 1783.
Dao, D. N., Kremer, L., Guérardel, Y., Molano, A., Jacobs, W. R., Porcelli, S. A., and Briken, V. (2004). Mycobacterium tuberculosis lipomannan Induces apoptosis and interleukin-12 production in macrophages. Infect. Immun., 72(4): 2067.
Dower, S. K., DeLisi, C., Titus, J. A., and Segal, D. M. (1981). Mechanism of binding of multivalent immune complexes to Fc receptors. 1. Equilibrium binding. Biochem., 20(22): 6326.
Eglinton, G., and Galbraith, A. (1956). Cyclic diynes. Chem. Ind. (london)(28): 737.
Elass, E., Aubry, L., Masson, M., Denys, A., Guérardel, Y., Maes, E., Legrand, D., Mazurier, J., and Kremer, L. (2005). Mycobacterial lipomannan induces matrix metalloproteinase-9 expression in human macrophagic cells through a Toll-like receptor 1 (TLR1)/TLR2- and CD14-dependent mechanism. Infect. Immun., 73(10): 7064.
Fraser-Reid, B., Chaudhuri, S. R., Jayaprakash, K. N., Lu, J., and Ramamurty, C. V. S. (2008). Efficient chemical synthesis of a dodecasaccharidyl lipomannan component of mycobacterial lipoarabinomannan. J. Org. Chem. , 73(24): 9732.
Glaser, C. (1869). Beiträge zur Kenntniss des Acetenylbenzols. Ber. Dtsch. Chem. Ges., 2(1): 422.
Glaser, C. (1870). Untersuchungen über einige Derivate der Zimmtsäure. Justus Liebigs Ann. Chem., 154(2): 137.
Guoli, M., Zaimin, T., Jiping, L., Guohua, W., and Xiaomin, Y. (2015). Silver-catalyzed Glaser coupling of alkynes. Appl. Organomet. Chem., 29(4): 231.
Haag, R. (2015). Multivalency as a chemical organization and action principle. Beilstein. J. Org. Chem, 11848.
Hay, A. S. (1962). Oxidative coupling of acetylenes. II1. J. Org. Chem., 27(9): 3320.
Huang, X., Yang, L., Emanuelsson, R., Bergquist, J., Strømme, M., Sjödin, M., and Gogoll, A. (2016). A versatile route to polythiophenes with functional pendant groups using alkyne chemistry. Beilstein. J. Org. Chem., 122682.
Huskens, J. (2006). Multivalent interactions at interfaces. Curr. Opin. Chem. Biol., 10(6): 537.
Jana, R., Pathak, T. P., and Sigman, M. S. (2011). Advances in transition metal (Pd,Ni,Fe)-catalyzed cross-coupling reactions using alkyl-organometallics as reaction partners. Chem. Rev., 111(3): 1417.
Kato, K., and Ishiwa, A. (2015). The role of carbohydrates in infection strategies of enteric pathogens. Trop. Med. Int. Health., 43(1): 41.
Kiessling, L. L., Young, T., and Mortell, K. H. (2001). Multivalency in protein-carbohydrate recognition. In: Glycoscience: chemistry and chemical biology I–III. Fraser-Reid, B. O., Tatsuta, K., and Thiem, J., (eds). Springer Berlin Heidelberg, Berlin, Heidelberg, p. 1817.
Koeller, K. M., and Wong, C.-H. (2000). Synthesis of complex carbohydrates and glycoconjugates: enzyme-based and programmable one-pot strategies. Chem. Rev., 100(12): 4465.
Kurita, T., Abe, M., Maegawa, T., Monguchi, Y., and Sajiki, H. (2007). Ligand- and base-free synthesis of 1,3-diynes catalyzed by low loading of heterogeneous Pd/C and CuI. Synlett, 2007(16): 2521.
Laura, M., Laura, P., and Luigi, L. (2011). Carbohydrates and immunology: synthetic oligosaccharide antigens for vaccine formulation. Eur. J. Org. Chem, 2011(29): 5723.
Lee, R. T., and Lee, Y. C. (2000). Affinity enhancement by multivalent lectin–carbohydrate interaction. Glycoconj. J., 17(7): 543.
Leelayuwapan, H., Kangwanrangsan, N., Chawengkirttikul, R., Ponpuak, M., Charlermroj, R., Boonyarattanakalin, K., Ruchirawat, S., and Boonyarattanakalin, S. (2017). Synthesis and immunological studies of the lipomannan backbone glycans found on the surface of Mycobacterium tuberculosis. J. Org. Chem., 82(14): 7190.
