ABSTRACT
The nitrone 4 (4,5-dideoxy-4-hydroxylamino-3,4-O-isopropylidene-L-lyxofuranose) was synthesised from D-ribose and used as key intermediate for the preparation of fucosidase inhibitors. We describe two transformations of 4. Hydrolysis with aqueous sulfur dioxide gave the known potent nanomolar inhibitor 4-amino-4,5-dideoxy-L-lyxofuranose (3). 1,3-Dipolar cycloaddition with enol ethers led to the related 1,2,5,6-tetradeoxy-2,5-imino-L-altroheptonic ester 2a, acid 2b and the corresponding heptitol 2c. The new iminosugars have been evaluated for their inhibitory activity against α-L-fucosidase from bovine kidney. The alcohol 2c turned out to be a potent inhibitor in the same range as the amino-sugar 3 (K(i)=8 vs 10nM).
Subject(s)
Amino Sugars/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pyrrolidines/chemical synthesis , alpha-L-Fucosidase/antagonists & inhibitors , Amino Sugars/chemistry , Amino Sugars/pharmacology , Animals , Cattle , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Furans/chemistry , Kidney/drug effects , Kidney/enzymology , Kidney/metabolism , Models, Chemical , Pentoses/chemistry , Pyrrolidines/pharmacology , Ribose/chemistry , Structure-Activity RelationshipABSTRACT
The mode of binding and the activity of the first two non-zinc chelating, potent, and selective inhibitors of human neutrophil collagenase are reported. The crystal structures of the catalytic domain of MMP-8, respectively complexed with each inhibitor, reveals that both ligands are deeply inserted into the primary specificity subsite S(1)', where they induce a similar conformational change of the surrounding loop that is endowed with the main specificity determinants of MMPs. Accord to this rearrangement, both inhibitors remove the floor of the pocket formed by the Y227 side-chain, rendering available an extra binding region never explored before. The present data show that potent and more selective inhibitors can be obtained by developing ligands able to interact with the selectivity regions of the enzyme rather than with the catalytic zinc ion, which is the common feature of all MMP members.
Subject(s)
Matrix Metalloproteinase Inhibitors , Protease Inhibitors/chemistry , Binding Sites , Catalytic Domain , Crystallography, X-Ray , Humans , Ligands , Matrix Metalloproteinase 8/chemistry , Protein Binding , Protein Conformation , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Cyclic D- and L-4-aminothreose were synthesised from ethyl D- and L-tartrate, respectively. D-aminothreose was a potent inhibitor of alpha-glucosidase and of alpha-mannosidase. From the glycosidase inhibition potencies of the four 4-amino-4-deoxy-tetroses, the contribution of binding of each functionality of the 5 and 6 membered ring amino-sugars towards the various glycosidases is discussed.
Subject(s)
Amino Sugars/pharmacology , Enzyme Inhibitors/pharmacology , Glycoside Hydrolases/antagonists & inhibitors , Tetroses/chemical synthesis , Tetroses/pharmacology , Magnetic Resonance Spectroscopy , Tetroses/chemistryABSTRACT
A concise and convergent total synthesis of the highly cytotoxic marine natural products iejimalide A-D (1-4) is reported, which relies on an effective ring-closing metathesis (RCM) reaction of a cyclization precursor containing no less than 10 double bonds. Because of the exceptional sensitivity of this polyunsaturated intermediate and its immediate precursors toward acid, base, and even gentle warming, the assembly process hinged upon the judicious choice of protecting groups and the careful optimization of all individual transformations. As a consequence, particularly mild protocols for Stille as well as Suzuki reactions of elaborate coupling partners have been developed that hold considerable promise for applications in other complex settings. Moreover, a series of non-natural "iejimalide-like" compounds has been prepared, differing from the natural lead in the polar head groups linked to the macrolide's N-terminus. With the aid of these compounds it was possible to uncover the hitherto unknown effect of iejimalide and analogues on the actin cytoskeleton. Their capacity to depolymerize this microfilament network rivals that of the latrunculins which constitute the standard in the field. Structural modifications of the peptidic terminus in 2 are thereby well accommodated, without compromising the biological effects. The iejimalides hence constitute an important new class of probe molecules for chemical biology in addition to their role as promising lead structures for the development of novel anticancer agents.