Research

Research

The principal aim of a synthetic organic chemist is to create new, efficient ways in which molecules can be built. This ability to construct organic molecules is a vital scientific skill, the outcome of which underpins many other disciplines in academia and industry. In the Snape group, we aim to nurture these skills through the development of new synthetic methods to biologically important molecules and structural building blocks and also apply them to the synthesis of natural products and natural product mimics. We also endeavour to ascertain the biological activity of the compounds we synthesise.

MEDICINAL CHEMISTRY: ANTICANCER, ANTIMICROBIAL AND RELATED

We are currently very interested in the anticancer and antimicrobial properties of a number of the molecules we make. For example, we are currently looking at the effect our compounds have on different glioma and medulloblastoma cell cultures and against microbial membranes. As such, the group is a member of Brain Tumour North West – a strategic alliance designed to consolidate and exploit clinical and research-based brain tumour expertise which currently exists within the North West region.

Click on the BTNW logo to view their website.BTNW brochure (5MB) – download

Some recently published work in these therapeutic areas:

2021

  • A therapeutic update on PARP inhibitors: implications in the treatment of glioma: Samridhi Lal and Timothy J. Snape, Drug Discovery Today202126, 2, 532-541.

2020

  • Synthetic flavonoid derivatives targeting the glycogen phosphorylase inhibitor site: QM/MM-PBSA motivated synthesis of substituted 5,7-dihydroxyflavones, crystallography, in vitro kinetics and ex-vivo cellular experiments reveal novel potent inhibitors: Ben A. Chetter; Efthimios Kyriakis; Daniel Barr; Aikaterini G. Karra; Elisabeth Katsidou; Symeon M. Koulas; Vassiliki T. Skamnaki; Timothy J. Snape; Anna-Maria G. Psarra; Demetres D. Leonidas; Joseph M. Hayes, Bioorganic Chemistry2020, 102, 1040032. 
  • Biophysical studies on the antimicrobial activity of linearized esculentin 2EM: Erum Malik; David A Phoenix; Leslie G Morton, Frederick Harris; Kamal Badiani; Timothy J. Snape; Jaipaul Singh; Sarah Rachel Dennison, BBA – Biomembranes2020, 1862, 2, 183141.

2019

  • Identification of C-β-D-glucopyranosyl azole type inhibitors of glycogen phosphorylase that reduce glycogenolysis in hepatocytes: in silico design, synthesis, in vitro kinetics and ex-vivo studies: Daniel Barr, Eszter Szennyes, Eva Bokor, Ziad H. Al-Oanzi, Colin Moffatt, Sandor Kun, Tibor Docsa, Ádám Sipos, Matthew P. Davies, Rachel T. Mathomes, Timothy J. Snape, Loranne Agius, Laszlo Somsak, Joseph M. Hayes, ACS Chem. Biol., 2019, 14, 7, 1460-1470.
Joe hayes Abstracty
Joe hayes figure

2018

  • Towards Identifying Potent New Hits for Glioblastoma: Chris Sherer, Saurabh Prabhu, David Adams, Joseph Hayes, Farzana Rowther, Ibrahim Tolaymat, Tracy Warr and Timothy J. Snape*, MedChemComm, 2018, 9, 1850-1861.

2017

  • Preliminary SAR on indole-3-carbinol and related fragments reveals a novel anticancer lead compound against resistant glioblastoma cells: Christopher Sherer, Ibrahim Tolaymat, Farzana Rowther, Tracy Warr, Timothy J. Snape*, Bioorg. Med. Chem. Lett., 2017, 27, 7, 1561-1565.

2016

  • Functional foldamers that target bacterial membranes: the effect of charge, amphiphilicity and conformation: Yogita Patil-Sen, Sarah R. Dennison and Timothy J. Snape*, Bioorg. Med. Chem., 201624, 4241-4245.

2015

  • Functionalising the azobenzene motif delivers a light-responsive membrane-interactive compound with the potential for photodynamic therapy applications: Theodore J. Hester, Sarah R. Dennison, Matthew J. Baker and Timothy J. Snape,* Org. Biomol. Chem., 201513, 8067-8070.
  • Heterocyclic scaffolds as promising anticancer agents against tumours of the central nervous system: exploring the scope of indole and carbazole derivatives: Chris Sherer and Timothy J. Snape,* Eur. J. Med. Chem., 2015, 97, 552-560.
  • Approaches Towards Improving the Prognosis of Paediatric Glioma Patients: Pursuing Mutant Drug Targets with Emerging Small Molecules: Timothy J. Snape* and Tracy Warr, Seminars in Pediatric Neurology2015, 22, 28–34.
  • Foldamers as anticancer therapeutics: targeting protein-protein interactions and the cell membrane: Sara Fahs, Yogita Patil-Sen and Timothy J. Snape,* ChemBioChem2015, 16, 13, 1840–1853.

