Skip to main content
Advertisement

Main menu

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET

User menu

  • My alerts
  • Log in
  • My Cart

Search

  • Advanced search
Molecular Pharmacology
  • Other Publications
    • Drug Metabolism and Disposition
    • Journal of Pharmacology and Experimental Therapeutics
    • Molecular Pharmacology
    • Pharmacological Reviews
    • Pharmacology Research & Perspectives
    • ASPET
  • My alerts
  • Log in
  • My Cart
Molecular Pharmacology

Advanced Search

  • Home
  • Articles
    • Current Issue
    • Fast Forward
    • Latest Articles
    • Archive
  • Information
    • Instructions to Authors
    • Submit a Manuscript
    • FAQs
    • For Subscribers
    • Terms & Conditions of Use
    • Permissions
  • Editorial Board
  • Alerts
    • Alerts
    • RSS Feeds
  • Virtual Issues
  • Feedback
  • Visit molpharm on Facebook
  • Follow molpharm on Twitter
  • Follow molpharm on LinkedIn
Research ArticleArticle

DNA-Interactive Anticancer Aza-Anthrapyrazoles: Biophysical and Biochemical Studies Relevant to the Mechanism of Action

C. Sissi, S. Moro, S. Richter, B. Gatto, E. Menta, S. Spinelli, A. P. Krapcho, F. Zunino and M. Palumbo
Molecular Pharmacology January 2001, 59 (1) 96-103; DOI: https://doi.org/10.1124/mol.59.1.96
C. Sissi
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Moro
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Richter
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
B. Gatto
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
E. Menta
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
S. Spinelli
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
A. P. Krapcho
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
F. Zunino
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
M. Palumbo
1 2 3 4
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF
Loading

Abstract

The physicochemical and DNA-binding properties of anticancer 9-aza-anthrapyrazoles (9-aza-APs) were investigated and compared with the carbocyclic analogs losoxantrone (LX) and mitoxantrone (MX). Unlike their carbocyclic counterparts, the tested 9-aza-APs do not undergo self-aggregation phenomena. The pyridine nitrogen at position 9, missing in the carbocyclic derivatives, is involved in protonation equilibria at physiological pH. In addition, 9-aza-APs are electrochemically reduced at a potential intermediate between LX and MX. These data fully agree with quantum mechanical calculations. Binding to nucleic acids was examined by spectroscopic, chiroptical, and DNase I footprinting techniques as a function of ionic strength and base composition. The 9-aza-APs exhibit prominent affinity for DNA, with an important electrostatic contribution to the binding free energy. A very remarkable sequence preference pattern dramatically favors GC steps in double-helical DNA, whereas the carbocyclic reference compounds show a substantially lower selectivity for GC. A common DNA complexation geometry, considerably differing from that of MX, characterizes all anthrapyrazoles. Hence, bioisosteric substitution and ring-hydroxy deletion play an important role in defining the physicochemical properties and in modulating the affinity of anthrapyrazoles for the nucleic acid, the geometry of the intercalation complex, and the sequence specific contacts along the DNA chain. Drug stimulation of topoisomerase II-mediated DNA cleavage is remarkably attenuated in the aza-bioisosteric derivatives, suggesting that other non-enzyme-mediated cytotoxic mechanism(s), possibly connected with free radical production, are responsible for efficient cell killing. The biophysical and biochemical properties exhibited by 9-aza-APs contribute to clarifying the peculiar pharmacological profile of this family of compounds.

Footnotes

    • Received February 28, 2000.
    • Accepted October 2, 2000.
  • Send reprint requests to: Manlio Palumbo, Dept. of Pharmaceutical Sciences, University of Padova, via Marzolo 5, 35131 Padova, Italy. E-mail: mpalumbo{at}purple.dsfarm.unipd.it

  • The American Society for Pharmacology and Experimental Therapeutics
View Full Text

MolPharm articles become freely available 12 months after publication, and remain freely available for 5 years. 

Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page. 

 

  • Click here for information on institutional subscriptions.
  • Click here for information on individual ASPET membership.

 

Log in using your username and password

Forgot your user name or password?

Purchase access

You may purchase access to this article. This will require you to create an account if you don't already have one.
PreviousNext
Back to top

In this issue

Molecular Pharmacology: 59 (1)
Molecular Pharmacology
Vol. 59, Issue 1
1 Jan 2001
  • Table of Contents
  • About the Cover
  • Index by author
Download PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Molecular Pharmacology article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
DNA-Interactive Anticancer Aza-Anthrapyrazoles: Biophysical and Biochemical Studies Relevant to the Mechanism of Action
(Your Name) has forwarded a page to you from Molecular Pharmacology
(Your Name) thought you would be interested in this article in Molecular Pharmacology.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Research ArticleArticle

DNA-Interactive Anticancer Aza-Anthrapyrazoles: Biophysical and Biochemical Studies Relevant to the Mechanism of Action

C. Sissi, S. Moro, S. Richter, B. Gatto, E. Menta, S. Spinelli, A. P. Krapcho, F. Zunino and M. Palumbo
Molecular Pharmacology January 1, 2001, 59 (1) 96-103; DOI: https://doi.org/10.1124/mol.59.1.96

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Research ArticleArticle

DNA-Interactive Anticancer Aza-Anthrapyrazoles: Biophysical and Biochemical Studies Relevant to the Mechanism of Action

C. Sissi, S. Moro, S. Richter, B. Gatto, E. Menta, S. Spinelli, A. P. Krapcho, F. Zunino and M. Palumbo
Molecular Pharmacology January 1, 2001, 59 (1) 96-103; DOI: https://doi.org/10.1124/mol.59.1.96
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Experimental Procedures
    • Results
    • Discussion
    • Footnotes
    • Abbreviations
    • References
  • Figures & Data
  • Info & Metrics
  • eLetters
  • PDF

Related Articles

Cited By...

More in this TOC Section

  • 6-Methylflavone Blocks Bitterness of Tenofovir
  • Positive Allosteric Modulation of the mGlu5 Receptor
  • Correction of mutant CNGA3 channel trafficking defect
Show more Article

Similar Articles

Advertisement
  • Home
  • Alerts
Facebook   Twitter   LinkedIn   RSS

Navigate

  • Current Issue
  • Fast Forward by date
  • Fast Forward by section
  • Latest Articles
  • Archive
  • Search for Articles
  • Feedback
  • ASPET

More Information

  • About Molecular Pharmacology
  • Editorial Board
  • Instructions to Authors
  • Submit a Manuscript
  • Customized Alerts
  • RSS Feeds
  • Subscriptions
  • Permissions
  • Terms & Conditions of Use

ASPET's Other Journals

  • Drug Metabolism and Disposition
  • Journal of Pharmacology and Experimental Therapeutics
  • Pharmacological Reviews
  • Pharmacology Research & Perspectives
ISSN 1521-0111 (Online)

Copyright © 2021 by the American Society for Pharmacology and Experimental Therapeutics