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Dioxonaphthoimidazoliums are Potent and Selective Rogue Stem Cell Clearing Agents with SOX2‐Suppressing Properties
Author(s) -
Ho SiHan Sherman,
Ali Azhar,
Ng YiCheng,
Lam KuenKuen Millie,
Wang Shu,
Chan WoonKhiong,
Chin TanMin,
Go MeiLin
Publication year - 2016
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201600262
Subject(s) - clearing , sox2 , stem cell , chemistry , computational biology , microbiology and biotechnology , biology , biochemistry , gene , business , finance , transcription factor
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.