Attractive Through-Space S−O Interaction in the DNA-Cleaving Antitumor Antibiotic Leinamycin

Abstract

We describe here a study on the intramolecular nonbonded 1, 5-sulfur-oxygen (S-O) interaction in the antitumor antibiotic leinamycin 1. The results from density-functional theoretical and semiempirical calculations on leinamycin 1 and model systems 2-5 provide evidence for the 1,5-S-O nonbonded interaction. Our results are used to explain previous experimental data on the X-ray structure of leinamycin 1 (Hirayama, N.; Matsuzawa, E. S. Chem. Lett. 1993, 1957). The amide oxygen (O5) alters the thiosulfinate ester conformation and stabilizes the 1,2-dithiolan-3-one 1-oxide heterocycle. The attractive interaction induces S1 of leinamycin to adopt a distorted trigonal bipyramidal geometry. The magnitude of this stabilizing interaction is approximately 6 kcal/mol.