The racemic 7-oxanorbornanyl and norbornanyl aminoalcohols 3, 4, 42, 45, and 46 were synthesized and tested as snail b-mannosidase inhibitors. The amino tetraol 3 was obtained from the known sulfonyl acrylate 9 and furan 10. Esterification provided 11 that underwent an intramolecular Diels-Alder reaction to the 7-oxanorbornene 12. Reduction of 12 to 13, desulfonylation, isopropylidenation, and cis-dihydroxylation gave 16. A second isopropylidenation to 17, followed by debenzylation and a Mitsunobu-Gabriel reaction provided 19 that was deprotected via 20 to 3. Diels-Alder cycloaddition of furfuryl acetate and maleic anhydride to 21, followed by alcoholysis of the anhydride, cis-dihydroxylation, isopropylidenation, and Barton decarboxylation gave the ester 25. Deacetylation to 26 and a Mitsunobu-Gabriel reaction led to 27 that was transformed into the NBoc analogue 29, reduced to the alcohol 30, and deprotected to 4. The 1-aminonorbornane 5 was obtained from Thiele's Acid 31. Diels-Alder cycloaddition of the cyclopentadiene obtained by thermolysis of the diester 32, methanolysis of the resulting anhydride 33, dihydroxylation, isopropylidenation, Barton decarboxylation, and Curtius degradation led to the benzyl carbamate 39 that was reduced to the alcohol 40, transformed into the N-Boc carbamate 41, and deprotected to 5. The alcohol 40 was also transformed into the benzylamine 42, aniline 45, and hydroxylamine 46. Snail b-mannosidase was hardly inhibited by 3, 4, 42, 45, and 46. Only the amino triol 5 proved a stronger inhibitor. The inhibition by 5 depends on the pH value (at pH 3.5: K i = 1900 mM; at pH 4.5: K i = 340 mM; at pH 5.5: K i = 110 mM). The results illustrate the strong dependence of the inhibition by bicyclic mimics upon the precise geometry and orientation of the amino group as determined by the scaffold. It is in keeping with the hypothesis that the reactive conformation imposed by snail b-mannosidase is close to aIntroduction. -The design, synthesis, and study of glycosidase inhibitors continue to attract interest, fuelled by the potential of strong and selective glycosidase inhibitors to act as drugs (e.g., against lysosomal storage disorders such as Gaucher's disease , and their use as tools in the elucidation of the mechanism of action of glycosidases on the basis of structure-activity relations, kinetic studies, and information provided by the structure determination of enzyme-inhibitor complexes [7]. Transition-state analogues promise to be most useful. Their design is based upon existent information about the mechanism of action, and particularly about the transition state of the rate-determining step, while their study may contribute to a more detailed understanding of the mechanisms of action as summarised in several reviews [8] [9]. Partial transition-state mimics may be thought of as being closer to a point of the reaction coordinate that either precedes, or follows the transition state of interest, and there are reasons to hypothesise that those preceding the rate-determining transition s...

Non-healing and partially healing wounds are an important problem not only for the patient but also for the public health care system. Current treatment solutions are far from optimal regarding the chosen material properties as well as price and source. Biodegradable polyurethane (PUR) scaffolds have shown great promise for in vivo tissue engineering approaches, but accomplishment of the goal of scaffold degradation and new tissue formation developing in parallel has not been observed so far in skin wound repair. In this study, the mechanical properties and degradation behavior as well as the biocompatibility of a low-cost synthetic, pathogen-free, biocompatible and biodegradable extracellular matrix mimicking a PUR scaffold was evaluated in vitro. The novel PUR scaffolds were found to meet all the requirements for optimal scaffolds and wound dressings. These three-dimensional scaffolds are soft, highly porous, and form-stable and can be easily cut into any shape desired. All the material formulations investigated were found to be nontoxic. One formulation was able to be defined that supported both good fibroblast cell attachment and cell proliferation to colonize the scaffold. Tunable biodegradation velocity of the materials could be observed, and the results additionally indicated that calcium plays a crucial role in PUR degradation. Our results suggest that the PUR materials evaluated in this study are promising candidates for next-generation wound treatment systems and support the concept of using foam scaffolds for improved in vivo tissue engineering and regeneration.

