Synthesis and alpha-mannosidase inhibitory evaluation of (2R,3R,4S)- and (2S,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol derivatives

The synthesis of 46 derivatives of (2R,3R,4S)-2-(aminomethyl)pyrrolidine-3,4-diol is reported (Scheme I and Fig. 3), and their inhibitory activities toward alpha-mannosidases from jack bean (B) and almonds (A) are evaluated (Table). ne most-potent inhibitors are (2R,3R,4S)-2-{[([1,1'-biphenyl]-4-ylmethyl)amino]methyl}pyrrolidine-3,4- diol (3fs; IC50(B) = 5 mum, K-i = 2.5 mum) and (2R,3R,4S)-2-{[(1R)-2,3-dihydro-1H-inden-1-ylamino]methyl)pyrrolidine-3, 4-diol (3fu; IC50(B) = 17 mum, K-i = 2.3 mum). (2S,3R,4S)-2-(Aminomethyl)pyrrolidine-3,4-diol (6, R=H) and the three 2-(N-alkylamino)methyl derivatives 6fh, 6fs, and 6f are prepared (Scheme 2) and found to inhibit also a-mannosidases from jack bean and almonds (Table). The best inhibitor of these series is (2S,3R,4S)-2-([(2-thienylmethyl)amino]methyl}pyrrolidine-3,4-diol (60; IC50(B) = 105 mum, K-i = 40 mum). As expected (see Fig. 4), diamines 3 with the configuration of alpha-D-mannosides are better inhibitors of alpha-marmosidases than their stereoisomers 6 with the configuration of beta-D-mannosides. The results show that an aromatic ring (benzyl, [1,1'-biphenyl]-4-yl, 2-thienyl) is essential for good inhibitory activity. If the C-chain that separates the aromatic system from the 2-(aminomethyl) substituent is longer than a methano group, the inhibitory activity decreases significantly (see Fig. 7). This study shows also that alpha-mannosidases from jack bean and from almonds do not recognize substrate mimics that are bulky around the O-glycosidic bond of the corresponding alpha-D-mannopyranosides. These observations should be very useful in the design of better alpha-mannosidase inhibitors.

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Helv. Chim. Acta, 86, 6, 1914-1948
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 Record created 2005-11-09, last modified 2018-03-17

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