Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 20, Pages 9132-9145Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00559
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Funding
- National Cancer Institute [1R15CA152914-01]
- CLL-Global Research Foundation Alliance grants
- Great Milwaukee Foundation
- UVVM Research Growth Initiative
- LTW System Applied Research Grant
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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 triplenegative 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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