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

Bioorganic & Medicinal Chemistry
Kayla M BorlandVladislav A Litosh

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±1μM. 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.

References

Jan 1, 1992·European Journal of Clinical Pharmacology·L Lennard
Apr 30, 1996·Proceedings of the National Academy of Sciences of the United States of America·M MagnaniU Benatti
Oct 5, 2002·Cellular and Molecular Life Sciences : CMLS·S ErikssonH Eklund
Sep 1, 2005·Breast Cancer Research and Treatment·Hyun Jung JiHyun Cheol Chung
Dec 13, 2005·Genome Research·Michael L Metzker
Mar 7, 2006·Best Practice & Research. Clinical Haematology·Martin S Tallman
Apr 25, 2006·Nucleosides, Nucleotides & Nucleic Acids·Lars P JordheimMarie-Claude Gagnieu
Mar 9, 2007·Cancer Metastasis Reviews·Jing ZhangCarol E Cass
Apr 25, 2008·Leukemia Research·Lisa S ChenVarsha Gandhi
Jul 5, 2008·Nature Protocols·Aida MuslimovicOla Hammarsten
Jan 29, 2010·Toxicological Sciences : an Official Journal of the Society of Toxicology·Ofelia A OliveroMiriam C Poirier
Nov 26, 2010·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Martijn P LolkemaJohann S de Bono
May 10, 2011·Cancer Chemotherapy and Pharmacology·Pierre-Yves CordierEric Peytel
Oct 12, 2012·Chemical Research in Toxicology·Amy R JonesEdward J Merino
Apr 13, 2013·Bioorganic & Medicinal Chemistry Letters·Tiffany R Bell-HorwathEdward J Merino
Jan 9, 2014·CA: a Cancer Journal for Clinicians·Rebecca SiegelAhmedin Jemal
Dec 4, 2014·Bioorganic & Medicinal Chemistry·Anish K VadukootEddie J Merino

❮ Previous
Next ❯

Citations

Oct 24, 2019·Drug Development Research·Balija SivakrishnaShantanu Pal

❮ Previous
Next ❯

Related Concepts

© 2021 Meta ULC. All rights reserved