Leelayuwapan, H., Ruchirawat, S., and Boonyarattanakalin, S. (2016). Optimizations of hydroxyl terminated polymerization of mannose tricyclic orthoester toward ready-to-use lipomannan backbone. Chiang Mai J. Sci., 43138.
Liu, Y., Lam, J. W. Y., and Tang, B. Z. (2015). Conjugated polymers developed from alkynes. Natl. Sci. Rev., 2(4): 493.
Luo, Y., Lu, Z., Raso, S. W., Entrican, C., and Tangarone, B. (2009). Dimers and multimers of monoclonal IgG1 exhibit higher in vitro binding affinities to Fcγ receptors. mAbs, 1(5): 491.
Mishra, A. K., Klein, C., Gurcha, S. S., Alderwick, L. J., Babu, P., Hitchen, P. G., Morris, H. R., Dell, A., Besra, G. S., and Eggeling, L. (2008). Structural characterization and functional properties of a novel lipomannan variant isolated from a Corynebacterium glutamicum pimB′ mutant. Antonie Leeuwenhoek, 94(2): 277.
Neyrolles, O., and Guilhot, C. (2011). Recent advances in deciphering the contribution of Mycobacterium tuberculosis lipids to pathogenesis. Tuberculosis, 91(3): 187.
Podlasek, C. A., Stripe, W. A., Carmichael, I., Shang, M., Basu, B., and Serianni, A. S. (1996). 13C−1H Spin-coupling constants in the β-d-ribofuranosyl ring: effect of ring conformation on coupling magnitudes. J. Am. Chem. Soc., 118(6): 1413.
Quesniaux, V. J., Nicolle, D. M., Torres, D., Kremer, L., Guérardel, Y., Nigou, J., Puzo, G., Erard, F., and Ryffel, B. (2004). Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independent-negative regulation of proinflammatory cytokines by mycobacterial lipomannans. J. Immunol. , 172(7): 4425.
Sahloul, K., and Lowary, T. L. (2015). Development of an orthogonal protection strategy for the synthesis of mycobacterial arabinomannan fragments. J. Org. Chem., 80(22): 11417.
Siemsen, P., Livingston Robert, C., and Diederich, F. (2000). Acetylenic coupling: a powerful tool in molecular construction. Angew. Chem. Int. Ed., 39(15): 2632.
Sonogashira, K., Tohda, Y., and Hagihara, N. (1975). A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Lett., 16(50): 4467.
Vignal, C., Guérardel, Y., Kremer, L., Masson, M., Legrand, D., Mazurier, J., and Elass, E. (2003). Lipomannans, but not lipoarabinomannans, purified from Mycobacterium chelonae and Mycobacterium kansasii induce TNF-alpha and IL-8 secretion by a CD14-toll-like receptor 2-dependent mechanism. J. Immunol. , 171(4): 2014.
Wang, D., Li, J., Li, N., Gao, T., Hou, S., and Chen, B. (2010). An efficient approach to homocoupling of terminal alkynes: solvent-free synthesis of 1,3-diynes using catalytic Cu(II) and base. Green Chem., 12(1): 45.
Wattanasiri, C., Paha, J., Ponpuak, M., Ruchirawat, S., and Boonyarattanakalin, S. (2017). Synthesis of synthetic mannan backbone polysaccharides found on the surface of Mycobacterium tuberculosis as a vaccine adjuvant and their immunological properties. Carbohydr. Polym., 175746.
Wittmann, V. (2013). Structural investigation of multivalent carbohydrate–protein interactions using synthetic biomolecules. Curr. Opin. Chem. Biol., 17(6): 982.
Yongyat, C., Ruchirawat, S., and Boonyarattanakalin, S. (2010). Polymerization of mannosyl tricyclic orthoesters for the synthesis of α(1–6) mannopyranan—the backbone of lipomannan. Bioorg. Med. Chem., 18(11): 3726.
Yu, B., van Ingen, H., Vivekanandan, S., Rademacher, C., Norris, S. E., and Freedberg, D. I. (2012). More accurate 1JCH coupling measurement in the presence of 3JHH strong coupling in natural abundance. J. Magn. Reson., 21510.
Zeng, X., Andrade, C. A. S., Oliveira, M. D. L., and Sun, X.-L. (2012). Carbohydrate–protein interactions and their biosensing applications. Anal. Bioanal. Chem., 402(10): 3161
