Title

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

Authors

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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