1055030-05-1Relevant academic research and scientific papers
Sialyltransferase inhibitors based on CMP-quinic acid
Schaub, Christoph,Mueller, Bernd,Schmidt, Richard R.
, p. 1745 - 1758 (2007/10/03)
Quinic acid was transformed into phosphitamides 16, 25, and 36, which could be readily linked to 5'-O-unprotected cytidine derivative 17. Ensuing oxidation of the obtained phosphite triesters with tBuO2H and hydrogenolytic de-O-benzylation furnished the corresponding phosphate diesters 18, 26, and 38. Base catalyzed removal of acetyl protecting groups, and methyl ester hydrolysis furnished CMP-Neu5Ac analogues 1d, 1e, and 2. Quinic acid was also transformed into 1,2-unsaturated diallyl α-hydroxymethyl-phosphate derivatives (R)- and (S)-46, which on reaction with cytidine phosphitamide 47 afforded the phosphite triesters. Subsequent oxidation with tBuO2H and then 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 base led to acetic acid elimination, thus yielding, after de-O-allylation, acetyl group cleavage, and ester hydrolysis, diene derivative (E)-4. Donor substrate analogues 1d and 1e exhibited good α(2-6)-sialyltransferase inhibition (K(i): 2.0 · 10-4 and 2.0 · 10-5 M). However, transition state analogues (R)-, and particularly (S)-3 showed excellent inhibition properties (K(i): 1.6 · 10-6 and 2.7 · 10-7 M).
