Synthesis and biological evaluation of a unique heparin mimetic hexasaccharide for structure-activity relationship studies.

To date, the structure-activity relationship studies of heparin/heparan sulfate with their diverse binding partners such as growth factors, cytokines, chemokines, and extracellular matrix proteins have been limited yet provide early insight that specific sequences contribute to this manifold biological role. This has led to an impetus for the chemical synthesis of oligosaccharide fragments of these complex polysaccharides, which can provide an effective tool for this goal. The synthesis of three heparin mimetic hexasaccharides with distinct structural patterns is described herein, and the influence of the targeted substitution on their bioactivity profiles is studied using in vitro affinity and/or inhibition toward different growth factors and proteins. Additionally, the particularly challenging synthesis of an irregular hexasaccharide is reported, which, interestingly, in spite of being considerably structurally similar with its two counterparts, displayed a unique and remarkably distinct profile in the test assays.

Rational design of anticoagulant drugs using oligosaccharide chemistry.

For a long time, heparin and low molecular weight heparins have been the drugs of choice for the management of thrombosis. Discovery of the antithrombin binding domain in heparin, a critical element in the anticoagulant activity of this polysaccharide, allowed a rational approach based on medicinal carbohydrate chemistry in the design of new anticoagulants. The fully synthetic pentasaccharide fondaparinux that selectively targets blood coagulation factor Xa was first to be developed as a drug. Fondaparinux was followed by various heparin mimicking oligosaccharides prepared with a view to replace polydisperse heparin and low molecular weight heparins by structurally-defined anticoagulants with no unwanted side-effects.

N-Substituted 4-amino-3,3-dipropyl-2(3H)-furanones: new positive allosteric modulators of the GABA(A) receptor sharing electrophysiological properties with the anticonvulsant loreclezole.

1,4-Addition of benzylamine to 2(5H)-furanone followed by dialkylation of the 3-position with allylbromide gave (+/-)-4-benzyl-3,3-diallyl-2(3H)-furanone (8), which served as the intermediate for the synthesis of various N-substituted 4-amino-3,3-dipropyl-2(3H)-furanones (+/-)-9a-l. The compounds were evaluated for their capacity to potentiate or inhibit GABA-evoked currents in Xenopus laevis oocytes expressing recombinant alpha1beta2gamma2 GABA(A) receptors. The benzyl, ethyl, and allyl carbamates ((R)-9a (100 microM), (+/-)-9b (100 microM), (+/-)-9c (200 microM)) stimulated GABA currents by 279 +/- 47%, 426 +/- 8%. and 765 +/- 61%, respectively, while the phenylcarboxamide (+/-)-9f (200 microM) stimulated currents by 420 +/- 33%. Concentration-response studies showed that compound 9c was approximately twice as potent in stimulating GABA currents as alpha-EMTBL (2), the most potent 3,3-dialkylbutyrolactone known to date. On the other hand, the N-sulfonyl analogues were much less active or even inhibited GABA-evoked currents. In vitro radioligand displacement studies on rat brain membranes showed that these compounds did not bind to the benzodiazepine or GABA recognition sites of the GABA(A) receptor. However, these compounds generally weakly displaced [(35)S]-TBPS (approximately 50% displacement at 100 microM), though potencies did not correlate with GABA current potentiation. Results obtained with alpha1beta1 and mutant alpha1beta2N265S receptors, which compared to alpha1beta2 receptors are both much less sensitive to current stimulation produced by the anticonvulsant loreclezole, suggest that at least some of these aminobutyrolactones, (e.g., 9a, 9c), and interestingly also alpha-EMTBL, share stimulatory properties with loreclezole.