Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells

Kayla M. Borland, Safnas F. AbdulSalam, Morwena J. Solivio, Matthew P. Burke, Patrick R. Wolfkiel, Sean M. Lawson, Courtney A. Stockman, Joel M. Andersen, Skyler Smith, Julia N. Tolstolutskaya, Purujit N. Gurjar, Aron P. Bercz, Edward J. Merino, Vladislav A. Litosh

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5′-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9 ± 1 μM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5′-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork.

Original languageEnglish (US)
Pages (from-to)1869-1881
Number of pages13
JournalBioorganic and Medicinal Chemistry
Volume23
Issue number8
DOIs
StatePublished - Apr 15 2015
Externally publishedYes

Bibliographical note

Funding Information:
We gratefully acknowledge the University of Cincinnati start-up and the University of Cincinnati Individual Faculty Research Grant funds to Prof. Litosh, and the NIH-NCI award ( R21CA185370 ) to Prof. Merino. We also acknowledge the National Cancer Institute Developmental Therapeutics Program for performing compound screening in a variety of cancer cell lines. Additionally, we would like to thank Prof. James Mack for granting access to his mechanochemistry facilities, making it possible to synthesize a key control compound that was inaccessible by conventional synthetic methods.

Publisher Copyright:
© 2015 Elsevier Ltd. All rights reserved.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

Keywords

  • Antimetabolites
  • Cancer
  • Chemotherapeutics
  • DNA termination
  • Nucleosides
  • Nucleotides

Fingerprint Dive into the research topics of 'Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells'. Together they form a unique fingerprint.

Cite this