Design of a New Warhead for the Natural Enediyne Dynemicin A. An Increase of Biological Activity

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.

The thermal C2–C6 (Schmittel)/ene cyclization of enyne–allenes – crossing the boundary between classical and nonstatistical kinetics

“…[8][9][10] Their extraordinary reactivity and cytotoxicity have sparked considerable research and a great deal of efforts are being spent up to date to study the various factors influencing the Bergman cyclization. [11][12][13][14][15][16][17][18][19][20] In comparison with the pristine enediyne antitumor antibiotics cited above, neocarzinostatin (NCS) [21] although belonging likewise to the group of natural enediyne antitumor antibiotics contains a slightly different active chromophore, a dienediyne. [22] Like the natural enediynes, NCS shows a remarkable antitumor activity that is based on a related diradical cyclization.…”

Enediynes, enyne‐allenes, their reactions, and beyond

“…If the modifications are constrained to the warhead, the natural docking and triggering device will not be affected and can be used. In any case, one has to develop a strategy how the enediyne shall differentiate between normal and cancer cells …”

“…(ii) Also favorable is that protonated biradical 40 does not convert back to 37 at room temperature (activation enthalpy for the retro‐Bergman reaction: 27.0 kcal/mol, Table ). It would abstract an H atom from DNA, which requires 6–12 kcal/mol . (iii) The protonated biradical 40 should be strongly reactive in view of a S‐T splitting of 3.8 kcal/mol.…”

“…The first prototype of a pH‐dependent natural enediyne by replacing the enediyne moiety in dynemicin by an dialkynyl amidine warhead was suggested on the basis of QM+MM calculations . The resulting dynemicin‐amidine (DAD) is biologically not active because is forms an extremely labile singlet biradical that can no longer abstract H atoms from DNA because it rearranges immediately to a cumulene (see Figure ).…”

“…Energetics of dynemicin (blue) versus dynemicin‐amidine (DAD; purple). (Reproduced from Ref . Copyright 2008, American Chemical Society.…”