Bromopyridone Nucleotide Analogues, Anoxic Selective Radiosensitizing Agents That Are Incorporated in DNA by Polymerases.
Ionizing radiation is frequently used to kill tumor cells. However, hypoxic solid tumor cells are more resistant to this treatment, providing the impetus to develop molecules that sensitize cells to ionizing radiation. 5-Bromo-2'-deoxyuridine (BrdU) has been investigated as a radiosensitizing agent in the lab and clinic for almost 5 decades. Recent reports that BrdU yields DNA interstrand cross-links (ICLs) in non-base-paired regions motivated us to develop radiosensitizing agents that generate cross-links in duplex DNA selectively under anoxic conditions. 4-Bromo- and 5-bromopyridone analogues of BrdU were synthesized and incorporated into oligonucleotides via solid-phase synthesis. Upon irradiation, these molecules yield DNA interstrand cross-links under anaerobic conditions. The respective nucleotide triphosphates are substrates for some DNA polymerases. ICLs are produced upon irradiation under anoxic conditions when the 4-bromopyridone is present in a PCR product. Because the nucleoside analogue is a poor phosphorylation substrate for human deoxycytidine kinase, a pro-nucleotide form of the 4-bromopyridone was used to incorporate this analogue into cellular DNA. Despite these efforts, the 4-bromopyridone nucleotide was not detected in cellular DNA. Although these molecules are improvements over previously reported nucleotide analogues designed to be hypoxic radiosensitizing agents, additional advances are needed to create molecules that function in cells.
Department of Chemistry, Johns Hopkins University , 3400 N. Charles Street, Baltimore, Maryland 21218, United States.
Arnab
A
Rudra
Department of Chemistry, Johns Hopkins University , 3400 N. Charles Street, Baltimore, Maryland 21218, United States.
Dianjie
D
Hou
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine , 401 N. Broadway, Baltimore, Maryland 21231, United States.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
Yonggang
Y
Zhang
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine , 401 N. Broadway, Baltimore, Maryland 21231, United States.
Jonathan
J
Coulter
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine , 401 N. Broadway, Baltimore, Maryland 21231, United States.
Haoming
H
Zhou
Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine , 401 N. Broadway, Baltimore, Maryland 21231, United States.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine , Baltimore, Maryland 21231, United States.
Theodore L
TL
DeWeese
Department of Chemistry, Johns Hopkins University , 3400 N. Charles Street, Baltimore, Maryland 21218, United States.
Marc M
MM
Greenberg
D001483:Base Sequence; D001973:Bromodeoxyuridine / Q000737:chemistry* / Q000494:pharmacology*; D003432:Cross-Linking Reagents / Q000737:chemistry*; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D004249:DNA Damage / Q000528:radiation effects*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry* / Q000378:metabolism; D003857:Deoxyuridine / Q000737:chemistry*; D006801:Humans; D009711:Nucleotides / Q000737:chemistry* / Q000378:metabolism; D011728:Pyridones / Q000737:chemistry* / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000737:chemistry* / Q000494:pharmacology*; D060327:Solid-Phase Synthesis Techniques; D014466:Ultraviolet Rays
C000606271:4-bromopyridone; C000606270:5-bromopyridone; D003432:Cross-Linking Reagents; D009711:Nucleotides; D011728:Pyridones; D011838:Radiation-Sensitizing Agents; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D001973:Bromodeoxyuridine; D003857:Deoxyuridine