Design, Synthesis, and Analytical Evaluation of Fsp3‐Inspired Raman Probes for Cellular Imaging

Craig F. Steven; Martin Lee; Gary S. Nichol; Paul R. J. Davey; Elisabetta Chiarparin; Valerie G. Brunton; Alison Nicola Hulme

doi:10.1002/ejoc.202200393

Design, Synthesis, and Analytical Evaluation of Fsp3‐Inspired Raman Probes for Cellular Imaging

Craig F. Steven, Martin Lee, Gary S. Nichol, Paul R. J. Davey, Elisabetta Chiarparin, Valerie G. Brunton, Alison Nicola Hulme

Research output: Contribution to journal › Article › peer-review

Abstract

The fraction of sp 3 -hybdrised carbons (Fsp 3 ) in drug candidates and other biologically relevant compounds has been proposed to be an important physicochemical consideration within medicinal chemistry. Currently available small-molecule probes for Raman imaging are not optimised for biological applications. We sought to improve upon the highly Raman-active, yet rigid, lipophilic, and aggregative, bisarylbutadiyne (BADY) motif by introducing Fsp 3 character. BADY analogues were designed, efficiently synthesised, and analysed by mass spectrometry – revealing a statistical correlation between compound aggregation and cLog P , but no correlation with sp 3 . However, X-ray crystallography demonstrated that the modifications to the BADY structure had a marked effect on crystal packing, suggesting Fsp 3 may still be important in reducing intermolecular stacking, and thus aggregation, of BADY. Cellular imaging by stimulated Raman scattering (SRS) microscopy allowed comparison of the intracellular distribution of the tags, guiding the design of future Raman probes.

Original language	English
Journal	European Journal of Organic Chemistry
Early online date	17 Jun 2022
DOIs	https://doi.org/10.1002/ejoc.202200393
Publication status	E-pub ahead of print - 17 Jun 2022

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10.1002/ejoc.202200393Licence: Other

20220812_Hulme_EurJOC-VoRFinal published version, 3.1 MBLicence: Creative Commons: Attribution (CC-BY)

https://onlinelibrary.wiley.com/doi/10.1002/ejoc.202200393

New Bioorthogonal Raman Tags As Tools For Preclinical Oncology Drug Development
Brunton, V. (Principal Investigator)
UK-based charities
1/06/19 → 31/10/22
Project: Research

Advanced Imaging Resource
Wheeler, A. (Manager), Murphy, L. (Other), Lee, M. (Other), Caldwell, H. (Other), Pearson, M. (Other) & Iremonger, J. (Other)
Deanery of Molecular, Genetic and Population Health Sciences
Facility/equipment: Facility

Cite this

@article{4bad334153a7446884292af89587f01b,

title = "Design, Synthesis, and Analytical Evaluation of Fsp3‐Inspired Raman Probes for Cellular Imaging",

abstract = "The fraction of sp 3 -hybdrised carbons (Fsp 3 ) in drug candidates and other biologically relevant compounds has been proposed to be an important physicochemical consideration within medicinal chemistry. Currently available small-molecule probes for Raman imaging are not optimised for biological applications. We sought to improve upon the highly Raman-active, yet rigid, lipophilic, and aggregative, bisarylbutadiyne (BADY) motif by introducing Fsp 3 character. BADY analogues were designed, efficiently synthesised, and analysed by mass spectrometry – revealing a statistical correlation between compound aggregation and cLog P , but no correlation with sp 3 . However, X-ray crystallography demonstrated that the modifications to the BADY structure had a marked effect on crystal packing, suggesting Fsp 3 may still be important in reducing intermolecular stacking, and thus aggregation, of BADY. Cellular imaging by stimulated Raman scattering (SRS) microscopy allowed comparison of the intracellular distribution of the tags, guiding the design of future Raman probes.",

author = "Steven, {Craig F.} and Martin Lee and Nichol, {Gary S.} and Davey, {Paul R. J.} and Elisabetta Chiarparin and Brunton, {Valerie G.} and Hulme, {Alison Nicola}",

