Organometallic nucleoside analogues: effect of hydroxylalkyl linker length on cancer cell line toxicity

Jonathan Kedge; Van Huy Nguyen; Zahra Khan; Louise Male; Media Ismail; Holly Roberts; Nikolas Hodges; Sarah L Horswell; Youcef Mehellou; James Tucker

doi:10.1002/ejic.201600853

Organometallic nucleoside analogues: effect of hydroxylalkyl linker length on cancer cell line toxicity

Jonathan Kedge, Van Huy Nguyen, Zahra Khan, Louise Male, Media Ismail, Holly Roberts, Nikolas Hodges, Sarah L Horswell, Youcef Mehellou, James Tucker

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Abstract

A new series of chiral ferrocene derivatives containing both a hydroxyalkyl group and a thyminyl group on one cyclopentadienyl ring have been synthesised in order to probe structure activity relationships in cancer cell-line cytotoxicities. Stereoisomers of enantiomeric pairs of these so-called ferronucleosides have been studied and characterised by a combination of chiral analytical HPLC and single crystal X-Ray diffraction. Biological activity studies reveal that changing the length of the hydroxyalkyl group had marked effects on IC50 values, with compounds having shorter arms that more closely resemble endogenous nucleosides exhibiting lower cytotoxicities. Lipophilicities and electrochemical properties of this compound series have been studied in order to rationalise these trends and indicate future directions of study.

Original language	English
Pages (from-to)	466-476
Number of pages	11
Journal	European Journal of Inorganic Chemistry
Volume	2017
Issue number	2
Early online date	17 Oct 2016
DOIs	https://doi.org/10.1002/ejic.201600853
Publication status	Published - 10 Jan 2017

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10.1002/ejic.201600853

Tucker_et_al-2016-European_Journal_of_Inorganic_Chemistry
This is the peer reviewed version of the following article: Kedge, J. L., Nguyen, H. V., Khan, Z. , Male, L. , Hodges, M. K., Horswell, S. L., Mehellou, Y. and Tucker, J. H. (2017), Organometallic Nucleoside Analogues: Effect of Hydroxyalkyl Linker Length on Cancer Cell Line Toxicity. Eur. J. Inorg. Chem., 2017: 466-476, which has been published in final form at: http://dx.doi.org/10.1002/ejic.201600853. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions
Accepted author manuscript, 1.59 MBLicence: None: All rights reserved

Functional DNA-based assemblies
Tucker, J.
Engineering & Physical Science Research Council
16/03/09 → 31/03/14
Project: Research Councils

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title = "Organometallic nucleoside analogues: effect of hydroxylalkyl linker length on cancer cell line toxicity",

abstract = "A new series of chiral ferrocene derivatives containing both a hydroxyalkyl group and a thyminyl group on one cyclopentadienyl ring have been synthesised in order to probe structure activity relationships in cancer cell-line cytotoxicities. Stereoisomers of enantiomeric pairs of these so-called ferronucleosides have been studied and characterised by a combination of chiral analytical HPLC and single crystal X-Ray diffraction. Biological activity studies reveal that changing the length of the hydroxyalkyl group had marked effects on IC50 values, with compounds having shorter arms that more closely resemble endogenous nucleosides exhibiting lower cytotoxicities. Lipophilicities and electrochemical properties of this compound series have been studied in order to rationalise these trends and indicate future directions of study.",

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T1 - Organometallic nucleoside analogues: effect of hydroxylalkyl linker length on cancer cell line toxicity

AU - Kedge, Jonathan

AU - Nguyen, Van Huy

AU - Khan, Zahra

AU - Male, Louise

AU - Ismail, Media

AU - Roberts, Holly

AU - Hodges, Nikolas

AU - Horswell, Sarah L

AU - Mehellou, Youcef

AU - Tucker, James

PY - 2017/1/10

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N2 - A new series of chiral ferrocene derivatives containing both a hydroxyalkyl group and a thyminyl group on one cyclopentadienyl ring have been synthesised in order to probe structure activity relationships in cancer cell-line cytotoxicities. Stereoisomers of enantiomeric pairs of these so-called ferronucleosides have been studied and characterised by a combination of chiral analytical HPLC and single crystal X-Ray diffraction. Biological activity studies reveal that changing the length of the hydroxyalkyl group had marked effects on IC50 values, with compounds having shorter arms that more closely resemble endogenous nucleosides exhibiting lower cytotoxicities. Lipophilicities and electrochemical properties of this compound series have been studied in order to rationalise these trends and indicate future directions of study.

AB - A new series of chiral ferrocene derivatives containing both a hydroxyalkyl group and a thyminyl group on one cyclopentadienyl ring have been synthesised in order to probe structure activity relationships in cancer cell-line cytotoxicities. Stereoisomers of enantiomeric pairs of these so-called ferronucleosides have been studied and characterised by a combination of chiral analytical HPLC and single crystal X-Ray diffraction. Biological activity studies reveal that changing the length of the hydroxyalkyl group had marked effects on IC50 values, with compounds having shorter arms that more closely resemble endogenous nucleosides exhibiting lower cytotoxicities. Lipophilicities and electrochemical properties of this compound series have been studied in order to rationalise these trends and indicate future directions of study.

U2 - 10.1002/ejic.201600853

DO - 10.1002/ejic.201600853

M3 - Article

SN - 1434-1948

VL - 2017

SP - 466

EP - 476

JO - European Journal of Inorganic Chemistry

JF - European Journal of Inorganic Chemistry

IS - 2

ER -

Organometallic nucleoside analogues: effect of hydroxylalkyl linker length on cancer cell line toxicity

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