title: Hydrogen peroxide activated quinone methide precursors with enhanced DNA cross-linking capability and cytotoxicity towards cancer cells.
abstract: Quinone methide (QM) formation induced by endogenously generated H2O2is 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 H2O2and 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.
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Yibin
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Heli
authors.initials: H
authors.lastname: Fan
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Kumudha
authors.initials: K
authors.lastname: Balakrishnan
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Zechao
authors.initials: Z
authors.lastname: Lin
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Sheng
authors.initials: S
authors.lastname: Cao
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Wenbing
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Yukai
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Quibria A
authors.initials: QA
authors.lastname: Guthrie
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Huabing
authors.initials: H
authors.lastname: Sun
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Kelly A
authors.initials: KA
authors.lastname: Teske
authors.affiliation: Department of Experimental Therapeutics, MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Varsha
authors.initials: V
authors.lastname: Gandhi
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
authors.affiliation: Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, University of Wisconsin-Milwaukee, 3210 N. Cramer Street, Milwaukee, WI, 53211, USA. Electronic address: pengx@uwm.edu.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Peng
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001483:Base Sequence / Q000187:drug effects; D001555:Benzene Derivatives / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D045744:Cell Line, Tumor; D004247:DNA / Q000737:chemistry*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism*; D045563:Indolequinones / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D007364:Intercalating Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D001897:Boronic Acids; D045563:Indolequinones; D007364:Intercalating Agents; C068040:quinone methide; D004247:DNA; D006861:Hydrogen Peroxide
keywords: Anticancer activity; Arylboronates; DNA interstrand cross-linking agents; Hydrogen peroxide activation; Quinone methide