Natural biological enzymes possess catalytic sites that are generally surrounded by a large three-dimensional scaffold. However, the proportion of the protein molecule that participates in the catalytic reaction is relatively small. The generation of artificial or miniature enzymes has long been a focus of research because enzyme mimetics can be produced with high activity at low cost. These enzymes aim to mimic the active sites without the additional architecture contributed by the protein chain. Previous work has shown that amyloidogenic peptides are able to self-assemble to create an active site that is capable of binding zinc and catalysing an esterase reaction. Here, we describe the structural characterisation of a set of designed peptides that form an amyloid-like architecture and reveal that their capability to mimic carbonic anhydrase and serve as enzyme-like catalysts is related to their ability to self-assemble. These amyloid fibril structures can bind the metal ion Znvia a three-dimensional arrangement of His residues created by the amyloid architecture. Our results suggest that the catalytic efficiency of amyloid-like assembly is not only zinc-dependent but also depends on an active centre created by the peptides which is, in turn, dependent on the ordered architecture. These fibrils have good esterase activity, and they may serve as good models for the evolution of modern-day enzymes. Furthermore, they may be useful in designing self-assembling fibrils for applications as metal ion catalysts. This study also demonstrates that the ligands surrounding the catalytic site affect the affinity of the zinc-binding site to bind the substrate contributing to the enzymatic activity of the assembled peptides.
The thiopeptide (or thiostrepton) antibiotics are a class of sulfur-containing highly modified cyclic
peptides with interesting biological activity. Described herein is the total synthesis of the thiopeptide antibiotic
promothiocin A, which utilizes a modified Bohlmann−Rahtz pyridine synthesis to establish the oxazolyl−thiazole−pyridine heterocyclic centerpiece of the antibiotic. The oxazole building blocks were obtained by a
dirhodium(II)-catalyzed chemoselective carbenoid N−H insertion reaction followed by cyclodehydration, and
the thiazoles by the Hantzsch reaction. Two different strategies for macrocyclization were successfully employed,
with the dehydroalanine side chain of the natural product being introduced in the last steps of the synthesis.
A new simple procedure for microwave-assisted organic synthesis under continuous flow processing has been developed for use in a monomodal microwave synthesizer with direct temperature control using the instrument's in-built IR sensor. This design makes optimum use of the standing wave cavity to improve the energy efficiency of microwave-assisted flow reactions.
Synthesis of Tetrasubstituted Pyridines by the Acid-CatalyzedBohlmann-Rahtz Reaction.-An improved methodology for the Bohlmann-Rahtz reaction is presented, which allows the synthesis of pyridine derivatives in one step and at lower temperatures. Thus, enamino esters (I) and (V) react with alkynones in the presence of acetic acid or catalytic amounts of ZnBr 2 or Yb(O-Tf) 3 to furnish directly the poly-substituted pyridines in moderate to good yields. The reaction can additionally be extended to acid-labile educts when Amberlyst 15 is used as the catalyst.
The results of our research into the Bohlmann-Rahtz pyridine synthesis are summarized. The historic discovery of this reaction and its mechanism are discussed; followed by recent improvements in methodology, such as Brønsted and Lewis acid catalysis, microwave assistance, process in a continuous flow reactor, and incorporation into multicomponent and tandem reactions. Applications of these methods in the synthesis of pyrido[2,3-d]pyrimidines, combinatorial pyridine libraries, heterocyclic a-and gamino acids, a-helix mimetics, and complex natural products are discussed, along with a consideration of future perspectives.
Microwave irradiation of substituted hydrazines and beta-ketoesters gives 5-aminopyrazoles in excellent yield, which can be transformed to the corresponding N-carbonyl derivatives by treatment with an isocyanate or chloroformate. Derivatization of 4-nitronaphth-1-ol using predominantly microwave heating methods and reaction with an N-pyrazole carbamate provides a rapid route to the N-pyrazole urea BIRB 796 in high purity, as a potent and selective inhibitor of p38alpha mitogen-activated protein kinase for the study of accelerated ageing in Werner syndrome cells.
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