Synthesis and α‐Mannosidase Inhibitory Evaluation of (2R,3R,4S)‐ and (2S,3R,4S)‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol Derivatives

Abstract

AbstractThe synthesis of 46 derivatives of (2R,3R,4S)‐2‐(aminomethyl)pyrrolidine‐3,4‐diol is reported (Scheme 1 and Fig. 3), and their inhibitory activities toward α‐mannosidases from jack bean (B) and almonds (A) are evaluated (Table). The most‐potent inhibitors are (2R,3R,4S)‐2‐{[([1,1′‐biphenyl]‐4‐ylmethyl)amino]methyl}pyrrolidine‐3,4‐diol (3fs; IC50(B)=5 μM, Ki=2.5 μM) and (2R,3R,4S)‐2‐{[(1R)‐2,3‐dihydro‐1H‐inden‐1‐ylamino]methyl}pyrrolidine‐3,4‐diol (3fu; IC50(B)=17 μM, Ki=2.3 μM). (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 α‐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 (6o; IC50(B)=105 μM, Ki=40 μM). As expected (see Fig. 4), diamines 3 with the configuration of α‐D‐mannosides are better inhibitors of α‐mannosidases than their stereoisomers 6 with the configuration of β‐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 α‐mannosidases from jack bean and from almonds do not recognize substrate mimics that are bulky around the O‐glycosidic bond of the corresponding α‐D‐mannopyranosides. These observations should be very useful in the design of better α‐mannosidase inhibitors.