Carbenoid insertion into the peroxide bond vs the olefin bond of cyclic peroxides

Herein we report examples of the insertion of a carbenoid into a peroxide linkage. This study reveals that intramolecular insertion of carbenes into the peroxide linkage of 3,6-dihydro-1,2-dioxines is preferred over olefin insertion. The initial scope of the reaction and mechanistic considerations, have been probed. This methodology also generates unusual bicyclic hemiacetals (2) and tricyclic peroxides (3).Ondrej Zvarec, Thomas D. Avery and Dennis K. Taylo

Cyclisation of 1,2-dioxines containing tethered hydroxyl and carboxylic acid functionality: synthesis of tetrahydrofurans and dihydrofuran-2(3H)-ones

Herein we outline cyclisations of tethered hydroxyl and carboxylic acid moieties onto the olefinic motif of 1,2-dioxines to generate tetrahydrofurans and dihydrofuran-2(3H)-ones, whilst maintaining the peroxide linkage intact. This work demonstrates the first examples of intramolecular cyclisation of tethered hydroxyl groupings onto 1,2-dioxines generating functionalised THFs in a highly stereoselective manner and includes improved methods for previously reported carboxylic acid tether cyclisations. Additionally, improved methods for the oxidation of 1,2-dioxines containing tethered alcohols to furnish tethered carboxylic acids are also detailed. Subsequent reduction of the peroxide linkage enables the generation of functionalised tetrahydrofurans and dihydrofuran-2(3H)-ones, which are useful building blocks for the construction of natural products. © 2009 Elsevier Ltd. All rights reserved.Ondrej Zvarec, Thomas D. Avery, Dennis K. Taylor and Edward R.T. Tiekin

Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors

Peptide-derived protease inhibitors are an important class of compounds with the potential to treat a wide range of diseases. Herein, we describe the synthesis of a series of triazole- containing macrocyclic protease inhibitors pre-organized into a b-strand conformation and an evaluation of their activity against a panel of proteases. Acyclic azidoalkyne-based aldehydes are also evaluated for comparison. The macrocyclic peptidomimetics showed considerable activity towards calpain II, cathepsin L and S, and the 20S proteasome chymotrypsin-like activity. Some of the first examples of highly potent macrocyclic inhibitors of cathepsin S were identified. These adopt a well-defined b-strand geometry as shown by NMR spectroscopy, X-ray analysis, and molecular docking studies. © 2013 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim.Associated Grant:Australian Research Counci

Electron transfer through alpha-peptides attached to vertically aligned carbon nanotube arrays: a mechanistic transition

This article is part of the Artificial photosynthesis web themed issueThe mechanism of electron transfer in α-aminoisobutyric (Aib) homoligomers is defined by the extent of secondary structure, rather than just chain length. Helical structures (Aib units ≥3) undergo an electron hopping mechanism, while shorter disordered sequences (Aib units <3) undergo an electron superexchange mechanism.Jingxian Yu, Ondrej Zvarec, David M. Huang, Mark A. Bissett, Denis B. Scanlon, Joe G. Shapter and Andrew D. Abel

5-Benzylidenerhodanine and 5-benzylidene-2-4-thiazolidinedione based antibacterials

Herein we outline the antibacterial activity of amino acid containing thiazolidinediones and rhodanines against Gram-positive bacteria Staphylococcus aureus ATCC 31890, Staphylococcus epidermidis and Bacillus subtilis ATCC 6633. The rhodanine derivatives were generally more active than the analogous thiazolidinediones. Compounds of series 5 showed some selectivity for Bacillus subtilis ATCC 6633, the extent of which is enhanced by the inclusion of a non-polar amino acid at the 5-position of the core thiazolidinediones and rhodanines scaffolds. SAR data of series 8 demonstrated improved activity against the clinically more significant Staphylococci with selectivity over Bacillus subtilis ATCC 6633 induced by introduction of a bulky aryl substituent at the 5-position of the core scaffolds.Ondrej Zvarec, Steven W. Polyak, William Tieu, Kevin Kuan, Huanqin Dai, Daniel Sejer Pedersen, Renato Morona, Lixin Zhang, Grant W. Booker, Andrew D. Abel

Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors

Peptide-derived protease inhibitors are an important class of compounds with the potential to treat a wide range of diseases. Herein, we describe the synthesis of a series of triazole-containing macrocyclic protease inhibitors pre-organized into a β-strand conformation and an evaluation of their activity against a panel of proteases. Acyclic azido-alkyne-based aldehydes are also evaluated for comparison. The macrocyclic peptidomimetics showed considerable activity towards calpain II, cathepsin L and S, and the 20S proteasome chymotrypsin-like activity. Some of the first examples of highly potent macrocyclic inhibitors of cathepsin S were identified. These adopt a well-defined β-strand geometry as shown by NMR spectroscopy, X-ray analysis, and molecular docking studies.Ashok D. Pehere, Markus Pietsch, Michael Gütschow, Paul M. Neilsen, Daniel Sejer Pedersen, Steven Nguyen, Ondrej Zvarec, Matthew J. Sykes, David F. Callen, and Andrew D. Abel

Biotin analogues with antibacterial activity are potent inhibitors of biotin protein ligase

There is a desperate need to develop new antibiotic agents to combat the rise of drug-resistant bacteria, such as clinically important Staphylococcus aureus. The essential multifunctional enzyme, biotin protein ligase (BPL), is one potential drug target for new antibiotics. We report the synthesis and characterization of a series of biotin analogues with activity against BPLs from S. aureus, Escherichia coli, and Homo sapiens. Two potent inhibitors with K i 20-fold selectivity between the isozymes were identified and characterized. The antibacterial mode of action was shown to be via inhibition of BPL. The bimolecular interactions between the BPL and the inhibitors were defined by surface plasmon resonance studies and X-ray crystallography. These findings pave the way for second-generation inhibitors and antibiotics with greater potency and selectivity.Tatiana P. Soares da Costa, William Tieu, Min Y. Yap, Ondrej Zvarec, Jan M. Bell, John D. Turnidge, John C. Wallace, Grant W. Booker, Matthew C. J. Wilce, Andrew D. Abell, and Steven W. Polya

Synthesis and extended activity of triazole-containing macrocyclic protease inhibitors

Peptide-derived protease inhibitors are an important class of compounds with the potential to treat a wide range of diseases. Herein, we describe the synthesis of a series of triazole- containing macrocyclic protease inhibitors pre-organized into a b-strand conformation and an evaluation of their activity against a panel of proteases. Acyclic azidoalkyne-based aldehydes are also evaluated for comparison. The macrocyclic peptidomimetics showed considerable activity towards calpain II, cathepsin L and S, and the 20S proteasome chymotrypsin-like activity. Some of the first examples of highly potent macrocyclic inhibitors of cathepsin S were identified. These adopt a well-defined b-strand geometry as shown by NMR spectroscopy, X-ray analysis, and molecular docking studies. © 2013 Wiley-VCH Verlag GmbH and Co. KGaA, Weinheim