The racemic gluco-configured norbornanes 4 and 16 were prepared and tested as inhibitors of b-glucosidases. The known alcohol 5 was deprotected to provide the triol 6. Silylation (! 7), monobenzoylation (! 8/9), and oxidation provided the regioisomeric ketones 10 and 11. Reduction of 10 gave the desired endo-alcohol 13, albeit in low yield, while reduction of the isomeric ketone 11 provided mostly the altro-configured endo-alcohol 12. The alcohol 13 was desilylated to 14. Debenzoylation to 15 followed by hydrogenolytic deprotection gave the amino triol 4 that was reductively aminated to the benzylamine 16. The amino triols 4 and 16 proved weak inhibitors of the b-glucosidase from Caldocellum saccharolyticum (4: IC 50 = 5.6 mM; 16: IC 50 = 3.3 mM) and from sweet almonds (16: IC 50 = 5.5 mM). A comparison of 4 with the manno-configured norbornane 3 shows that 3 is a better inhibitor of snail b-mannosidase than 4 is of b-glucosidases, in keeping with earlier results suggesting that these b-glycosidases enforce a different conformational itinerary.Introduction. -b-Glycosidases impose a conformational change on their substrates to comply with the stereoelectronic control of glycoside cleavage [1 -4]. Several conformations allow the required coplanar arrangement of a non-bonding, doubly occupied orbital of the ring O-atom and the s* orbital of the scissile bond [5], and it was considered likely that all of them are enforced by different glycosidases [6]. Stable mimics of the individual acceptable conformers may act as selective inhibitors and contribute in assessing the conformational itinerary enforced by a specific glycosidase. It was claimed that inhibitors mimicking such distorted conformers should be inherently more selective than mimics of an intermediate oxocarbenium cation and be more sensitive to small geometric changes [7] [8]. In keeping with these considerations, the manno-configured isoquinuclidine 1 [9] mimicking a 1,4 B/

The racemic 2-azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as b-glycosidase inhibitors. The intramolecular Diels-Alder reaction of the masked o-benzoquinone generated from 2-(allyloxy)phenol (6) gave the a-keto acetal 7 which was reduced with SmI 2 to the hydroxy ketone 8. Dihydroxylation, isopropylidenation (! 12), and Beckmann rearrangement provided lactam 15. N-Benzylation of this lactam, reduction to the amine 17, and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5. Both 5 and 19 proved weak inhibitors of snail b-mannosidase (IC 50 > 10 mM), Caldocellum saccharolyticum b-glucosidase (IC 50 > 10 mM), sweet almond b-glucosidase (IC 50 > 10 mM), yeast a-glucosidase (5: IC 50 > 10 mM; 19: IC 50 = 1.2 mM), and Jack bean a-mannosidase (no inhibition detected).Introduction. -Together with the crystal-structure analysis of glycosidase-inhibitor complexes [1] and the use of isotopically labelled compounds [2], the synthesis and evaluation of inhibitors contribute to elucidating the mechanism of action of the enzymatic hydrolysis of glycosides, as summarized in several reviews [3]. For example, the determination and interpretation of inhibition constants and kinetics of conformationally biased (more or less close) mimics of the transition state are a valuable source of information about the stereoelectronically required [4] conformational change of the substrate imposed by b-glycosidases [5]. Thus, the isoquinuclidine 1 [6], mimicking the 1,4 B conformation of a D-mannopyranoside, inhibits snail b-mannosidase strongly (K i = 1 mM) and selectively, while the corresponding gluco-configured diastereoisomer is inactive against b-glucosidases, evidencing a different conformational itinerary. The norbornane 2 and its 7-oxa analogues 3 and 4 [7], possessing a shorter bridge between the centers corresponding to C(1) and C(4), and mimicking a 1,4 B conformation more closely than the isoquinuclidine 1 differ considerably in the location and orientation of the N-atom, and are rather weak inhibitors of snail b-mannosidase. In this context, 2-azabicyclo[3.2.2]nonanes ('homoisoquinuclidines') such as 5 appeared of interest, as they possess a longer bridge ensuring a boat-like conformation of the cyclohexane ring mimicking the pyranosyl (glycon) moiety. We anticipated differences to 1 in the orientation of the CÀN bond and in the location of the basic N-atom ('the glycosidic heteroatom') that is to interact with the catalytic acid. An evaluation of the inhibition of b-glycosidases by such amines may allow to more precisely assess the optimal pre-transition state conformation of this type of glycosidase inhibitors.

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