Sialyltransferase inhibitors based on CMP-quinic acid

Quinic acid was transformed into phosphitamides 16, 25, and 36, which could be readily linked to 5'-O-unprotected cytidine derivative 17. Ensuing oxid ation of the obtained phosphite triesters with tBuO(2)H and hydrogenolytic de-O-benzylation furnished the corresponding phosphate diesters 18, 26, and 38, Base catalyzed removal of acetyl protecting groups, and methyl ester h ydrolysis furnished CMP-Neu5Ac analogues Id, le, and 2, Quinic acid was als o transformed into 1,2-unsaturated diallyl alpha-hydroxymethyl-phosphate de rivatives (R)- and (S)-46,which on reaction with cytidine phosphitamide 47 afforded the phosphite triesters. Subsequent oxidation with tBuO(2)H and th en treatment with NEt3 gave phosphate diester derivatives (R)- and (S)-48. Deallylation, acetyl group removal, and methyl ester hydrolysis furnished ( R)- and (S)-3, respectively. Treatment of (R)- and (S)-48 with DBU as a bas e led to acetic acid elimination, thus yielding, after de-O-allylation, ace tyl group cleavage, and ester hydrolysis, diene derivative (E)-4. Donor sub strate analogues Id and 1e exhibited good alpha(2-6)-sialyltransferase inhi bition (K-i: 2.0.10(-4) and 2.0.10(-5) M). However, transition state analog ues (R)-, and particularly (S)-3 showed excellent inhibition properties (K- i,: 1.6.10(-6) and 2.7.10(-7) M).