TY - JOUR
T1 - Discovery and Optimization of Novel Hydrogen Peroxide Activated Aromatic Nitrogen Mustard Derivatives as Highly Potent Anticancer Agents
AU - Chen, Wenbing
AU - Fan, Heli
AU - Balakrishnan, Kumudha
AU - Wang, Yibin
AU - Sun, Huabing
AU - Fan, Yukai
AU - Gandhi, Varsha
AU - Arnold, Leggy A.
AU - Peng, Xiaohua
N1 - Funding Information:
We are grateful for financial support for this research from the National Cancer Institute (1R15CA152914-01), CLL-Global Research Foundation Alliance grants, UW System Applied Research Grant, the Great Milwaukee Foundation (Shaw Scientist Award), and the UWM Research Growth Initiative.
PY - 2018/10/25
Y1 - 2018/10/25
N2 - We describe several new aromatic nitrogen mustards with various aromatic substituents and boronic esters that can be activated with H2O2 to efficiently cross-link DNA. In vitro studies demonstrated the anticancer potential of these compounds at lower concentrations than those of other clinically used chemotherapeutics, such as melphalan and chlorambucil. In particular, compound 10, bearing an amino acid ester chain, is selectively cytotoxic toward breast cancer and leukemia cells that have inherently high levels of reactive oxygen species. Importantly, 10 was 10-14-fold more efficacious than melphalan and chlorambucil for triple-negative breast-cancer (TNBC) cells. Similarly, 10 is more toxic toward primary chronic-lymphocytic-leukemia cells than either chlorambucil or the lead compound, 9. The introduction of an amino acid side chain improved the solubility and permeability of 10. Furthermore, 10 inhibited the growth of TNBC tumors in xenografted mice without obvious signs of general toxicity, making this compound an ideal drug candidate for clinical development.
AB - We describe several new aromatic nitrogen mustards with various aromatic substituents and boronic esters that can be activated with H2O2 to efficiently cross-link DNA. In vitro studies demonstrated the anticancer potential of these compounds at lower concentrations than those of other clinically used chemotherapeutics, such as melphalan and chlorambucil. In particular, compound 10, bearing an amino acid ester chain, is selectively cytotoxic toward breast cancer and leukemia cells that have inherently high levels of reactive oxygen species. Importantly, 10 was 10-14-fold more efficacious than melphalan and chlorambucil for triple-negative breast-cancer (TNBC) cells. Similarly, 10 is more toxic toward primary chronic-lymphocytic-leukemia cells than either chlorambucil or the lead compound, 9. The introduction of an amino acid side chain improved the solubility and permeability of 10. Furthermore, 10 inhibited the growth of TNBC tumors in xenografted mice without obvious signs of general toxicity, making this compound an ideal drug candidate for clinical development.
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U2 - 10.1021/acs.jmedchem.8b00559
DO - 10.1021/acs.jmedchem.8b00559
M3 - Article
C2 - 30247905
AN - SCOPUS:85054882189
SN - 0022-2623
VL - 61
SP - 9132
EP - 9145
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 20
ER -