2014

  • A review of small molecule clinical trial candidates for the treatment of glioma: Saurabh Prabhu, Frederick Harris, Robert Lea and Timothy J. Snape,* Drug Discovery Today201419 (9), 1298-1308.
  • Development of a novel, multifunctional, membrane-interactive pyridinium salt with potent anticancer activity: Sara Fahs, Farjana B. Rowther, Sarah R. Dennison, Yogita Patil-Sen, Tracy Warr, Timothy J. Snape,* Bioorg. Med. Chem. Lett., 201424, 15, 3430–3433.
  • Cn-AMP2 from green coconut water is an anionic anticancer peptide: Saurabh Prabhu, Sarah R. Dennison, Manuela Mura, Robert Lea, Timothy J. Snape and Frederick Harris, J. Pept. Sci., 201420, 909–915.

2013

  • Preliminary biological evaluation and mechanism of action studies of selected 2-arylindoles against glioblastoma: Saurabh Prabhu, Zaheer Akbar, Frederick Harris, Katherine Karakoula, Robert Lea, Farzana Rowther, Tracy Warr and Timothy Snape,* Bioorg. Med.Chem., 201321, 1918-1924.
  • Anionic antimicrobial and anticancer peptides from plants: Saurabh Prabhu, Sarah R. Dennison, Bob Lea, Timothy J. Snape, Iain D. Nicholl, Iza Radek and Frederick Harris, Crit. Rev. Plant Sci., 201332, 303–320.
  • Synthetic oligoureas of metaphenylenediamine mimic host defence peptides in their antimicrobial behaviour: Sarah R. Dennison, David A. Phoenix, and Timothy J. Snape,* Bioorg. Med. Chem. Lett., 201323, 9, 2518–2521.
  • Chiral 1,1-diaryl compounds as important pharmacophores: Dana M. Hamad Ameen and Timothy J. Snape,* Med. Chem. Commun., 20134 (6), 893 – 907.

2012

  • Thermodynamic interactions of a cis and trans benzanilide with Escherichia coli bacterial membranes: Sarah R. Dennison, David A. Phoenix and Timothy J. Snape, Eur. Biophys. J.201241, 8, 687-693.       
Eur Biophy J
  • Interactions between suitably functionalised conformationally distinct benzanilides and phospholipid monolayers: Sarah R. Dennison, Zaheer Akbar, David A. Phoenix and Timothy J. Snape,* Soft Matter, 2012, 8, 11, 3258 – 3264.
  • Exploiting conformationally restricted N,N’-dimethyl-N,N’-diarylureas as biologically active C=C double bond analogues: synthesis and biological evaluation of combretastatin A-4 analogues: Timothy J. Snape,* Katherine Karakoula, Farzana Rowther and Tracy Warr, RSC Adv., 2012, 2, 19, 7557 – 7560.
CAP analogues

2011

  • Towards establishing the effects and mechanism of action of a series of indoles in an in vitro chemosensitivity system for glioma treatment, Saurabh Prabhu, Frederick Harris, Robert Lea and Timothy J Snape, Neuro. Oncol.201113 (suppl 2): ii1-ii14.
  • Exploiting conformationally restricted ureas as biologically active C=C double bond analogues against GBM cells in vitro, TJ Snape, A Karakoula, F Rowther and TJ Warr, Neuro. Oncol.201113 (suppl 2): ii1-ii14.

2010

  • Effects of Momordica charantia fruit extract with the combination of temozolamide and cisplatin in the treatment of glioma cancer: G. Manoharan, R. W. Lea, T. J. Snape, J. Singh, Proc. Physiol. Soc., 2010, 18, PC22.

REARRANGEMENT REACTIONS

Semi-pinacol rearrangement: We applied the semi-pinacol rearrangement to the synthesis of highly-functionalised cyclopentenones, and we hope to exploit this and other related rearrangements to the synthesis of natural products, for example, pumiliotoxin C and litseaverticillol A.

