Rapid, regioselective living ring-opening metathesis polymerization of bio-derivable asymmetric tricyclic oxanorbornenes

The synthesis of a range of alkyl esters (methyl, n-butyl, and n-decyl) prepared via Steglich esterification of the thermodynamically controlled exo, exo Diels���Alder adduct of furfuryl alcohol and maleic anhydride is reported. Subsequent ring-opening metathesis polymerization of these bio-derivable tricyclic oxanorbornene analogs delivers polymers with targeted molar mass and low molar mass dispersity. The polymerizations are rapid with complete monomer conversion achieved within 15 min. Significantly, the presence of the cyclic lactone at the bridgehead of these monomers leads to polymers with high regioregularity (>85% head-to-tail) and high stereoregularity (>75% trans). The resultant polymers display both high thermal stability and high glass transition temperatures. This new class of oxanorbornene monomer, accessed from bio-derivable furfuryl alcohol and maleic anhydride, may be further tailored to incorporate a range of functional moieties. Furthermore, the exceptional properties of the derived polymers indicate potential in a range of applications

Rapid Ring-Opening Metathesis Polymerization of Monomers Obtained from Biomass-Derived Furfuryl Amines and Maleic Anhydride

Well-controlled and extremely rapid ring-opening metathesis polymerization of unusual oxanorbornene lactam esters by Grubbs third-generation catalyst is used to prepare a range of bio-based homo- and copolymers. Bio-derived oxanorbornene lactam monomers were prepared at room temperature from maleic anhydride and secondary furfuryl amines by using a 100 % atom economical, tandem Diels–Alder lactamization reaction, followed by esterification. Several of the resulting homo- and copolymers show good control over polymer molecular weight and have narrow molecular weight distributions

Grand Challenges in global eye health: a global prioritisation process using Delphi method

Background We undertook a Grand Challenges in Global Eye Health prioritisation exercise to identify the key issues that must be addressed to improve eye health in the context of an ageing population, to eliminate persistent inequities in health-care access, and to mitigate widespread resource limitations. Methods Drawing on methods used in previous Grand Challenges studies, we used a multi-step recruitment strategy to assemble a diverse panel of individuals from a range of disciplines relevant to global eye health from all regions globally to participate in a three-round, online, Delphi-like, prioritisation process to nominate and rank challenges in global eye health. Through this process, we developed both global and regional priority lists. Findings Between Sept 1 and Dec 12, 2019, 470 individuals complete round 1 of the process, of whom 336 completed all three rounds (round 2 between Feb 26 and March 18, 2020, and round 3 between April 2 and April 25, 2020) 156 (46%) of 336 were women, 180 (54%) were men. The proportion of participants who worked in each region ranged from 104 (31%) in sub-Saharan Africa to 21 (6%) in central Europe, eastern Europe, and in central Asia. Of 85 unique challenges identified after round 1, 16 challenges were prioritised at the global level; six focused on detection and treatment of conditions (cataract, refractive error, glaucoma, diabetic retinopathy, services for children and screening for early detection), two focused on addressing shortages in human resource capacity, five on other health service and policy factors (including strengthening policies, integration, health information systems, and budget allocation), and three on improving access to care and promoting equity. Interpretation This list of Grand Challenges serves as a starting point for immediate action by funders to guide investment in research and innovation in eye health. It challenges researchers, clinicians, and policy makers to build collaborations to address specific challenge

New peptide-based templates constrained into a β-strand by Huisgen cycloaddition.

Chapter One introduces the concept of peptide 'secondary structure' with an emphasis on β-strand geometry in macrocycles. This structural design is crucial for targeting different proteases. The significance of the macrocylic β-strand ‘bioactive’ conformation is discussed in detail. In particular the exploitation of the conformationally constrained peptidomimetic macrocylic backbone, which is constrained by a number of synthetic approaches to lock the ‘bioactive’ conformation in place. Chapter Two describes simple and scalable methodology for the preparation of N-Cbz protected amino acids by reaction with Cbz-Cl which uses a mixture of aqueous sodium carbonate and sodium bicarbonate to maintain the appropriate pH. This method proceeds without the formation of by-products. The method is extended to large scale preparation of an intermediate zofenopril, an ACE inhibitor. Chapter Three describes new peptidic templates constrained into a β-strand geometry by linking acetylene and azide containing P₁ and P₃ residues of a tripeptide by Huisgen cycloaddition. The conformations of the macrocycles are defined by NMR studies and those that best define a β-strand are shown to be potent inhibitors of the protease calpain. The β-strand templates presented and defined here are prepared under optimized conditions and should be suitable for targeting a range of proteases and other applications requiring such geometry. Chapter four describes a new approach to non-covalent peptide-based nanotubular or rodlike structures, whereby the monomeric units are preorganised into a β-strand geometry that templates the formation of an extended and unusual parallel β-sheet rod-like structure. The conformational constraint is introduced by Huisgen cycloaddition to give a triazolebased macrocycle, with the resulting self-assembled structures stabilized by a well-defined series of intermolecular hydrogen bonds. Chapter Five the 26S proteasome has emerged over the past decade as an attractive therapeutic target in the treatment of cancers. Here, we report new tripeptide aldehydes that are highly specific for the chymotrypsin-like catalytic activity of the proteasome. These new CT-L specific proteasome inhibitors demonstrated high potency and specificity for cancer cells, with therapeutic windows superior to those observed for benchmark proteasome inhibitors, MG132 and Bortezomib. Constraining the peptide backbone into the β-strand geometry was associated with decreased activity in vitro and reduced anticancer activity, suggesting that the proteasome prefers to bind a conformationally flexible ligand. Using these new proteasome inhibitors, we show that the presence of an intact p53 pathway significantly enhances cytotoxic activity, thus suggesting that this tumor suppressor is a critical downstream mediator of cell death following proteasomal inhibition. Chapter Six peptide derived protease inhibitors represent an important class of compounds with the potential to treat a wide range of serious medical conditions. Herein we describe the synthesis of a series of triazole containing macrocylic protease inhibitors preorganised in a β-strand conformation and evaluate their selectivity and potency against a panel of protease inhibitors. A series of acyclic azido-alkyne-based aldehydes is also evaluated for comparison. The macrocyclic peptidomimetics showed considerable activity towards Calpain II, Cathepsin L and S and the 26S proteasome chymotrypsin-like activity. Importantly, the first examples of potent and selective inhibitors of Cathepsin S were identified and shown to adopt a well-defined β-strand geometry by NMR, X-ray and molecular docking studies. Chapter Seven describes simple and efficient methodology for the selective acylation and alkylation of biotin at its 3′-nitrogen. This methodology is used to prepare of other biotin derivatives.Thesis (Ph.D.) -- University of Adelaide, School of Chemistry and Physics, 201

