title: Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells.
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.
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Kayla M
authors.initials: KM
authors.lastname: Borland
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Safnas F
authors.initials: SF
authors.lastname: AbdulSalam
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Morwena J
authors.initials: MJ
authors.lastname: Solivio
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Burke
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Wolfkiel
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Lawson
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Courtney A
authors.initials: CA
authors.lastname: Stockman
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Joel M
authors.initials: JM
authors.lastname: Andersen
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Skyler
authors.initials: S
authors.lastname: Smith
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Julia N
authors.initials: JN
authors.lastname: Tolstolutskaya
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Purujit N
authors.initials: PN
authors.lastname: Gurjar
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Aron P
authors.initials: AP
authors.lastname: Bercz
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA.
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Merino
authors.affiliation: Department of Chemistry, University of Cincinnati, 301 Clifton Ct. ML 0172, Cincinnati, OH 45221-0172, USA. Electronic address: Vladislav.Litosh@uc.edu.
authors.forename: Vladislav A
authors.initials: VA
authors.lastname: Litosh
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D004261:DNA Replication / Q000187:drug effects*; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D019384:Nucleic Acid Synthesis Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013936:Thymidine / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D000964:Antimetabolites, Antineoplastic; D019384:Nucleic Acid Synthesis Inhibitors; D013936:Thymidine
keywords: Antimetabolites; Cancer; Chemotherapeutics; DNA termination; Nucleosides; Nucleotides