Balachandran, R and Hopkins, TD and Thomas, CA and Wipf, P and Day, BW
(2008)
Tubulin-perturbing naphthoquinone spiroketals.
Chemical Biology and Drug Design, 71 (2).
117 - 124.
ISSN 1747-0277
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Abstract
Several natural and synthetic naphthoquinone spiroketals are potent inhibitors of the thioredoxin-thioredoxin reductase redox system. Based on the antimitotic and weak antitubulin actions noted for SR-7 ([8-(furan-3-ylmethoxy)- 1-oxo-1,4-dihydronaphthalene-4-spiro-2′-naphtho[1″,8″-de] [1′,3′][dioxin]), a library of related compounds was screened for tubulin-perturbing properties. Two compounds, TH-169 (5′-hydroxy- 4′H-spiro[1,3-dioxolane-2,1′-naphthalen]-4′-one) and TH-223 (5′-methoxy-4′H-spiro[1,3-dioxane-2,1′-naphthalen] -4′-one), had substantial effects on tubulin assembly and were antiproliferative at low micromolar concentrations. TH-169 was the most potent at blocking GTP-dependent polymerization of 10 μm tubulin in vitro with a remarkable 50% inhibitory concentration of ca. 400 nm. It had no effect on paclitaxel-induced microtubule assembly and did not cause microtubule hypernucleation. TH-169 failed to compete with colchicine for binding to β-tubulin. The 50% antiproliferative concentration of TH-169 against human cancer cells was at or slightly below 1 μm. Flow cytometry showed that 1 μm TH-169 caused an increase in G2/M and hypodiploid cells. TH-169 eliminated the PC-3 cells' polyploid population and increased their expression of p21WAF1 and Hsp70 in a concentration-dependent manner. The antiproliferative effect of TH-169 was irreversible and independent of changes in caspases, actin, tubulin, glyceraldehyde phosphate dehydrogenase or Bcl-xS/L. This structurally simple naphthoquinone spiroketal represents a small molecule, tubulin-interactive agent with a novel apoptotic pathway and attractive biological function. © 2008 The Authors.
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Item Type: |
Article
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Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID ![](/images/orcid_id_24x24.png) |
---|
Balachandran, R | | | | Hopkins, TD | | | | Thomas, CA | | | | Wipf, P | pwipf@pitt.edu | PWIPF | | Day, BW | | | |
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Date: |
1 February 2008 |
Date Type: |
Publication |
Journal or Publication Title: |
Chemical Biology and Drug Design |
Volume: |
71 |
Number: |
2 |
Page Range: |
117 - 124 |
DOI or Unique Handle: |
10.1111/j.1747-0285.2007.00616.x |
Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
Refereed: |
Yes |
ISSN: |
1747-0277 |
MeSH Headings: |
Antineoplastic Agents--chemistry; Antineoplastic Agents--pharmacology; Apoptosis--drug effects; Cell Cycle--drug effects; Cell Line, Tumor; Cell Proliferation--drug effects; Cyclin-Dependent Kinase Inhibitor p21--genetics; Drug Screening Assays, Antitumor; Furans--pharmacology; Guanosine Triphosphate--pharmacology; HSP70 Heat-Shock Proteins--genetics; Humans; Naphthoquinones--pharmacology; Paclitaxel--pharmacology; Spiro Compounds--pharmacology; Tubulin--drug effects; Up-Regulation |
PubMed ID: |
18194192 |
Date Deposited: |
22 Jul 2013 18:26 |
Last Modified: |
13 Jun 2021 00:55 |
URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/19347 |
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