Structure and stability of enediynes containing heteroatoms—a quantum chemical investigation

Abstract

Structure and stability of 12 enediynes containing N and being potential candidates for the design of new antitumor drugs are investigated at the B3LYP/6-31G(d,p) level of theory using (Z)-hex-3-ene-1,5-diyne (1) and more than 30 alkenes, alkines, amides, amidines, and cumulenes as appropriate reference molecules. 1 is found to be stabilized by 18kcal/mol due to π-delocalization. Incorporation of a N atom in position 3 of 1 destabilizes the enediyne because of a reduction of π delocalization while incorporation of the N atom in a terminal position strongly stabilizes the enediyne, and by this it is no longer useful as a starting point for the design of a new antitumor drug. Heterocumulenes are also not useful since they easily rearrange to more stable molecules. The most promising candidates for new antitumor drugs are amidines possessing two ethinyl substituents. They can be easily protonated in the weakly acidic medium of the tumor cell and should rearrange to produce biologically active biradicals.