DNA Triplex-Formation by a Covalent Conjugate of the Anticancer Drug Temozolomide

Abstract

Background/Objectives: Temozolomide is an important drug used for the treatment of glioblastoma multiforme. Covalent conjugation of temozolomide to triplex-forming oligonucleotides could facilitate better sequence discrimination when targeted to DNA to lessen off-target effects and potentially reduce side-effects associated with conventional chemotherapy. The base sensitivity of temozolomide precludes use of basic deprotection conditions that typify the solid-supported synthesis of oligonucleotides. Methods: A novel di-iso-propylsilylene-linked solid support was developed and used in solid-supported synthesis of oligonucleotide conjugates. Results: Conditions were established whereby fully deprotected, solid-supported oligonucleotides could be prepared for derivatization. Cleavage of the di-iso-propylsilylene linker was possible using mild, acidic conditions. Conclusions: The di-iso-propylsilylene-linked solid support was developed and shown to be compatible with base-sensitive oligonucleotide conjugate formation. The DNA triplex formation exhibited by a temozolomide oligonucleotide conjugate was equal in stability to the unconjugated control, opening new possibilities for sequence-selective delivery of temozolomide to targeted DNA.

Publication DOI: https://doi.org/10.3390/dna5030036
Divisions: College of Health & Life Sciences > Aston Pharmacy School
College of Health & Life Sciences
Funding Information: This research was funded by Cancer Research UK SP2283/0101.
Additional Information: Copyright © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Uncontrolled Keywords: anticancer,conjugate,glioblastoma multiforme,oligonucleotide,solid-supported,synthesis,temozolomide,triplex
Publication ISSN: 2673-8856
Last Modified: 30 Jul 2025 08:12
Date Deposited: 29 Jul 2025 12:25
Full Text Link:
Related URLs: https://www.mdp ... 673-8856/5/3/36 (Publisher URL)
PURE Output Type: Article
Published Date: 2025-07-22
Accepted Date: 2025-06-26
Authors: Fraser, William (ORCID Profile 0000-0001-6588-0166)
Walsh, Andrew J.

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