Cossy, J and Belotti, D and Brisson, M and Skoko, JJ and Wipf, P and Lazo, JS
(2006)
Biological evaluation of newly synthesized quinoline-5,8-quinones as Cdc25B inhibitors.
Bioorganic and Medicinal Chemistry, 14 (18).
6283 - 6287.
ISSN 0968-0896
![[img]](http://d-scholarship-dev.library.pitt.edu/style/images/fileicons/text_plain.png) |
Plain Text (licence)
Available under License : See the attached license file.
Download (1kB)
|
Abstract
Cdc25B protein phosphatase represents an attractive potential therapeutic target for small molecule intervention because of its central role in positively regulating cyclin dependent kinases and thus cell proliferation, as well as its elevated levels observed in many human tumors. Among the most potent previously identified Cdc25 inhibitors have been quinoline quinones, which have a rich legacy as therapeutic agents but have also been associated with nonspecific interactions. In this study, we have interrogated the structure-activity relationship of a focused series of C2-, C3-, or C4-modified quinoline-5,8-quinones on Cdc25B inhibition in vitro. Substitution at the C3-position in this small chemical series were slightly superior to substitutions at the C3-position. For all compounds, recombinant human Cdc25B was approximately 5-fold more sensitive compared to recombinant human PTP1B. Two compounds inhibited HeLa cell growth with IC50 values of approximately 2 μM. Consistent with other para-quinones, some members of this series generated intracellular reactive oxygen species and the in vitro enzyme inhibition was mitigated by addition of reductants or catalase. These results indicate that chemical modifications on the pyridine core are tolerated, providing additional sites for future structural modification of this biologically active pharmacophore. © 2006 Elsevier Ltd. All rights reserved.
Share
Citation/Export: |
|
Social Networking: |
|
Details
Item Type: |
Article
|
Status: |
Published |
Creators/Authors: |
Creators | Email | Pitt Username | ORCID ![](/images/orcid_id_24x24.png) |
---|
Cossy, J | | | | Belotti, D | | | | Brisson, M | | | | Skoko, JJ | | | | Wipf, P | pwipf@pitt.edu | PWIPF | | Lazo, JS | | | |
|
Date: |
15 September 2006 |
Date Type: |
Publication |
Journal or Publication Title: |
Bioorganic and Medicinal Chemistry |
Volume: |
14 |
Number: |
18 |
Page Range: |
6283 - 6287 |
DOI or Unique Handle: |
10.1016/j.bmc.2006.05.053 |
Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
Refereed: |
Yes |
ISSN: |
0968-0896 |
MeSH Headings: |
Cell Cycle Proteins--antagonists & inhibitors; Cell Proliferation--drug effects; Drug Screening Assays, Antitumor; Enzyme Inhibitors--chemical synthesis; Enzyme Inhibitors--chemistry; Enzyme Inhibitors--pharmacology; HeLa Cells; Humans; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases--antagonists & inhibitors; Quinolones--chemical synthesis; Quinolones--chemistry; Quinolones--pharmacology; Quinones--chemical synthesis; Quinones--chemistry; Quinones--pharmacology; Reactive Oxygen Species--metabolism; Recombinant Proteins--antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship; cdc25 Phosphatases--antagonists & inhibitors |
PubMed ID: |
16782352 |
Date Deposited: |
30 Oct 2013 16:59 |
Last Modified: |
12 Jun 2021 22:55 |
URI: |
http://d-scholarship-dev.library.pitt.edu/id/eprint/19906 |
Metrics
Monthly Views for the past 3 years
Plum Analytics
Altmetric.com
Actions (login required)
![View Item View Item](/style/images/action_view.png) |
View Item |