title: Dioxonaphthoimidazoliums are Potent and Selective Rogue Stem Cell Clearing Agents with SOX2-Suppressing Properties.
abstract: Pluripotent stem cells are uniquely positioned for regenerative medicine, but their clinical potential can only be realized if their tumorigenic tendencies are decoupled from their pluripotent properties. Deploying small molecules to remove remnant undifferentiated pluripotent cells, which would otherwise transform into teratomas and teratomacarcinomas, offers several advantages over non-pharmacological methods. Dioxonapthoimidazolium YM155, a survivin suppressant, induced selective and potent cell death of undifferentiated stem cells. Herein, the structural requirements for stemotoxicity were investigated and found to be closely aligned with those essential for cytotoxicity in malignant cells. There was a critical reliance on the quinone and imidazolium moieties but a lesser dependence on ring substituents, which served mainly to fine-tune activity. Several potent analogues were identified which, like YM155, suppressed survivin and decreased SOX2 in stem cells. The decrease in SOX2 would cause an imbalance in pluripotent factors that could potentially prompt cells to differentiate and hence decrease the risk of aberrant teratoma formation. As phosphorylation of the NF-κB p50 subunit was also suppressed, the crosstalk between phospho-p50, SOX2, and survivin could implicate a causal role for NF-κB signaling in mediating the stem cell clearing properties of dioxonaphthoimidazoliums.
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Si-Han Sherman
authors.initials: SH
authors.lastname: Ho
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
authors.forename: Azhar
authors.initials: A
authors.lastname: Ali
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Yi-Cheng
authors.initials: YC
authors.lastname: Ng
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Kuen-Kuen Millie
authors.initials: KK
authors.lastname: Lam
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.|Institute of Bioengineering and Nanotechnology, 31 Biopolis Way, Singapore, 138669, Singapore.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Biological Sciences, National University of Singapore, 14 Science Drive 4, Singapore, 117543, Singapore.
authors.forename: Woon-Khiong
authors.initials: WK
authors.lastname: Chan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
authors.forename: Tan-Min
authors.initials: TM
authors.lastname: Chin
authors.affiliation: Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore. phagoml@nus.edu.sg.
authors.forename: Mei-Lin
authors.initials: ML
authors.lastname: Go
mesh_terms: D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D039904:Pluripotent Stem Cells / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D007093:Imidazoles; D009285:Naphthoquinones; D012333:RNA, Messenger; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C523798:sepantronium
keywords: antiproliferation; dioxonaphthoimidazoliums; factor SOX2; stem cell clearing agents; structure-activity relationships