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Tubulin-perturbing naphthoquinone spiroketals

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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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
Status: Published
CreatorsEmailPitt UsernameORCID
Balachandran, R
Hopkins, TD
Thomas, CA
Wipf, Ppwipf@pitt.eduPWIPF
Day, BW
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: 22 Jun 2021 13:55


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