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Synthesis and α ‐Mannosidase Inhibitory Evaluation of (2 R ,3 R ,4 S )‐ and (2 S ,3 R ,4 S )‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol Derivatives
Author(s) -
Popowycz Florence,
GerberLemaire Sandrine,
RodriguezGarcía Eliazar,
Schütz Catherine,
Vogel Pierre
Publication year - 2003
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.200390153
Subject(s) - pyrrolidine , chemistry , stereochemistry , diol , substituent , organic chemistry
The synthesis of 46 derivatives of (2 R ,3 R ,4 S )‐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 (2 R ,3 R ,4 S )‐2‐{[([1,1′‐biphenyl]‐4‐ylmethyl)amino]methyl}pyrrolidine‐3,4‐diol ( 3fs ; IC 50 (B)=5 μ M , K i =2.5 μ M ) and (2 R ,3 R ,4 S )‐2‐{[(1 R )‐2,3‐dihydro‐1 H ‐inden‐1‐ylamino]methyl}pyrrolidine‐3,4‐diol ( 3fu ; IC 50 (B)=17 μ M , K i =2.3 μ M ). (2 S ,3 R ,4 S )‐2‐(Aminomethyl)pyrrolidine‐3,4‐diol ( 6 , RH) 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 (2 S ,3 R ,4 S )‐2‐{[(2‐thienylmethyl)amino]methyl}pyrrolidine‐3,4‐diol ( 6o ; IC 50 (B)=105 μ M , K i =40 μ M ). 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.