Chirality-matched catalyst-controlled macrocyclization reactions

2021 ◽  
Vol 118 (40) ◽  
pp. e2113122118
Author(s):  
Jaeyeon Hwang ◽  
Brandon Q. Mercado ◽  
Scott J. Miller
Keyword(s):  
Transition State ◽  
Macrocyclic Compounds ◽  
Environmental Sciences ◽  
Remarkable Effect ◽  
Naturally Occurring ◽  
Additional Challenge ◽  
Intermolecular Reactions

Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue to attract great interest due to their important applications in physical, pharmacological, and environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over intermolecular reactions in the ring-closing step is often a key challenge. Furthermore, syntheses of macrocycles with stereogenic elements confer an additional challenge, while access to such macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts can have in promoting efficient macrocyclization reactions. We show that the chirality of the catalyst is essential for promoting favorable, matched transition-state relationships that favor macrocyclization of substrates with preexisting stereogenic elements; curiously, the chirality of the catalyst is essential for successful reactions, even though no new static (i.e., not “dynamic”) stereogenic elements are created. Control experiments involving either achiral variants of the catalyst or the enantiomeric form of the catalyst fail to deliver the macrocycles in significant quantity in head-to-head comparisons. The generality of the phenomenon, demonstrated here with a number of substrates, stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles, presumably through related, catalyst-defined peripheral interactions with their acyclic substrates.

scholarly journals Chirality-Matched Catalyst-Controlled Macrocyclization Reactions

2021 ◽  
Author(s):  
Jaeyeon Hwang ◽  
Brandon Q. Mercado ◽  
Scott Miller
Keyword(s):  
Transition State ◽  
Outer Sphere ◽  
Macrocyclic Compounds ◽  
Environmental Sciences ◽  
Remarkable Effect ◽  
Naturally Occurring ◽  
Additional Challenge ◽  
Intermolecular Reactions

<p>Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue</p><p>to attract great interest due to their important applications in physical, pharmacological and</p><p>environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over</p><p>intermolecular reactions in the ring-closing step, is often a key challenge. Furthermore, syntheses</p><p>of macrocycles with stereogenic elements confer an additional challenge, while access to such</p><p>macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts</p><p>can have in promoting efficient macrocyclization reactions. We show that the chirality of the</p><p>catalyst is essential for promoting favorable, matched transition state relationships that favor</p><p>macrocyclization of substrates with pre-existing stereogenic elements; curiously, the chirality of</p><p>the catalyst is essential for successful reactions, even though no new stereogenic elements are</p><p>created. Control experiments involving either achiral variants of the catalyst, or the enantiomeric</p><p>form of the catalyst, fail to deliver the macrocycles in significant quantity in head-to-head</p><p>comparisons. The generality of the phenomenon, demonstrated here with a number of substrates,</p><p>stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles,</p><p>presumably through related, catalyst-defined outer-sphere interactions with their acyclic substrates.</p>

scholarly journals Chirality-Matched Catalyst-Controlled Macrocyclization Reactions

2021 ◽  
Author(s):  
Jaeyeon Hwang ◽  
Brandon Q. Mercado ◽  
Scott Miller
Keyword(s):  
Transition State ◽  
Outer Sphere ◽  
Macrocyclic Compounds ◽  
Environmental Sciences ◽  
Remarkable Effect ◽  
Naturally Occurring ◽  
Additional Challenge ◽  
Intermolecular Reactions

