SOLUTION CONFORMATION OF THE ANTITUMOR DRUG STREPTONIGRIN

The solution conformation of the antitumor drug streptonigrin in THF-d8 has been determined by dynamic H-1 NMR spectroscopy (400 MHz). The major solution conformation agrees with the structure observed in the solid state [Chiu, Y.-Y.; Lipscomb, W. N. J. Am. Chem. Soc. 1975, 97, 2525-30]. Rings A, B, and C are coplanar, with ring C held in place by a hydrogen bond from the amino group on ring C and the pyridyl nitrogen in ring B. This conformation is stable in the range pH 3.9-8.9. At lower pH, the hydrogen bond is disrupted due to protonation of the pyridyl nitrogen in ring B. The major species present at pH 3.9-8.9 and 180 K is the zwitterion 1b (80%). Below 190 K, slow proton transfer between the free acid la and the zwitterion 1b is observed on the NMR time scale. Addition of a catalytic amount of base to the solution increases the rate of exchange 1a half arrow right over half arrow left 1b, and only one set of resonances is observed. In CD2Cl2 this proton transfer is not observed. Implications for the structure(s) of metal complexes formed by streptonigrin are discussed.