Rearrangement OBC

Some recently published work in this area:

  • Application of the Semi-Pinacol Rearrangement Towards the Generation of Alkenyl-Substituted Quaternary Carbon Centres: Timothy J. Snape*, Org. Biomol. Chem., 20064, 4144-4148.
  • Recent Advances in the Semi-Pinacol Rearrangement of α-Hydroxy Epoxides and Related Compounds: Timothy J. Snape*, Chem. Soc. Rev., 200736, 11, 1823-1842.

Truce-Smiles rearrangement: We are also interested in the relatively under utilised Truce-Smiles rearrangement, and hope to be able to develop it into a synthetically useful procedure for the preparation of a whole range of biologically interesting compounds and molecular building blocks.

Truce Smiles

Some recently published work in this area:

  • A Truce on the Smiles Rearrangement: Revisiting an Old Reaction – The Truce-Smiles Rearrangement: Timothy J. Snape*, Chem. Soc. Rev., 200811, 2452-2458.
  • α-Arylation of Aryl-Ketones: Expanding the Scope of the Truce-Smiles Rearrangement: Timothy J. Snape*, Synlett2008, 2689-2691.
  • Developing the scope of O→C aryl migrations; exploring amide substrates as potential precursors for new asymmetric reactions: Dana Ameen and Timothy J. Snape,* Eur. J. Org. Chem., 2014, 1925–1934.
  • Mechanism and application of Baker-Venkataraman O→C acyl migration reactions: Dana Ameen and Timothy J. Snape,* Synthesis201447(02), 141-158.
  • A Baker-Venkataraman retro-Claisen cascade delivers a novel alkyl migration process for the synthesis of amides: Dana Ameen and Timothy J. Snape,* Tetrahedron Lett., 201556, 1816–1819.

BIOCATALYSIS AND BIOTRANSFORMATIONS 

Monoamine oxidase chemistry: In collaboration with the Turner group at the University of Manchester, we have developed a template-based mnemonic to allow the prediction of substrates for the enzyme variants of a monoamine oxidase from Aspergillus niger. The model has been exemplified by the asymmetric synthesis of the natural product crispine A and a deoxygenated congener.

Crispine A CC2

Some recently published work in this area:

  • A Template-Based Mnemonic for Monoamine Oxidase (MAO-N) Catalyzed Reactions and its Application Towards the Chemo-Enzymatic Deracemisation of the Alkaloid (±)-Crispine A: Kevin R. Bailey, Andrew J. Ellis, Renate Reiss, Timothy J. Snape* and Nicholas J. Turner*, Chem. Commun., 2007, 3640-3642. Designated a Chem. Commun. Hot Article


Asymmetric synthesis of tertiary alcohols:
 We are interested in developing an asymmetric and flexible chemoenzymatic route to tertiary alcohols. The direct synthesis of such molecules is not trivial and the development of a more indirect but flexible approach to them would prove extremely useful, especially since they constitute an important class of compound and are found in numerous natural products and pharmaceuticals.

Synthesis of tertiary alcohol precursors:

Andreas TA
  • Enzymatic desymmetrisation of (2-hydroxymethyl-oxiranyl)-methanol in organic solvents: Andrea March Cortijos and Timothy J. Snape*, Tetrahedron: Asymmetry200819, 15, 1761-1763.

 Asymmetric synthesis of tertiary alcohols:

Andrea 2
  • Towards a chemo-enzymatic method for the asymmetric synthesis of β-amino tertiary alcohols: Andrea March-Cortijos and Timothy J. Snape*, Org. Biomol. Chem., 20097, 5163-5165.

 Synthesis of symmetrical azetidines bearing tertiary alcohols:

  • Synthesis of 1,3-disubstituted azetidines via a tandem ring-opening ring-closing procedure: Andrea March-Cortijos, Timothy Snape* and Nicholas Turner, Synlett201223, 1511-1515.

Enzymatic methods for the synthesis of hindered amides: We are interested in developing new tandem processes which enable the chemoenzymatic synthesis of sterically hindered amides which are currently not accessible using current biocatalytic methods.
Some recently published work in this area:

  • Exploitation of a Candida antarctica lipase B-catalyzed in situ carboxylic acid activation method for the synthesis of acetanilides: Samridhi Lal and Timothy J. Snape,* Journal of Molecular Catalysis B: Enzymatic201283, 80-86.
  • Towards a sustainable synthesis of aniline-derived amides using an indirect chemoenzymatic process: challenges and successes: Samridhi Lal and Timothy J. Snape,* RSC Adv.20144 (4), 1609 – 1615.