1P22: t) Synthesis of sialyl Lewis x mimetics as selectin inhibitors by enzymatic aldol condensation reactions

C.-C. Lin et al.⁵⁶ prepared several D-mannosyl phosphate/phosphonate derivatives have been enzymatically prepared as sialyl Lewis x tetrasaccharide mimics, which showed strong-to-moderate inhibition against E-, P-, and L-selectins. The synthesis of these mimics is very straight forward; mannosyl aldehyde derivatives are condensed with dihydroxyacetone phosphate (DHAP) in the presence of a DHAP-dependent aldolase to provide mannosyl phosphates. According to C.-C. Lin et al. in their preliminary work⁵⁷ reported that mannosyl phosphates 115 and 116 are good inhibitors of P- and L-selectins. Molecular modeling showed that both 115 and 116 overlap well with the active conformations of SLe^x. In this paper present the detailed synthesis of 115 and 116 and related structures using enzymatic aldol condensation, and analysis of those structures as inhibitors of the three selectins. As shown in Scheme 22a, O- and C-mannosyl aldehydes were chosen as aldolase substrates because D-mannose has been successfully used as the L-fucose equivalent in the design of SLe^x mimetics.⁵⁸ The aldol condensation of the aldehyde with dihydroxyacetone phosphate (DHAP) and the corresponding phosphonate (C-DHAP) using different DHAP-dependent aldolases generates two hydroxyl groups which they postulate to mimic the 4- and 6-hydroxy groups of the galactose moiety, and the phosphate/phosphonate group which mimics the carboxylate negative charge. This strategy creates two new stereogenic centers for use to screen for the best mimic of the galactose residue and is flexible enough to furnish a number of derivatives while keeping the other essential groups in appropriate spatial distance and orientation (see 3-7, Scheme 22b). In addition, the 6-position of the sugar moiety can be changed to hydrophobic functional groups which are expected to increase the binding activity with E- and P- selectin.^{57, 59}

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56. C.-C. Lin, F. Morís-Varas, G. Weitz-Schmidt, and C.-H. Wonga, Bioorg. Med. Chem., 1999, 7, 425.

57. C.-H. Wong, M.-V. Francisco, S.-C. Hung, T.-G. Marron, C.-C. Lin, K. W. Gong, and G. Weitz-Schmidt, J. Am. Chem. Soc., 1997, 119, 8152.

58. (a) B. Dupré, H. Bui, I. L. Scott, R. V. Market, K. M. Keller, P. J. Beck, and T. P. Kogan, Bioorg. Med. Chem. Lett., 1996, 6, 569. (b) T. G. Marron, T. J. Woltering, G. Weitz-Schmidt, and C.-H. Wong, Tetrahedron Lett., 1996, 37, 9037. (c) K. Hiruma, T. Kayimoto, G. Weitz-Schmidt, I. Ollmann, and C.-H. Wong, J. Am. Chem. Soc., 1996, 118, 9265.

59. (a) J. Y. Ramphal, M. Hiroshige, B. Lou, J. J. Gaudino, M. Hayashi, S. M. Chen, L. C. Chiang, F. C. A. Gaeta, and S. A. DeFrees, J. Med. Chem., 1996, 39, 1357. (b) M. Hayashi, T. Tanaka, M. Itoh, and H. Miyauchi, J. Org. Chem., 1996, 61,2938.
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