A Novel Series Of Phenolic Temozolomide (TMZ) Esters With 4 To 5 ...

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RSC Advances

A novel series of phenolic temozolomide (TMZ) esters with 4 to 5-fold increased potency, compared to TMZ, against glioma cells irrespective of MGMT expression†

Leroy Shervington, *a Oliver Inghama and Amal Shervingtona Author affiliations

* Corresponding authors

a Faculty of Pharmacy and Biomedical Science, The University of Central Lancashire, Preston, UK E-mail: [email protected]

Abstract

The standard of care treatment for patients diagnosed with glioblastoma multiforme (GBM) is temozolomide (TMZ). Tumour resistance to TMZ results in significantly limited clinical effectiveness. There is therefore an inherent need for alternatives to TMZ capable of overcoming resistance associated with MGMT and MMR. In the present study, a series of ester and amide analogues of TMZ, modified at position 8 on the imidazole ring, were prepared and investigated for antiproliferative properties. It was found that phenolic ester analogues of TMZ displayed increased potency, of up to 5-fold, against specified glioblastoma cell lines. The encouraging results displayed by the phenolic TMZ esters prompted further investigations against patient-derived primary glioblastoma cultures. The primary cultures, BTNW914 and BTNW374, were MGMT positive and MGMT negative, respectively. Lead phenolic TMZ esters were found to decrease viability in primary cells at clinically relevant concentrations, irrespective of MGMT expression. Furthermore, TMZ was found to be ineffective against the same primary cells at clinically relevant concentrations. The novel phenyl ester analogues of TMZ, described in this study, could have potential chemotherapeutic properties for the treatment of GBM, overcoming the resistance associated with the expression of MGMT.

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Article information

DOI https://doi.org/10.1039/D0RA02686G Article type Paper Submitted 23 Mar 2020 Accepted 26 Apr 2020 First published 06 May 2020 This article is Open Access

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RSC Adv., 2020,10, 17561-17570 BibTex EndNote MEDLINE ProCite ReferenceManager RefWorks RIS

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A novel series of phenolic temozolomide (TMZ) esters with 4 to 5-fold increased potency, compared to TMZ, against glioma cells irrespective of MGMT expression

L. Shervington, O. Ingham and A. Shervington, RSC Adv., 2020, 10, 17561 DOI: 10.1039/D0RA02686G

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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