Title
Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I
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
DOI Link
Language
English
First Page
5670
Last Page
5682
WOS Identifier
ISSN
0002-7863
Recommended Citation
"Gold(III) Macrocycles: Nucleotide-Specific Unconventional Catalytic Inhibitors of Human Topoisomerase I" (2014). Faculty Bibliography 2010s. 4967.
https://stars.library.ucf.edu/facultybib2010/4967
Comments
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