Abstract
BackgroundMultimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities. Due to their multimodal effect on perturbation of cellular oxidative state, these compounds hold great potential as therapeutic agents against highly proliferative neoplastic cells. In our previous work, we developed a series of novel dimeric naphthoquinones and showed that they were selectively cytotoxic to human acute myeloid leukemia (AML), breast and prostate cancer cell lines. We subsequently identified the oxidoreductase NAD(P)H dehydrogenase, quinone 1 (NQO1) as the major target of dimeric naphthoquinones and proposed a mechanism of action that entailed induction of a futile redox cycling.ResultsHere, for the first time, we describe a direct physical interaction between the bromohydroxy dimeric naphthoquinone E6a and NQO1. Moreover, our studies reveal an extensive binding interface between E6a and the isoalloxazine ring of the flavin adenine dinucleotide (FAD) cofactor of NQO1 in addition to interactions with protein side chains in the active site. We also present biochemical evidence that dimeric naphthoquinones affect the redox state of the FAD cofactor of NQO1. Comparison of the mode of binding of E6a with those of other chemotherapeutics reveals unique characteristics of the interaction that can be leveraged in future drug optimization efforts.ConclusionThe first structure of a dimeric naphthoquinone-NQO1 complex was reported, which can be used for design and synthesis of more potent next generation dimeric naphthoquinones to target NQO1 with higher affinity and specificity.Electronic supplementary materialThe online version of this article (doi:10.1186/s12900-016-0052-x) contains supplementary material, which is available to authorized users.
Highlights
Multimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities
* Correspondence: etoth@som.umaryland.edu 1Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, MD 21201, USA 2Marlene and Stewart Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA Full list of author information is available at the end of the article synthesize conocurvone, we previously developed a series of novel dimeric naphthoquinones and showed that they were selectively cytotoxic to human acute myeloid leukemia (AML), breast and prostate cancer cell lines and in particular those cell lines that rely on oxidative phosphorylation [6,7,8]
NQO1 exists as a homodimer with two tightly-associated flavin adenine dinucleotide (FAD) cofactors that reside at the deepest point of each active site of two monomers of 274 residues [11]
Summary
Multimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities. Due to their multimodal effect on perturbation of cellular oxidative state, these compounds hold great potential as therapeutic agents against highly proliferative neoplastic cells. Multimeric naphthoquinones are reduction/oxidation (redox)-active compounds that possess a wide array of therapeutic activities. These compounds have exhibited well tolerated antibacterial, antifungal, antiviral, and antithrombotic activities [1]. The resulting hydroquinone is highly unstable and spontaneously gives electrons to oxygen and reverts to the oxidized form of Pidugu et al BMC Structural Biology (2016) 16:1 quinone, producing two moles of superoxide per one mole of NAD(P)H [10]. The obligate two electron reduction performed by NQO1 averts oneelectron reduction of quinones by other flavoproteins such as cytochrome P450, which produces highly reactive radical semiquinone
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