Design of a new warhead for the natural enediyne dynemicin A. An increase of biological activity

Elfi Kraka, Tell Tuttle, Dieter Cremer

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

A concept for designing nontoxic enediyne-based antitumor drugs that was previously suggested (J. Am. Chem. Soc. 2000, 122, 8245) is converted into reality by merging amidines with the natural enediyne dynemicin A. The dynemicin-amidines (DADs) resulting from this combination are biologically not active because they form extremely labile singlet biradicals that can no longer abstract H from DNA. However, if protonated in the acidic environment of the tumor cell, they possess increased biological activity, as is reflected by a lowering of the activation enthalpy for the Bergman cyclization from 16.7 (dynemicin A) to 11 - 12 kcal/mol (DADs), kinetic stability of the singlet biradicals formed in the cyclization reaction, increased H abstraction ability of the singlet biradicals, and improved docking properties in the minor groove of the duplex 10-mer B-DNA sequence d(CTACTACTGG)·d(CCAGTAGTAG) throughout the triggering and Bergman reactions. The implications and the consequences of using DADs to exploit the differences between normal and tumor cells and to design a nontoxic antitumor drugs are discussed.

Original languageEnglish
Pages (from-to)2661-2670
Number of pages10
JournalJournal of Physical Chemistry B
Volume112
Issue number9
Early online date13 Feb 2008
DOIs
Publication statusPublished - 1 Mar 2008

Fingerprint

Enediynes
warheads
Amidines
Cyclization
activity (biology)
Bioactivity
Tumors
drugs
tumors
deoxyribonucleic acid
Cells
DNA sequences
Merging
grooves
Antineoplastic Agents
Enthalpy
DNA
enthalpy
Chemical activation
activation

Keywords

  • antitumor drugs
  • dynemicin A

Cite this

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Design of a new warhead for the natural enediyne dynemicin A. An increase of biological activity. / Kraka, Elfi; Tuttle, Tell; Cremer, Dieter.

In: Journal of Physical Chemistry B , Vol. 112, No. 9, 01.03.2008, p. 2661-2670.

Research output: Contribution to journalArticle

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