Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I

    Authors

    K. J. Akerman; A. M. Fagenson; V. Cyril; M. Taylor; M. T. Muller; M. P. Akerman;O. Q. Munro

    Comments

    Authors: contact us about adding a copy of your work at STARS@ucf.edu

    Abbreviated Journal Title

    J. Am. Chem. Soc.

    Keywords

    DNA SUPERCOIL RELAXATION; NUCLEIC-ACID STRUCTURES; SYBR-GREEN-I; ANTICANCER DRUG; CANCER-CELLS; BIOLOGICAL EVALUATION; CRYSTAL-STRUCTURES; BINDING; CAMPTOTHECIN; COMPLEXES; Chemistry, Multidisciplinary

    Abstract

    Topoisomerase IB (Top 1) is a key eukaryotic nuclear enzyme that regulates the topology of DNA during replication and gene transcription. Anticancer drugs that block Top1 are either well-characterized interfacial poisons or lesser-known catalytic inhibitor compounds. Here we describe a new class of cytotoxic redox-stable cationic Au3+ macrocycles which, through hierarchical cluster analysis of cytotoxicity data for the lead compound, 3, were identified as either poisons or inhibitors of Top1. Two pivotal enzyme inhibition assays prove that the compounds are true catalytic inhibitors of Top1. Inhibition of human topoisomerase 11 alpha (Top2 alpha) by 3 was 2 orders of magnitude weaker than its inhibition of Top1, confirming that 3 is a type I-specific catalytic inhibitor. Importantly, Au3+ is essential for both DNA intercalation and enzyme inhibition. Macromolecular simulations show that 3 intercalates directly at the 5'-TA-3' dinucleotide sequence targeted by Top1 via crucial electrostatic interactions, which include pi-pi stacking and an Au center dot center dot center dot O contact involving a thymine carbonyl group, resolving the ambiguity of conventional (drug binds protein) vs unconventional (drug binds substrate) catalytic inhibition of the enzyme. Surface plasmon resonance studies confirm the molecular mechanism of action elucidated by the simulations.

    Journal Title

    Journal of the American Chemical Society

    Volume

    136

    Issue/Number

    15

    Publication Date

    1-1-2014

    Document Type

    Article

    Language

    English

    First Page

    5670

    Last Page

    5682

    WOS Identifier

    WOS:000334657600032

    ISSN

    0002-7863

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