Alkyne-Bridged α-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models

Authors

Alessia Belgi, James V. Burnley, Christopher A. MacRaild, Sandeep Chhabra, Khaled A. Elnahriry, Samuel D. Robinson, Simon G. Gooding, Han-Shen Tae, Peter Bartels, Mahsa Sadeghi, Fei-Yue Zhao, Haifeng Wei, David Spanswick, David J. Adams, Ray S. Norton, Andrea. J. Robinson

Published Journal of Medicinal Chemistry
Graphical abstract  
Abstract

Several Conus-derived venom peptides are promising lead compounds for the management of neuropathic pain, with α-conotoxins being of particular interest. Modification of the interlocked disulfide framework of α-conotoxin Vc1.1 has been achieved using on-resin alkyne metathesis. Although introduction of a metabolically stable alkyne motif significantly disrupts backbone topography, the structural modification generates a potent and selective GABAB receptor agonist that inhibits Cav2.2 channels and exhibits dose-dependent reversal of mechanical allodynia in a behavioral rat model of neuropathic pain. The findings herein support the hypothesis that analgesia can be achieved via activation of GABABRs expressed in dorsal root ganglion (DRG) sensory neurons.

Citation

A. Belgi, J. V. Burnley, C. A. MacRaild, S. Chhabra, K. A. Elnahriry, S. D. Robinson, S. G. Gooding, H. S. Tae, P. Bartels, M. Sadeghi, F. Y. Zhao, H. Wei, D. Spanswick, D. J. Adams, R. S. Norton, A. J. Robinson, “Alkyne-Bridged α-Conotoxin Vc1.1 Potently Reverses Mechanical Allodynia in Neuropathic Pain Models”, J. Med. Chem., 2021, 64(6), 3233-3233.

Pdf  
Doi

https://doi.org/10.1021/acs.jmedchem.0c02151

Subjects

Hydrocarbons, Peptides and proteins, Organic polymers, Catalysts, Conformation

Posted in Conotoxins, Publications 2021 | Leave a comment

[18 F]Ethenesulfonyl Fluoride as a Practical Radiofluoride Relay Reagent

Authors

Bo Zhang, Benjamin H. Fraser, Mitchell A. Klenner, Zhen Chen, Steven H. Liang, Massimiliano Massi, Andrea J. Robinson, Giancarlo Pascali

Published Chemistry – A European Journal
Graphical abstract
Abstract

Fluorine-18 is the most utilized radioisotope in positron emission tomography (PET), but the wide application of fluorine-18 radiopharmaceuticals is hindered by its challenging labelling conditions. As such, many potentially important radiotracers remain underutilized. Herein, we describe the use of [18F]ethenesulfonyl fluoride (ESF) as a novel radiofluoride relay reagent that allows radiofluorination reactions to be performed in minimally equipped satellite nuclear medicine centres. [18F]ESF has a simple and reliable production route and can be stored on inert cartridges. The cartridges can then be shipped remotely and the trapped [18F]ESF can be liberated by simple solvent elution. We have tested 18 radiolabelling precursors, inclusive of model and clinically used structures, and most precursors have demonstrated comparable radiofluorination efficiencies to those obtained using a conventionally dried [18F]fluoride source.

Citation

B. Zhang, B. H. Fraser, M. A. Klenner, Z. Chen, S. H. Liang, M Massi, A. J. Robinson, G. Pascali, “[ 18 F]Ethenesulfonyl Fluoride as a Practical Radiofluoride Relay Reagent”, Chemistry – A European Journal, 2019, 25(32), 7613-7617

Pdf  
Doi

https://doi.org/10.1002/chem.201900930

Keywords

fluorine, medicinal chemistry, positron emission tomography, radiopharmaceuticals, sulfonyl fluoride

Posted in Publications 2019 | Leave a comment

Bioinspired carrier-free peptide conjugated BF2-oxasmaragdyrin dye-based nano self-assemblies: a photostable NIR cancer theragnostic agent

Authors

Kandala Laxman, B. Pradeep K. Reddy, Sumit K. Mishra, Andrea Robinson, Abhijit De, Rohit Srivastava, Mangalampalli Ravikanth

