title: Novel ROS-activated agents utilize a tethered amine to selectively target acute myeloid leukemia.
abstract: This study explores the possible use of reactive oxygen-activated DNA modifying agents against acute myeloid leukemia (AML). A key amine on the lead agent was investigated via cytotoxicity assays and was found necessary for potency. The two best compounds were screened via the NCI-60 cell panel. These two compounds had potency between 200 and 800nM against many of the leukemia cancer cell types. Subsequent experiments explored activity against a transformed AML model that mimics the molecular signatures identified in primary AML patient samples. A lead compound had an IC50 of 760nM against this AML cell line as well as a therapeutic index of 7.7±3 between the transformed AML model cell line and non-cancerous human CD34+ blood stem/progenitor cells (UCB). The selectivity was much greater than the mainstays of AML treatment: doxorubicin and cytarabine. This manuscript demonstrates that this novel type of agent may be useful against AML.
authors.affiliation: Department of Chemistry, University of Cincinnati, Cincinnati, OH 45221-0172, United States.
authors.forename: Tiffany R
authors.initials: TR
authors.lastname: Bell-Horwath
authors.forename: Anish K
authors.initials: AK
authors.lastname: Vadukoot
authors.forename: Fathima Shazna
authors.initials: FS
authors.lastname: Thowfeik
authors.forename: Guorui
authors.initials: G
authors.lastname: Li
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Merino
mesh_terms: D000588:Amines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006367:HeLa Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D000588:Amines; D000970:Antineoplastic Agents; D017382:Reactive Oxygen Species; D004247:DNA