Heptakis(2,3‐di‐O‐methyl‐6‐O‐sulfopropyl)‐β‐cyclodextrin: A Genuine Supramolecular Carrier for Aqueous Organometallic Catalysis

The behavior of heptakis(2,3‐di‐O‐methyl‐6‐O‐sulfopropyl)‐β‐cyclodextrin as inverse phase transfer catalyst in biphasic Tsuji–Trost and hydroformylation reactions has been investigated. In terms of activity, this methylated sulfopropyl ether β‐cyclodextrin is much more efficient than the randomly methylated β‐cyclodextrin, which was the most active cyclodextrin known to date. From a selectivity point of view, the intrinsic properties of the catalytic system are fully preserved in the presence of this cyclodextrin as the chemo‐ or regioselectivity was found to be identical to that observed without a mass transfer promoter in the hydroformylation reaction. The efficiency of this cyclodextrin was attributed to its high surface activity and to the absence of interactions with the catalytically active species and the water‐soluble phosphane used to dissolve the organometallic catalyst in the aqueous phase.     

A Unique Amino Transfer Mechanism for Constructing the β‐Amino Fatty Acid Starter Unit in the Biosynthesis of the Macrolactam Antibiotic Cremimycin

Cremimycin is a 19‐membered macrolactam glycoside antibiotic based on three distinctive substructures: 1) a β‐amino fatty acid starter moiety, 2) a bicyclic macrolactam ring, and 3) a cymarose unit. To elucidate the biosynthetic machineries responsible for these three structures, the cremimycin biosynthetic gene cluster was identified. The cmi gene cluster consists of 33 open reading frames encoding eight polyketide synthases, six deoxysugar biosynthetic enzymes, and a characteristic group of five β‐amino‐acid‐transfer enzymes. Involvement of the gene cluster in cremimycin production was confirmed by a gene knockout experiment. Further, a feeding experiment demonstrated that 3‐aminononanoate is a direct precursor of cremimycin. Two characteristic enzymes of the cremimycin‐type biosynthesis were functionally characterized in vitro. The results showed that a putative thioesterase homologue, CmiS1, catalyzes the Michael addition of glycine to the β‐position of a non‐2‐enoic acid thioester, followed by hydrolysis of the thioester to give N‐carboxymethyl‐3‐aminononanoate. Subsequently, the resultant amino acid was oxidized by a putative FAD‐dependent glycine oxidase homologue, CmiS2, to produce 3‐aminononanoate and glyoxylate. This represents a unique amino transfer mechanism for β‐amino acid biosynthesis.     

Engineering of a Cytidine 5′‐Monophosphate‐Sialic Acid Synthetase for Improved Tolerance to Functional Sialic Acids

Sialic acid‐containing glycoconjugates at the cell surface are of high importance in carbohydrate‐mediated recognition phenomena in physiological and pathological events, as well as in bacterial or viral infection. A key step in the enzymatic synthesis of natural sialoconjugates and functional synthetic analogues is the activation of sialic acids to cytidine 5′‐monophosphate (CMP)‐sialic acid intermediates catalyzed by CMP‐sialic acid synthetase (CSS). Based on our recently developed aligned protein model of substrate binding and a simple colorimetric screening assay, we have engineered the CSS from Neisseria meningitidis by structure‐guided site‐specific saturation mutagenesis at positions 192/193 to generate enzymes with broadened substrate scope. Top hits, including the F192S/F193Y variant, display an improvement of up to 70‐fold catalytic efficiency relative to wild‐type CSS for the conversion of sterically demanding N‐acyl modified sialic acid analogues, without compromising protein stability. Such significantly enhanced substrate capacity is a major step forward to realizing a generalized chemo‐enzymatic strategy for the efficient preparation of neo‐sialoconjugate libraries, demonstrated by the highly efficient, regio‐ and stereospecific synthesis of 2,6‐sialyllactose analogues by enzymatic coupling to the highly substrate tolerant α2,6‐sialyltransferase from Photobacterium leiognathi JT‐SHIZ‐145. Our results further document the unusual versatility of the N. meningitidis CSS and engineered variants for a common synthetic approach to sialoconjugates comprising a large diversity of natural and non‐natural sialic acid forms without the need for post‐synthetic enzymatic modification.

     

Polyaniline salts and complexes: Efficient and reusable catalyst for the one‐pot synthesis of 5‐(methoxycarbonyl)‐6‐methyl‐4‐phenyl‐3,4‐dihydropyrimidin‐2(1h)‐one

Polyaniline salts were prepared by doping polyaniline base with different Bronsted acids (sulfuric, nitric, phosphoric, perchloric, hydrochloric acid) and organic acids (p‐toluene sulfonic acid, 5‐sulfosalicylic acid). Polyaniline complexes were also prepared using Lewis acids (aluminum chloride, ferric chloride). Polyaniline salts and polyaniline complexes were used as catalysts in Biginelli reaction for 5‐(methoxycarbonyl)‐6‐methyl‐4‐phenyl‐3,4‐dihydropyrimidin‐2(1H)‐one synthesis. Benzaldehyde and urea were reacted with methyl acetoacetate using polyaniline‐p‐toluene sulfonate salt as catalyst with different reaction time, temperature, and amount of catalyst. The use of polyaniline catalysts is feasible because of the easy preparation, easy handling, stability, easy recovery, simple work‐up procedure, reusability, excellent activity with less amount of catalyst, and eco‐friendly nature. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 102: 1741–1745, 2006     

Chemistry and Pharmacology of Nicotinic Ligands Based on 6‐[5‐(Azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol (AMOP‐H‐OH) for Possible Use in Depression

AMOP‐H‐OH (sazetidine‐A; 6‐[5‐(azetidin‐2‐ylmethoxy)pyridin‐3‐yl]hex‐5‐yn‐1‐ol) and some sulfur‐bearing analogues were tested for their activities in vitro against human α4β2‐, α4β4‐, α3β4*‐ and α1*‐nicotinic acetylcholine receptors (nAChRs). AMOP‐H‐OH was also assessed in an antidepressant efficacy model. AMOP‐H‐OH and some of its analogues have high potency and selectivity for α4β2‐nAChRs over other nAChR subtypes. Effects are manifested as partial agonism, perhaps reflecting selectivity for high sensitivity (α4)₃(β2)₂‐nAChRs. More prolonged exposure to AMOP‐H‐OH and its analogues produces inhibition of subsequent responses to acute challenges with full nicotinic agonists, again selectively for α4β2‐nAChRs over other nAChR subtypes. The inhibition is mediated either via antagonism or desensitization of nAChR function, but the degree of inhibition of α4β2‐nAChRs is limited by the partial agonist activity of the drugs. Certain aspects of the in vitro pharmacology suggest that AMOP‐H‐OH and some of its analogues have a set of binding sites on α4β2‐nAChRs that are distinct from those for full agonists. The in vitro pharmacological profile suggests that peripheral side effects of AMOP‐H‐OH or its analogues would be minimal and that their behavioral effects would be dominated by central nAChR actions. AMOP‐H‐OH also has profound and high potency antidepressant‐like effects in the forced swim test. The net action of prolonged exposure to AMOP‐H‐OH or its analogues, as for nicotine, seems to be a selective decrease in α4β2‐nAChR function. Inactivation of nAChRs may be a common neurochemical endpoint for nicotine dependence, its treatment, and some of its manifestations, including relief from depression.