Published NPG Asia Materials
Graphical abstract  
Abstract

Photothermal therapy (PTT) has attracted great interest in cancer treatment, and the quest for potential organic photothermal agents is underway owing to the nonbiodegradable nature and chronic toxicity of existing inorganic nanomaterials. Organic material-based nanoformulations with good photothermal and fluorescence properties in the near-infrared (NIR-I) window are scarce. However, porphyrins are one category of biocompatible systems that are advantageous for photothermal therapy but are currently based in the visible region, causing limited depth of tissue penetration and leading to compromised photothermal and near-infrared fluorescence (NIRF) imaging applications. To overcome these limitations, we report the synthesis of L,L-diphenylalanine conjugated BF2-oxasmaragdyrin (FF-BSC) and the fabrication of monodispersed spherical self-assemblies (FF-BSC NPs) using a USP class 3 solvent-water mixture. The resulting product exhibited excellent photostability (NIR exposure), multicycle photothermal efficacy, and NIR fluorescence. In vitro studies revealed good biocompatibility, efficient cellular internalization, and photothermal efficacy. Preclinical studies of these nano-self-assemblies demonstrated nontoxicity, efficient whole-body NIRF imaging, fractional passive tumor homing, and excellent photothermal tumor ablation potential. The absorbance and fluorescence of FF-BSC NPs in NIR-I make them suitable for theragnostic applications over existing porphyrins/ inorganic nanomaterials for future clinical applications.

Citation

K. Laxman, B. P. K. Reddy, S. K. Mishra, A. Robinson, A. De, R. Srivastava, M. Ravikanth, “Bioinspired carrier-free peptide conjugated BF2-oxasmaragdyrin dye-based nano self-assemblies: a photostable NIR cancer theragnostic agent”, NPG Asia Materials, 2020, 12(1).

Pdf  
Doi

https://doi.org/10.1038/s41427-020-00256-x

Subjects

Biomedical materials, Nanoparticles

Posted in Publications 2020 | Leave a comment

Design, Development, In Vitro and Preliminary In Vivo Evaluation of a Novel Photo-Angioplasty Device: Lumi-Solve

Authors

HongBin Liu, Gopal R. Sama, Andrea Robinson, Simon Mountford, Philip E. Thompson, Andrew Rodda, John Forsythe, Patrick J. Mornane, Paul Pasic, Helmut Thissen, Melissa Byrne, David M. Kaye & Anthony E. Dear 

Published Cardiovascular Engineering and Technology
Graphical abstract  
Abstract

Purpose

Paclitaxel (PTX)-coated drug eluting balloon catheters (DEBc) used in the management of neointimal hyperplasia (NIH) have been associated with safety concerns. Alternative coating agents and targeted delivery systems may improve safety and DEBc efficacy. Utilizing a multi-platform approach we designed, developed and evaluated Lumi-Solve, a novel DEBc, coated with ultraviolet (UV) 365 nm-activated caged metacept-3 (c-MCT-3), an epigenetic agent from the histone deacetylase inhibitor (HDACi) class.

Methods

In vitro catheter and contrast media transmission of UV365nm was evaluated spectroscopically. UV365nm conversion of c-MCT-3 to MCT-3 was evaluated chromatographically. Cellular toxicity and HDACi activity of c-MCT-3 ∓UV365nm was evaluated in vitro. In vivo UV365nm conversion of c-MCT-3 to MCT-3 was evaluated in an ovine carotid artery model.

Results

Catheter material and dilute contrast media did not attenuate UV365nm transmission or c-MCT-3 activation. c-MCT-3 demonstrated less cellular toxicity than MCT-3 and PTX. UV365nm-activated c-MCT-3 demonstrated HDACi activity. In vivo activation of c-MCT-3 produced MCT-3.

Conclusions

Lumi-Solve, a novel DEBc device developed utilizing a combination of chemical, fibre-optic and catheter based technology platforms, demonstrated potential for targeted delivery of bioactive HDACi to the blood vessel wall supporting direct application to the management of NIH and warranting additional in vivo studies.

Citation

Liu, H., Sama, G.R., Robinson, A. et al. Design, Development, In Vitro and Preliminary In Vivo Evaluation of a Novel Photo-Angioplasty Device: LumiSolve. Cardiovasc Eng Tech(2021). 

Pdf  
Doi

https://doi.org/10.1007/s13239-021-00525-y

Keywords

Drug eluting balloon catheter, Photo-angioplasty Neointimal hyperplasia, Epigenetics

Posted in Publications 2021 | Leave a comment

BF2-Oxasmaragdyrin Nanoparticles: A Non-toxic, Photostable, Enhanced Non-radiative Decay-Assisted Efficient Photothermal Cancer Theragnostic Agent

Authors

Kandala Laxman, B. Pradeep K. Reddy, Sumit K. Mishra, Maddala Bala Gopal, Andrea Robinson, Abhijit De,  Rohit Srivastava, Mangalampalli Ravikanth

