title: Glycoconjugated Site-Selective DNA-Methylating Agent Targeting Glucose Transporters on Glioma Cells.
abstract: DNA-alkylating drugs continue to remain an important weapon in the arsenal against cancers. However, they typically suffer from several shortcomings because of the indiscriminate DNA damage that they cause and their inability to specifically target cancer cells. We have developed a strategy for overcoming the deficiencies in current DNA-alkylating chemotherapy drugs by designing a site-specific DNA-methylating agent that can target cancer cells because of its selective uptake via glucose transporters, which are overexpressed in most cancers. The design features of the molecule, its synthesis, its reactivity with DNA, and its toxicity in human glioblastoma cells are reported here. In this molecule, a glucosamine unit, which can facilitate uptake via glucose transporters, is conjugated to one end of a bispyrrole triamide unit, which is known to bind to the minor groove of DNA at A/T-rich regions. A methyl sulfonate moiety is tethered to the other end of the bispyrrole unit to serve as a DNA-methylating agent. This molecule produces exclusively N3-methyladenine adducts upon reaction with DNA and is an order of magnitude more toxic to treatment resistant human glioblastoma cells than streptozotocin is, a Food and Drug Administration-approved, glycoconjugated DNA-methylating drug. Cellular uptake studies using a fluorescent analogue of our molecule provide evidence of uptake via glucose transporters and localization within the nucleus of cells. These results demonstrate the feasibility of our strategy for developing more potent anticancer chemotherapeutics, while minimizing common side effects resulting from off-target damage.
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Mairin K
authors.initials: MK
authors.lastname: Buchanan
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Chase N
authors.initials: CN
authors.lastname: Needham
authors.affiliation: Department of Biology and Marine Biology, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Nina E
authors.initials: NE
authors.lastname: Neill
authors.affiliation: Department of Biology and Marine Biology, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Maria C
authors.initials: MC
authors.lastname: White
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Kelly
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mastro-Kishton
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Lacie M
authors.initials: LM
authors.lastname: Chauvigne-Hines
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Tyler J
authors.initials: TJ
authors.lastname: Goodwin
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Andrew L
authors.initials: AL
authors.lastname: McIver
authors.affiliation: Department of Chemistry, East Carolina University , Greenville, North Carolina 27858, United States.
authors.forename: Libero J
authors.initials: LJ
authors.lastname: Bartolotti
authors.affiliation: Department of Biology and Marine Biology, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Frampton
authors.affiliation: MARBIONC, University of North Carolina Wilmington , Wilmington, North Carolina 28409, United States.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Bourdelais
authors.affiliation: Department of Chemistry and Biochemistry, University of North Carolina Wilmington , Wilmington, North Carolina 28403, United States.
authors.forename: Sridhar
authors.identifier: http://orcid.org/0000-0003-0986-9661
authors.initials: S
authors.lastname: Varadarajan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D000476:Alkanesulfonates / Q000737:chemistry; D018906:Antineoplastic Agents, Alkylating / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D018736:DNA Adducts / Q000096:biosynthesis* / Q000737:chemistry; D004249:DNA Damage; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015870:Gene Expression; D005944:Glucosamine / Q000737:chemistry; D051246:Glucose Transport Proteins, Facilitative / Q000235:genetics / Q000378:metabolism*; D006001:Glycoconjugates / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D056004:Molecular Dynamics Simulation; D058990:Molecular Targeted Therapy; D009457:Neuroglia / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009690:Nucleic Acid Conformation; D011758:Pyrroles / Q000737:chemistry; D013311:Streptozocin / Q000494:pharmacology
chemical_list: D000476:Alkanesulfonates; D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D004273:DNA, Neoplasm; D051246:Glucose Transport Proteins, Facilitative; D006001:Glycoconjugates; C580784:N3-methyladenine; D011758:Pyrroles; D013311:Streptozocin; D000225:Adenine; D005944:Glucosamine