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

Structure and stability of 12 enediynes containing N and being potential ca ndidates for the design of new antitumor drugs are investigated at the B3LY P/6-31G(d,p) level of theory using (Z)-hex-3-ene-1,5-diyne (1) and more tha n 30 alkenes, alkines, amides, amidines, and cumulenes as appropriate refer ence molecules. 1 is found to be stabilized by 18 kcal/mol due to pi-deloca lization. Incorporation of a N atom in position 3 of 1 destabilizes the ene diyne because of a reduction of pi delocalization while incorporation of th e N atom in a terminal position strongly stabilizes the enediyne, and by th is it is no longer useful as a starting point for the design of a new antit umor drag. Heterocumulenes are also not useful since they easily rearrange to more stable molecules. The most promising candidates for new antitumor d rugs are amidines possessing two ethinyl substituents. They can be easily p rotonated in the weakly acidic medium of the tumor cell and should rearrang e to produce biologically active biradicals. (C) 2000 Elsevier Science B.V. All rights reserved.