Published ACS Appl. Mater. Interfaces
Graphical abstract Abstract Image
Abstract

Photothermal therapy (PTT), a simple and minimally invasive procedure, is an attractive option for cancer therapy. To date, inorganic agents have been widely employed as photothermal agents; however, organic molecules may provide a solution to rapid metabolic/in vivo clearance. Herein, we prepared lipid (S 75)-stabilized meso-tritolyl-BF2-oxasmaragdyrin nanoparticles (TBSNPs) using thin-film hydration and homogenization. Assessment of the physicochemical properties of the TBSNPs reveals the formation of particles of size <12 nm stabilized within the lipid matrix. The TBSNPs exhibit near infrared fluorescence (NIRF) being accompanied by an increase in non-radiative decay, leading to excellent photothermal properties. In vitro studies demonstrate excellent biocompatibility, hemocompatibility, cellular internalization, and photothermal efficacy (p = 0.0004). Extensive in vivo assessment of TBSNPs also highlights the non-toxic nature of the material and passive tumor homing. The strong NIRF exhibited by the material is exploited for whole-body imaging in the rodent model. The novel material also shows excellent photothermal efficacy (p = 0.0002) in a 4T1 xenograft mice model. The organic nature of the material coupled with its small size and strong NIRF provides an advantage for bio-elimination and potential clinical image-guided therapy over the inorganic counterparts.

Citation

K. Laxman, B. P. K. Reddy, S. K. Mishra, M. B. Gopal, A. Robinson, A. De, R. Srivastava, M. Ravikanth, “BF2-Oxasmaragdyrin Nanoparticles: A Non-toxic, Photostable, Enhanced Non-radiative Decay-Assisted Efficient Photothermal Cancer Theragnostic Agent”, ACS Appl. Mater. Interfaces, 2020, 12(47), 52329– 52342

Pdf  
Doi

https://doi.org/10.1021/acsami.0c13326

Subjects

Fluorescence, Rodent models, Tumors, Materials, Lasers

Posted in Publications 2020 | Leave a comment

Synthesis and Studies of Glucosamine Conjugated BF2 -Oxasmaragdyrin

Authors

Kandala Laxman, B. Pradeep K. Reddy, Andrea Robinson, Rohit Srivastava, Mangalampalli Ravikanth

Published ChemistrySelect
Graphical abstract
Abstract

A value addition to the existing NIR fluorescence imaging agents has been synthesized in the form of glucosamine conjugated BF2-oxasmaragdyrin by treating mesop-carboxyphenyl BF2-oxasmaragdyrin with 6-amine-6-deoxy-1-O-Boc-2-N-Boc-β-D-glucosamine in the presence of HBTU. The glucosamine conjugated BF2-oxasmaragdyrin was thoroughly characterized by HRMS, 1D, and 2D NMR spectroscopy. The photophysical studies revealed that the conjugates are highly stable, absorb in visible- far-red region (400-700 nm) and emits in far-red region (715 nm) with moderate quantum yields. The electrochemical studies showed that the molecules are stable under redox conditions with one reversible reduction and three reversible oxidations. The glucosamine conjugated BF2-oxasmaragdyrin was found to be highly biocompatible with good cellular uptake in L929 and MDA-MB-231 cells.

Citation

K. Laxman, B. P. K. Reddy, A. Robinson, R. Srivastava, M. Ravikanth, “Synthesis and Studies of Glucosamine Conjugated BF 2 -Oxasmaragdyrin”, ChemistrySelect, 2020, 5(3), 938–943

Pdf  
Doi

https://doi.org/10.1002/slct.201903986

Keywords

BF2-Oxasmaragdyrin, Covalent conjugates, Glucosamine, Macrocycles, NIR fluorescence

Posted in Publications 2020 | Leave a comment

Cell-Penetrating Peptide-Conjugated BF 2 -Oxasmaragdyrins as NIRF Imaging and Photothermal Agents”

Authors

Kandala Laxman, B. Pradeep K. Reddy, Andrea Robinson, Rohit Srivastava, Mangalampalli Ravikanth

Published ChemMedChem
Graphical abstract
Abstract

Cell-penetrating peptides (CPPs) are excellent cell internalizing agents for hydrophobic drug/dye moieties. We exploited this property of CPPs for the cell internalization of BF2-oxasmaragdyrin by constructing covalent conjugates of BF2-oxasmaragdyrin with CPPs (CRGDK and polyarginine (R9)) using a solid-phase peptide synthesis (SPPS) methodology. The CPP-conjugated BF2-oxasmaragdyrins were purified by reversed-phase HPLC and characterized by mass spectrometry. The CPP-conjugated BF2-oxasmaragdyrins were found to be photostable, absorb in the visible-NIR region (400–700 nm), emit in the NIR−I region (∼715–720 nm) with moderate quantum yields, and be biocompatible, with excellent cellular imaging potential in breast cancer cells (MDA-MB-231). The R9conjugate, being the first water-soluble BF2-oxasmaragdyrin, also possesses excellent photothermal transduction efficacy with 750 nm laser irradiation and is a potential theranostic agent.