note = "Funding Information: We thank J. Sakas and Dr. C. Logan Mackay for their expertise in the mass spectrometry experiments and M. T. J. Bluntzer for assistance in running DFT calculations. We thank the EPSRC (studentship to CFS, grant ref EP/R513209/1) and AstraZeneca for funding. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: {\textcopyright} 2022 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH.",

year = "2022",

month = jun,

day = "17",

doi = "10.1002/ejoc.202200393",

language = "English",

journal = "European Journal of Organic Chemistry",

issn = "1434-193X",

publisher = "Wiley-VCH Verlag",

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TY - JOUR

T1 - Design, Synthesis, and Analytical Evaluation of Fsp3‐Inspired Raman Probes for Cellular Imaging

AU - Steven, Craig F.

AU - Lee, Martin

AU - Nichol, Gary S.

AU - Davey, Paul R. J.

AU - Chiarparin, Elisabetta

AU - Brunton, Valerie G.

AU - Hulme, Alison Nicola

N1 - Funding Information: We thank J. Sakas and Dr. C. Logan Mackay for their expertise in the mass spectrometry experiments and M. T. J. Bluntzer for assistance in running DFT calculations. We thank the EPSRC (studentship to CFS, grant ref EP/R513209/1) and AstraZeneca for funding. For the purpose of open access, the author has applied a Creative Commons Attribution (CC BY) licence to any Author Accepted Manuscript version arising from this submission. Publisher Copyright: © 2022 The Authors. European Journal of Organic Chemistry published by Wiley-VCH GmbH.

PY - 2022/6/17

Y1 - 2022/6/17

N2 - The fraction of sp 3 -hybdrised carbons (Fsp 3 ) in drug candidates and other biologically relevant compounds has been proposed to be an important physicochemical consideration within medicinal chemistry. Currently available small-molecule probes for Raman imaging are not optimised for biological applications. We sought to improve upon the highly Raman-active, yet rigid, lipophilic, and aggregative, bisarylbutadiyne (BADY) motif by introducing Fsp 3 character. BADY analogues were designed, efficiently synthesised, and analysed by mass spectrometry – revealing a statistical correlation between compound aggregation and cLog P , but no correlation with sp 3 . However, X-ray crystallography demonstrated that the modifications to the BADY structure had a marked effect on crystal packing, suggesting Fsp 3 may still be important in reducing intermolecular stacking, and thus aggregation, of BADY. Cellular imaging by stimulated Raman scattering (SRS) microscopy allowed comparison of the intracellular distribution of the tags, guiding the design of future Raman probes.

AB - The fraction of sp 3 -hybdrised carbons (Fsp 3 ) in drug candidates and other biologically relevant compounds has been proposed to be an important physicochemical consideration within medicinal chemistry. Currently available small-molecule probes for Raman imaging are not optimised for biological applications. We sought to improve upon the highly Raman-active, yet rigid, lipophilic, and aggregative, bisarylbutadiyne (BADY) motif by introducing Fsp 3 character. BADY analogues were designed, efficiently synthesised, and analysed by mass spectrometry – revealing a statistical correlation between compound aggregation and cLog P , but no correlation with sp 3 . However, X-ray crystallography demonstrated that the modifications to the BADY structure had a marked effect on crystal packing, suggesting Fsp 3 may still be important in reducing intermolecular stacking, and thus aggregation, of BADY. Cellular imaging by stimulated Raman scattering (SRS) microscopy allowed comparison of the intracellular distribution of the tags, guiding the design of future Raman probes.

U2 - 10.1002/ejoc.202200393

DO - 10.1002/ejoc.202200393

M3 - Article

SN - 1434-193X

JO - European Journal of Organic Chemistry

JF - European Journal of Organic Chemistry

ER -

Design, Synthesis, and Analytical Evaluation of Fsp3‐Inspired Raman Probes for Cellular Imaging

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New Bioorthogonal Raman Tags As Tools For Preclinical Oncology Drug Development

Equipment

Advanced Imaging Resource

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