Stereochemical aspects of the interaction between steroidal diamines and DNA

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Abstract
A complete series of stereoisomeric quatermsed diaminoandrostanes, differing in their stereochemistry at the 3,5 and 17 positions, has been examined for effects on the thermal denaturation of calf thymus DNA and for the ability to remove and reverse the supercoiling of closed circular duplex PM2 DNA. In both types of test the eight isomers rank in the same order of effectiveness. The preferred stereochemistry for the quaternary substituents at positions 3 and 17 is β; of these the orientation of the 17-substituent is the more critical. Folding of the steroid skeleton between the A and B rings, as in 5β-androstanes, diminishes effectiveness but does not necessarily abolish the effect on supercoiling. The over-riding importance of the C-D ring end of the steroid nucleus bearing a 17β-amino substituent is confirmed by a comparison of the effects of five mono-amino androstanes. Relative helix-unwinding angles per bound steroidal diamine molecule have been determined for four of the isomers; for three 17β compounds the estimated values are similar to that previously reported for irehdiamine A. For a fourth isomer the angle is 0.22 times that of ethidium, the lowest yet determined for any DNA-binding drug. The results lend further support to the argument that intercalation can be ruled out, and alternative models for the binding mechanism are discussed.