title: Antiproliferative, DNA intercalation and redox cycling activities of dioxonaphtho[2,3-d]imidazolium analogs of YM155: A structure-activity relationship study.
abstract: The anticancer agent YM155 is widely investigated as a specific survivin suppressant. More recently, YM155 was found to induce DNA damage and this has raised doubts as to whether survivin is its primary target. In an effort to assess the contribution of DNA damage to the anticancer activity of YM155, several analogs were prepared and evaluated for antiproliferative activity on malignant cells, participation in DNA intercalation and free radical generation by redox cycling. The intact positively charged scaffold was found to be essential for antiproliferative activity and intercalation but was less critical for redox cycling where the minimal requirement was a pared down bicyclic quinone. Side chain requirements at the N(1) and N(3) positions of the scaffold were more alike for redox cycling and intercalation than antiproliferative activity, underscoring yet again, the limited structural overlaps for these activities. Furthermore, antiproliferative activities were poorly correlated to DNA intercalation and redox cycling. Potent antiproliferative activity (IC50 9-23 nM), exceeding that of YM155, was found for a minimally substituted methyl analog AB7. Like YM155 and other dioxonaphthoimidazoliums, AB7 was a modest DNA intercalator but with weak redox cycling activity. Thus, the capacity of this scaffold to inflict direct DNA damage leading to cell death may not be significant and YM155 should not be routinely classified as a DNA damaging agent.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Republic of Singapore.
authors.forename: Si-Han Sherman
authors.initials: SH
authors.lastname: Ho
authors.affiliation: Department of Urology, Singapore General Hospital, 20 College Road, 169856, Republic of Singapore.
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Sim
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Republic of Singapore.
authors.forename: Wei-Loong Sherman
authors.initials: WL
authors.lastname: Yee
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Republic of Singapore.
authors.forename: Tianming
authors.initials: T
authors.lastname: Yang
authors.affiliation: Department of Urology, Singapore General Hospital, 20 College Road, 169856, Republic of Singapore.
authors.forename: Shyi-Peng John
authors.initials: SP
authors.lastname: Yuen
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, 117543, Republic of Singapore. Electronic address: phagoml@nus.edu.sg.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Go
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007093:Imidazoles / Q000737:chemistry* / Q000494:pharmacology; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology; D009285:Naphthoquinones / Q000737:chemistry* / Q000494:pharmacology; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D007093:Imidazoles; D009281:Naphthalenes; D009285:Naphthoquinones; C000609848:dioxonaphtho(2,3-d)imidazolium; C523798:sepantronium
keywords: Apoptosis; Cell viability; DNA intercalation; Redox cycling; Survivin suppressant; YM155