ABSTRACT
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.
Subject(s)
Antineoplastic Agents, Alkylating/metabolism , Antineoplastic Agents, Alkylating/pharmacology , Drug Design , Hydrogen Peroxide/metabolism , Nitrogen Mustard Compounds/metabolism , Nitrogen Mustard Compounds/pharmacology , Antineoplastic Agents, Alkylating/chemistry , Boronic Acids/chemistry , Cell Line, Tumor , Esters/chemistry , Humans , Nitrogen Mustard Compounds/chemistryABSTRACT
Quinone methide (QM) formation induced by endogenously generated H2O2 is attractive for biological and biomedical applications. To overcome current limitations due to low biological activity of H2O2-activated QM precursors, we are introducing herein several new arylboronates with electron donating substituents at different positions of benzene ring and/or different neutral leaving groups. The reaction rate of the arylboronate esters with H2O2 and subsequent bisquinone methides formation and DNA cross-linking was accelerated with the application of Br as a leaving group instead of acetoxy groups. Additionally, a donating group placed meta to the nascent exo-methylene group of the quinone methide greatly improves H2O2-induced DNA interstrand cross-link formation as well as enhances the cellular activity. Multiple donating groups decrease the stability and DNA cross-linking capability, which lead to low cellular activity. A cell-based screen demonstrated that compounds 2a and 5a with a OMe or OH group dramatically inhibited the growth of various tissue-derived cancer cells while normal cells were less affected. Induction of H2AX phosphorylation by these compounds in CLL lymphocytes provide evidence for a correlation between cell death and DNA damage. The compounds presented herein showed potent anticancer activities and selectivity, which represent a novel scaffold for anticancer drug development.
Subject(s)
Antineoplastic Agents/pharmacology , Benzene Derivatives/pharmacology , DNA/chemistry , Hydrogen Peroxide/metabolism , Indolequinones/pharmacology , Intercalating Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/metabolism , Base Sequence/drug effects , Benzene Derivatives/chemistry , Benzene Derivatives/metabolism , Boronic Acids/chemistry , Boronic Acids/metabolism , Boronic Acids/pharmacology , Cell Line, Tumor , Humans , Indolequinones/chemistry , Indolequinones/metabolism , Intercalating Agents/chemistry , Intercalating Agents/metabolism , Neoplasms/drug therapy , Neoplasms/metabolismABSTRACT
UV irradiation of several aryl boronates efficiently produced bifunctional benzyl cations that selectively form guanine-cytosine cross-links in DNA. Photoinduced homolysis of the C-Br bond took place with the aryl boronate bromides 3a and 4a, generating free radicals that were oxidized to benzyl cations via electron transfer. However, photoirradiation of the quaternary ammonium salts 3b and 4b led to heterolysis of C-N bond, directly producing benzyl cations. The electron-donating group in the aromatic ring greatly enhanced cross-linking efficiency.
Subject(s)
Benzene Derivatives/chemistry , Cross-Linking Reagents/chemistry , Cytosine/chemistry , Guanine/chemistry , Base Sequence , Boronic Acids/chemistry , Cations , Cyclic N-Oxides/chemistry , DNA/chemistry , DNA Adducts/chemistry , Hydroxylamines/chemistry , Oxidation-Reduction , Photochemical ProcessesABSTRACT
A strategy to construct the hexacyclic skeleton of trigonoliimines A, B and their derivatives involving a carbanion-triggered intramolecular cyclization of a seven-membered ring and a subsequent six-membered ring formation in one pot is described.
Subject(s)
Indole Alkaloids/chemistry , Cyclization , Models, Molecular , Molecular StructureABSTRACT
A rapid approach to the skeleton of dalesconol A and B, unprecedented immunosuppressants, has been achieved through a convergent strategy featuring a carbocation-mediated dearomatization-cyclization and a following one-pot consecutive operation.
