Faculty Collaboration Database

Hydrogen peroxide activated quinone methide precursors with enhanced DNA cross-linking capability and cytotoxicity towards cancer cells. Eur J Med Chem 2017 Jun 16;133:197-207

Date

04/08/2017

Pubmed ID

28388522

Pubmed Central ID

PMC5652303

DOI

10.1016/j.ejmech.2017.03.041

Scopus ID

2-s2.0-85016812733 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

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.

Author List

Wang Y, Fan H, Balakrishnan K, Lin Z, Cao S, Chen W, Fan Y, Guthrie QA, Sun H, Teske KA, Gandhi V, Arnold LA, Peng X

Author

Alexander (Leggy) Arnold PhD Professor in the Chemistry & Biochemistry department at University of Wisconsin - Milwaukee

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents
Base Sequence
Benzene Derivatives
Boronic Acids
Cell Line, Tumor
DNA
Humans
Hydrogen Peroxide
Indolequinones
Intercalating Agents
Neoplasms