<p>Macrocycles, formally defined as compounds that contain a ring with 12 or more atoms, continue</p><p>to attract great interest due to their important applications in physical, pharmacological and</p><p>environmental sciences. In syntheses of macrocyclic compounds, promoting intramolecular over</p><p>intermolecular reactions in the ring-closing step, is often a key challenge. Furthermore, syntheses</p><p>of macrocycles with stereogenic elements confer an additional challenge, while access to such</p><p>macrocycles are of great interest. Herein, we report the remarkable effect peptide-based catalysts</p><p>can have in promoting efficient macrocyclization reactions. We show that the chirality of the</p><p>catalyst is essential for promoting favorable, matched transition state relationships that favor</p><p>macrocyclization of substrates with pre-existing stereogenic elements; curiously, the chirality of</p><p>the catalyst is essential for successful reactions, even though no new stereogenic elements are</p><p>created. Control experiments involving either achiral variants of the catalyst, or the enantiomeric</p><p>form of the catalyst, fail to deliver the macrocycles in significant quantity in head-to-head</p><p>comparisons. The generality of the phenomenon, demonstrated here with a number of substrates,</p><p>stimulates analogies to enzymatic catalysts that produce naturally occurring macrocycles,</p><p>presumably through related, catalyst-defined outer-sphere interactions with their acyclic substrates.</p>

scholarly journals Even with nonnative interactions, the updated folding transition states of the homologs Proteins G & L are extensive and similar

2015 ◽  
Vol 112 (27) ◽  
pp. 8302-8307 ◽  
Author(s):  
Michael C. Baxa ◽  
Wookyung Yu ◽  
Aashish N. Adhikari ◽  
Liang Ge ◽  
Zhen Xia ◽  
...  
Keyword(s):  
Transition State ◽  
Triple Mutant ◽  
Homologous Proteins ◽  
Naturally Occurring ◽  
Folding Algorithm ◽  
Helical Content ◽  
State Ensemble ◽  
Transition Paths ◽  
Folding Simulations ◽  
Transition State Ensemble

Experimental and computational folding studies of Proteins L & G and NuG2 typically find that sequence differences determine which of the two hairpins is formed in the transition state ensemble (TSE). However, our recent work on Protein L finds that its TSE contains both hairpins, compelling a reassessment of the influence of sequence on the folding behavior of the other two homologs. We characterize the TSEs for Protein G and NuG2b, a triple mutant of NuG2, using ψ analysis, a method for identifying contacts in the TSE. All three homologs are found to share a common and near-native TSE topology with interactions between all four strands. However, the helical content varies in the TSE, being largely absent in Proteins G & L but partially present in NuG2b. The variability likely arises from competing propensities for the formation of nonnative β turns in the naturally occurring proteins, as observed in our TerItFix folding algorithm. All-atom folding simulations of NuG2b recapitulate the observed TSEs with four strands for 5 of 27 transition paths [Lindorff-Larsen K, Piana S, Dror RO, Shaw DE (2011) Science 334(6055):517–520]. Our data support the view that homologous proteins have similar folding mechanisms, even when nonnative interactions are present in the transition state. These findings emphasize the ongoing challenge of accurately characterizing and predicting TSEs, even for relatively simple proteins.

Pathology of Bone Cells in Pigs with Experimental Turbinate Osteoporosis (Atrophic Rhinitis)

1971 ◽  
Vol 29 ◽  
pp. 304-305
Author(s):  
A. W. Fetter ◽  
C. C. Capen
Keyword(s):  
Mucous Membrane ◽  
Bone Cells ◽  
Atrophic Rhinitis ◽  
Infectious Agents ◽  
Metabolic Disturbances ◽  
Progressive Reduction ◽  
Naturally Occurring ◽  
Fundamental Cause ◽  
Osteocytic Osteolysis ◽  
Uncertain Etiology

Atrophic rhinitis in swine is a disease of uncertain etiology in which infectious agents, hereditary predisposition, and metabolic disturbances have been reported to be of primary etiologic importance. It shares many similarities, both clinically and pathologically, with ozena in man. The disease is characterized by deformity and reduction in volume of the nasal turbinates. The fundamental cause for the localized lesion of bone in the nasal turbinates has not been established. Reduced osteogenesis, increased resorption related to inflammation of the nasal mucous membrane, and excessive resorption due to osteocytic osteolysis stimulated by hyperparathyroidism have been suggested as possible pathogenetic mechanisms.The objectives of this investigation were to evaluate ultrastructurally bone cells in the nasal turbinates of pigs with experimentally induced atrophic rhinitis, and to compare these findings to those in control pigs of the same age and pigs with the naturally occurring disease, in order to define the fundamental lesion responsible for the progressive reduction in volume of the osseous core.

