86] Cf. J . Alsfrr and L. A . B i m e i i r .by Newman in 1955, to describe the benzologues of phenanthrene in which the extra ortho-condensed rings give rise to a (regular) cylindrical helix. The pioneer work of Newman in this field cannot be overemphasized; his brillant synthesis and resolution of [6]helicene, achieved eighteen years ago, will remain as a landmark, for it opened the way to the study of a fascinating class of synthetic molecules. In the following review, an attempt is made to summarize the present state of our knowledge in this rapidly expanding field.
Transition state analogue boronic acid inhibitors mimicking the structures and interactions of good penicillin substrates for the TEM-1 beta-lactamase of Escherchia coli were designed using graphic analyses based on the enzyme's 1.7 A crystallographic structure. The synthesis of two of these transition state analogues, (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1) and (1R)-1-acetamido-2-(3-carboxy-2-hydroxyphenyl)ethylboronic acid (2), is reported. Kinetic measurements show that, as designed, compounds 1 and 2 are highly effective deacylation transition state analogue inhibitors of TEM-1 beta-lactamase, with inhibition constants of 5.9 and 13 nM, respectively. These values identify them as among the most potent competitive inhibitors yet reported for a beta-lactamase. The best inhibitor of the current series was (1R)-1-phenylacetamido-2-(3-carboxyphenyl)ethylboronic acid (1, K(I) = 5.9 nM), which resembles most closely the best known substrate of TEM-1, benzylpenicillin (penicillin G). The high-resolution crystallographic structures of these two inhibitors covalently bound to TEM-1 are also described. In addition to verifying the design features, these two structures show interesting and unanticipated changes in the active site area, including strong hydrogen bond formation, water displacement, and rearrangement of side chains. The structures provide new insights into the further design of this potent class of beta-lactamase inhibitors.
The structure of the plasmid-mediated beta-lactamase TEM-1 has been solved in complex with a designed boronic acid inhibitor (1R)-1-acetamido-2-(3-carboxyphenyl)ethane boronic acid at 1.7 A resolution. The boronate inhibitor was designed based on the crystallographic coordinates of the acyl-enzyme intermediate of TEM-1 bound to the substrate penicillin G. The boronate-TEM-1 complex is highly ordered and defines a novel transition state analogue of the deacylation step in the beta-lactamase reaction pathway. The design principles of this highly effective inhibitor (Ki = 110 nM) and the resulting structural and mechanistic implications are presented.
In order to study the effects carbohydrates have on glycoprotein structure and function, it is imperative to be able to synthesize the appropriate natural and non-natural glycoprotein variants in a single form. Because the available in ViVo techniques provide only heterogeneous mixtures of different glycoforms, enzymatic in Vitro methodologies have been pursued. Using the N-glycoprotein RNase B as a model system, the oligosaccharide was removed leaving only the N-acetylglucosamine as a "tag" to the site of glycosylation. Glycosyltransferases were then used to build a unique carbohydrate moiety. A new RNase glycoform containing the branched oligosaccharide, sialyl Lewis X or the Hg derivative, was synthesized enzymatically to demonstrate the feasibility of the method. In addition, the monoglycosylated protein was digested into several smaller pieces by subtilisin BPN′. These fragments were religated by subtilisin 8397 to the full length RNase by addition of glycerol; this method points to a new chemical-enzymatic process for the synthesis of glycoproteins using synthetic peptides and glycopeptides as substrates for enzymatic ligation followed by further enzymatic glycosylations.
The (dl) a-keto esters 16, were prepared from the (dl) carbinols 1 to and from (dl) -2-hydroxyheptaElicene 5. These (dl) a-keto esters underwent NaBHq reductions to give the corresponding diastereomeric (dl) a-hydroxy esters 11, with 54 to -100% diastereaneric excesses.Highly enantioselective and/or diastereoselective syntheses are of great importance in organic chemistry. As an ultimate goal we aimed at the preparation and use o f chiral secondary alcohols and phenolewhich could lead to highly effective asymmetric inductions.process to evaluate the steric approach control as it is easy to modulate the bulkyness of the alkoxy moety of the ester '.available2'3 and proved to be efficient inducers in the reduction of the corresponding a-keto esters with NaBH4.The NaBH' reduction of a-keto esters was considered to be an efficient We have studied four secondary (dl) alcohols (1 to i) which are readily
Cyclic imine sugars were prepared by a novel chemoenzymatic
strategy in which azido-sugars, constructed
by enzymatic aldol reactions, were hydrogenated under acidic
conditions. These cyclic imine sugars were found to
be potent inhibitors of glycoprocessing enzymes having
K
i's in the nanomolar and micromolar range for a
variety of
glycosidases. In comparison with their fully hydrogenated
counterparts the cyclic imine sugars generally showed
comparable or better inhibition against the glycosidases tested.
Because these cyclic imines are so readily available
and since imines are key intermediates in a variety of cycloadditions,
condensations, and nucleophilic additions,
they are valuable as versatile synthetic intermediates for the
preparation of novel iminocyclitols and derivatives.
An
example of such synthetic utility is demonstrated by the synthesis of
amino-iminocyclitol 24 via a three-center,
two-component Strecker reaction. A novel method for rapidly screening
glycosidase inhibitors using electrospray mass
spectrometry is also described and shown to be capable of identifying
potent fucosidase inhibitors for detailed kinetic
analysis. Also, in the reductive amination of azido-sugars for the
preparation of the five-membered ring iminocyclitol
8, rhodium was found to exhibit superior face selectivity
when compared to palladium or platinum catalysts.
The active site specificity of vertebrate collagenase was mapped with the synthesis of a variety of peptides, peptolides, and peptide esters. The enzyme was found to prefer very lipophilic sequences, and it was also found to be an esterase. The thio peptolide Ac-Pro-Leu-Gly-SCH[CH2CH(CH3)2]CO-Leu-Gly-OC2H5 was found to be an exceptional substrate. High-performance liquid chromatography and tandem mass spectrometry were used to unambiguously establish the cleavage site in several peptide substrates.
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