125878-05-9Relevant articles and documents
Synthetic 1-deoxynojirimycin N-substituted peptides offer prolonged disruption to N-linked glycan processing
Aguilar, Aim Lpez,Escribano, Jaime,Wentworth, Paul,Butters, Terry D.
, p. 2809 - 2813 (2014)
A panel of 1-deoxynojirimycin (DNJ) N-linked peptides were synthesized. Their IC50 values were measured in vitro against a-glucosidases I and II and were found to be in the micromolar range for both isozymes, and better than that of the iminosugar NB-DNJ (miglustat, 3) against a-glucosidase II. Cell-based studies revealed that although the free iminosugar 3 is most effective at disrupting N-linked glycan processing for shortterm incubations (one day), when the cell-based studies were extended to three days, the DNJ N-linked tetrapeptide KDEL, which is an endoplasmic reticulum (ER)-retaining sequence, performed far better than 3. In low inhibitor washout studies, NB-DNJ inhibition was decreased to zero after 24 h, but DNJ- KDEL retained 13% activity. This method offers a general approach for targeting drugs to the ER and prolonging their activity. Moreover, it is modular, so as new iminosugars of increased potency are discovered, they can be added to this template for targeting.
Cyclic five-membered phosphinate esters as transition state analogues for obtaining phosphohydrolase antibodies
Hum, Gabriel,Wooler, Krista,Lee, Jeremy,Taylor, Scott D.
, p. 642 - 655 (2007/10/03)
Two novel cyclic five-membered phosphinate esters (6 and 7) were synthesized and used as transition state analogues (TSAs) for raising phosphohydrolase antibodies. The key step in the syntheses was a McCormack reaction between (2-chloroethyl)dichlorophosphite and 1,4-diphenyl-1,3-butadiene to form isomeric cyclic phosphinyl chlorides which upon further elaboration yielded the TSAs. X-ray crystal structures of two cyclic phosphinate TSA precursors (14a and 14b) show highly compressed CPC bond angles of 94°-97° indicating that the CPC bond angles in 6 and 7 are significantly distorted towards the ideal trigonal bipyramidal equatorial-apical transition state angle of 90° formed during phosphate ester hydrolysis. Antibodies were raised to 6 and 7 using standard hybridoma technology. One antibody. Jel 541, an IgM class antibody, was obtained that was capable of catalyzing the hydrolysis of phosphonate substrate 9 and, to a much lesser extent, phosphate substrate 8. This antibody bound TSA 6 approximately 100 times more tightly than TSA 7 as determined by solid phase radio immune assays. The activity of the antibody-catalyzed reaction was completely inhibited by the presence of TSA 6. Although the relative instability and poor solubility of Jel 541 made it impossible to perform a detailed kinetic analysis of the antibody-catalyzed reactions, these results demonstrate that phospholydrolase antibodies can indeed be obtained using cyclic five membered phosphinates as haptens.
