Design of a new warhead for the natural enediyne dynemicin A. An increase of biological activity.
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.
Kraka
Elfi
E
Department of Chemistry and Department of Physics, University of the Pacific, 3601 Pacific Avenue, Stockton, California 95211-0110, USA.
Tuttle
Tell
T
Cremer
Dieter
D
D000578:Amidines / Q000737:chemistry*; D000880:Anthraquinones / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry*; D003500:Cyclization; D004247:DNA / Q000737:chemistry; D015195:Drug Design; D053281:Enediynes / Q000737:chemistry*; D005609:Free Radicals / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008956:Models, Chemical; D008958:Models, Molecular; D015394:Molecular Structure; D013816:Thermodynamics
D000578:Amidines; D000880:Anthraquinones; D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D053281:Enediynes; D005609:Free Radicals; D004247:DNA; C061229:dynemicin A