4-C-Me-DAB and 4-C-Me-LAB—enantiomeric alkyl-branched pyrrolidine iminosugars—are specific and potent α-glucosidase inhibitors; acetone as the sole protecting group

• Published in: Tetrahedron letters 2011-01, Vol.52 (2), p.219-223
• Main Authors: Cruz, Filipa P. da, Newberry, Scott, Jenkinson, Sarah F., Wormald, Mark R., Butters, Terry D., Alonzi, Dominic S., Nakagawa, Shinpei, Becq, Frederic, Norez, Caroline, Nash, Robert J., Kato, Atsushi, Fleet, George W.J.
• Format: Article
• Language: English
• Subjects: acetone; alpha-glucosidase; Chemical Sciences; endoplasmic reticulum; enzyme inhibitors; Human health and pathology; inhibitory concentration 50; Life Sciences; nuclear magnetic resonance spectroscopy; Organic chemistry; Pharmaceutical sciences; Pharmacology; Pulmonology and respiratory tract; rats; sucrose alpha-glucosidase; Tissues and Organs
• ISSN: 0040-4039; 1873-3581
• DOI: 10.1016/j.tetlet.2010.10.173

The syntheses of 4-C-Me-DAB [1,4-dideoxy-1,4-imino-4-C-methyl-d-arabinitol] from l-erythronolactone and of 4-C-Me-LAB [from d-erythronolactone] require only a single acetonide protecting group. The effect of pH on the NMR spectra of 4-C-Me-DAB [pKa of the salt around 8.4] is discussed and illustrates the need for care in the analysis of both coupling constants and chemical shift. 4-C-Me-DAB (for rat intestinal sucrase Ki 0.89μM, IC50 0.41μM) is a competitive—whereas 4-C-Me-LAB (for rat intestinal sucrase Ki 0.95μM, IC50 0.66μM) is a non-competitive—specific and potent α-glucosidase inhibitor. A rationale for the α-glucosidase inhibition by DAB, LAB, 4-C-Me-DAB, 4-C-Me-LAB and isoDAB—but not isoLAB—is provided. Both are inhibitors of endoplasmic reticulum (ER) resident α-glucosidase I and II.