Discovery and Optimization of Novel Hydrogen Peroxide Activated Aromatic Nitrogen Mustard Derivatives as Highly Potent Anticancer Agents

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.