High Resolution Replication of Organoclay Surfaces

1982 ◽  
Vol 40 ◽  
pp. 576-577
Author(s):  
W. W. Barker ◽  
W. E. Rigsby ◽  
V. J. Hurst ◽  
W. J. Humphreys
Keyword(s):  
Clay Mineral ◽  
Organic Molecule ◽  
Organic Molecules ◽  
X Ray Diffraction ◽  
Xrd Pattern ◽  
X Ray ◽  
Naturally Occurring ◽  
Silicate Layers ◽  
Mineral Identification

Experimental clay mineral-organic molecule complexes long have been known and some of them have been extensively studied by X-ray diffraction methods. The organic molecules are adsorbed onto the surfaces of the clay minerals, or intercalated between the silicate layers. Natural organo-clays also are widely recognized but generally have not been well characterized. Widely used techniques for clay mineral identification involve treatment of the sample with H2 O2 or other oxidant to destroy any associated organics. This generally simplifies and intensifies the XRD pattern of the clay residue, but helps little with the characterization of the original organoclay. Adequate techniques for the direct observation of synthetic and naturally occurring organoclays are yet to be developed.

SEM study of the morphological effects of kinetin and zeatin on the growth and development of the apical meristem in wheat

1995 ◽  
Vol 53 ◽  
pp. 978-979
Author(s):  
G. M. Hutchins ◽  
J. S. Gardner
Keyword(s):  
Growth And Development ◽  
Furfuryl Alcohol ◽  
Apical Meristem ◽  
Plant Cells ◽  
Triticum Aestivum L ◽  
Morphological Development ◽  
Naturally Occurring ◽  
Chinese Spring Wheat ◽  
Sem Study ◽  
Moist Environment

Cytokinins are plant hormones that play a large and incompletely understood role in the life-cycle of plants. The goal of this study was to determine what roles cytokinins play in the morphological development of wheat. To achieve any real success in altering the development and growth of wheat, the cytokinins must be applied directly to the apical meristem, or spike of the plant. It is in this region that the plant cells are actively undergoing mitosis. Kinetin and Zeatin were the two cytokinins chosen for this experiment. Kinetin is an artificial hormone that was originally extracted from old or heated DNA. Kinetin is easily made from the reaction of adenine and furfuryl alcohol. Zeatin is a naturally occurring hormone found in corn, wheat, and many other plants.Chinese Spring Wheat (Triticum aestivum L.) was used for this experiment. Prior to planting, the seeds were germinated in a moist environment for 72 hours.

Fine structure and properties of defects in naturally occurring silicates and oxides

1990 ◽  
Vol 48 (4) ◽  
pp. 460-461
Author(s):  
David R. Veblen
Keyword(s):  
Chemical Reactions ◽  
High Resolution Electron Microscopy ◽  
Extended Defects ◽  
Single Chain ◽  
Naturally Occurring ◽  
Resolution Electron ◽  
Fine Structures ◽  
Image Simulations ◽  
Similar Crystal Structure

Extended defects and interfaces control many processes in rock-forming minerals, from chemical reactions to rock deformation. In many cases, it is not the average structure of a defect or interface that is most important, but rather the structure of defect terminations or offsets in an interface. One of the major thrusts of high-resolution electron microscopy in the earth sciences has been to identify the role of defect fine structures in reactions and to determine the structures of such features. This paper will review studies using HREM and image simulations to determine the structures of defects in silicate and oxide minerals and present several examples of the role of defects in mineral chemical reactions. In some cases, the geological occurrence can be used to constrain the diffusional properties of defects.The simplest reactions in minerals involve exsolution (precipitation) of one mineral from another with a similar crystal structure, and pyroxenes (single-chain silicates) provide a good example. Although conventional TEM studies have led to a basic understanding of this sort of phase separation in pyroxenes via spinodal decomposition or nucleation and growth, HREM has provided a much more detailed appreciation of the processes involved.

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

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