Citation

K. Laxman, B. P. K. Reddy, A. Robinson, R. Srivastava, M. Ravikanth, “Cell-Penetrating Peptide-Conjugated BF 2 -Oxasmaragdyrins as NIRF Imaging and Photothermal Agents”, ChemMedChem, 2020, 15(19), 1783– 1787

Pdf  
Doi

https://doi.org/10.1002/cmdc.202000401

Keywords

BF2-oxasmaragdyrin, macrocycles, NIR fluorescence imaging, peptides, photothermal therapy

Posted in Publications 2020 | Leave a comment

α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia

Authors

Adam C. Kennedy, Alessia Belgi, Benjamin W. Husselbee, David Spanswick, Ray S. Norton, Andrea J. Robinson

Published Toxins
Graphical abstract  
Abstract

Several analgesic α-conotoxins have been isolated from marine cone snails. Structural modification of native peptides has provided potent and selective analogues for two of its known biological targets—nicotinic acetylcholine and γ-aminobutyric acid (GABA) G protein-coupled (GABAB) receptors. Both of these molecular targets are implicated in pain pathways. Despite their small size, an incomplete understanding of the structure-activity relationship of α-conotoxins at each of these targets has hampered the development of therapeutic leads. This review scrutinises the N-terminal domain of the α-conotoxin family of peptides, a region defined by an invariant disulfide bridge, a turn-inducing proline residue and multiple polar sidechain residues, and focusses on structural features that provide analgesia through inhibition of high-voltage-activated Ca2+ channels. Elucidating the bioactive conformation of this region of these peptides may hold the key to discovering potent drugs for the unmet management of debilitating chronic pain associated with a wide range of medical conditions

Citation

A. C. Kennedy, A. Belgi, B. W. Husselbee, D. Spanswick, R. S. Norton, A. J. Robinson, “α-Conotoxin Peptidomimetics: Probing the Minimal Binding Motif for Effective Analgesia”, Toxins, 2020, 12(8), 505

Pdf  
Doi

https://doi.org/10.3390/toxins12080505

Keywords conotoxins; peptides; analgesia; disulfide; dicarba peptides; GABAB; nAChR.

Posted in Conotoxins, Publications 2020 | Leave a comment

Divergent Approach to a Family of Tyrosine-Derived Ru−Alkylidene Olefin Metathesis Catalysts

Authors

Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson

Published Journal of Organic Chemistry
Graphical abstract

divergent

Abstract

A simple and generic approach to access a new family of Ru−alkylidene olefin metathesis catalysts with specialized properties is reported. This strategy utilizes a late stage, utilitarian Hoveyda-type ligand derived from tyrosine, which can be accessed via a multigram-scale synthesis. Further functionalization allows the catalyst properties to be tuned, giving access to modified second-generation Hoveyda−Grubbs-type catalysts. This divergent synthetic approach can be used to access solid-supported catalysts and catalysts that function under solvent-free and aqueous conditions.

Citation

Ellen C. Gleeson, Zhen J. Wang, W. Roy Jackson, and Andrea J. Robinson, J. Org. Chem., 201580(14), 7205–7211

Pdf Article
Doi https://doi.org/10.1021/acs.joc.5b01091
Subjects Ligands, Precursors, Catalysts, Olefin metathesis, Metathesis
Posted in Metathesis, Publications 2015 | Leave a comment

Stereoselective Synthesis and Structural Elucidation of Dicarba Peptides

Authors Ellen C. Gleeson, Zhen J. Wang, Samuel D. Robinson, Sandeep Chhabra, Christopher A. MacRaild, W. Roy Jackson, Raymond S. Norton and Andrea J. Robinson
Published Chemical Communications
Graphical abstract  
Robinson-cover final
Abstract Preformed, orthogonally-protected Z– and E-diaminosuberic acid residues can be used to synthesise target dicarba peptides. Stereochemical assignment of dicarba peptides generated via RCM of linear sequences can be achieved using 13C NMR spectroscopy.
Citation Ellen C. Gleeson, Zhen J. Wang, Samuel D. Robinson, Sandeep Chhabra, Christopher A. MacRaild, W. Roy Jackson, Raymond S. Norton and Andrea J. Robinson, Chem. Commun., 2016(24), 4446-4449
Pdf
Doi https://doi.org/10.1039/C5CC10540D
Related
Posted in Dicarba peptides, Metathesis, Publications 2016 | Leave a comment