An improved large scale procedure for the preparation of N-Cbz amino acids

A simple and scalable method for the preparation of N-Cbz protected amino acids is presented which uses a mixture of aqueous sodium carbonate and sodium bicarbonate to maintain the appropriate pH during the addition of benzyl chloroformate. The method has been extended to other N-protections and is amenable to large scale preparation of an intermediate toward Zofenopril, an ACE inhibitor. © 2011 Elsevier Ltd. All rights reserved.Ashok D. Pehere and Andrew D. Abellhttp://www.elsevier.com/wps/find/homepage.cws_hom

Selective N-acylation and N-alkylation of biotin

Simple and efficient methodology is presented for the selective acylation and alkylation of biotin at its 3'-nitrogen.Ashok D. Pehere and Andrew D. Abel

Cerebral visual impairment in children: Causes and associated ophthalmological problems

Purpose: The aim of this study is to identify common causes, associated ophthalmological abnormalities, and systemic comorbidities in children in Andhra Pradesh, India, with cerebral visual impairment (CVI). Methods: A retrospective review of case records of all children aged <16 years with diagnosis of CVI seen between January 2016 and December 2016 was carried out. Data were collected for their age, gender, cause of CVI, refraction, accommodation, anterior and posterior segment examination findings, and systemic problems. Results: A total of 124 patients were identified and studied (80 boys and 44 girls, mean age 5.23 years, 44.8% aged <2 years). The most common causes of CVI were hypoxic–ischemic encephalopathy (HIE) (34.4%), undetermined etiology (32.8%), neonatal seizures, and infantile spasms (16% each). The most common presenting complaints were poor vision (76%) and squint (11.2%). Profound visual impairment was seen in 88.8%, and 11.2% had high functioning CVI. Fifty-eight (46.4%) patients had significant refractive errors, 40 (32.25%) had strabismus, 4 (3.2%) had visually significant cataract, and 40 (32%) had optic atrophy. Motor delay was observed in 39.5%, speech delay was evident in 22.4%, and cognitive delay in 16%. Conclusion: HIE is the most common cause (one-third) of CVI in our population, and the majority of them presented at age <2 years (44.8%) with profound visual impairment (88.8%). A significant number of them have treatable ophthalmic conditions such as refractive errors (46.4%), accommodative insufficiency (12.1%), and cataract (3.2%), and more than one-third of them also have delay in other areas of development

New cylindrical peptide assemblies defined by extended parallel beta-sheets

Received 17 Aug 2012, Accepted 25 Sep 2012, First published on the web 26 Sep 2012 (from RCS website)A new approach to non-covalent peptide-based nanotubular or rod-like structures is presented, whereby the monomeric units are preorganised into a β-strand geometry that templates the formation of an extended and unusual parallel β-sheet rod-like structure. The conformational constraint is introduced by Huisgen cycloaddition to give a triazole-based macrocycle, with the resulting self-assembled structures stabilized by a well-defined series of intermolecular hydrogen bonds.Ashok D. Pehere, Christopher J. Sumby and Andrew D. Abel

Macrocyclic peptidomimetics prepared by ring-closing metathesis and azide-alkyne cycloaddition

Macrocycles are finding increasing use as a means to define the backbone geometries of peptides and peptidomimetics. Ring-closing metathesis and CuI-catalyzed azide–alkyne cycloaddition are particularly useful for introducing such rings and they do so in high yield and with a good functional group tolerance and compatibility. Here, we present an overview of the use of these two methods, with reference to selected examples and particular reference to b-strand peptidomimetics for use as protease inhibitors.Ashok D. Pehere, Xiaozhou Zhang, and Andrew D. Abel