DESIGN OF NOVEL ANTIESTROGENS

The physicochemical principle of ''die and coin'' complementarity prof fered by Pauling and Delbruck and exemplified in Watson and Crick DNA was used to design new antineoplastic compounds. In search of an expla nation for why certain molecules and not others are present in nature, biologically active small molecules were discovered to exhibit comple mentarity when inserted into cavities between base pairs in DNA. Ligan ds in the steroid/thyroid hormone/vitamin D family fit particularly we ll into the site 5'-dTdG-3'.5'-dCdA-3'. Degree of fit of various candi date compounds in the manner of a given hormone correlated with degree of hormonal activity. Hormone antagonists fit into the same site but in a different manner than the agonists. Computer graphics and energy calculations confirmed salient observations including the remarkable c omplementarity of estradiol and DNA. Using the above criteria, a new c andidate antiestrogen, para-hydroxyphenyl-acetylamino-2,6-piperidinedi one was successfully designed. Taken as a whole, these results coupled with recent independent findings raise the possibility that the mode of action of certain hormones and hormone antagonists may involve dire ct insertion into DNA mediated by classical protein receptors and othe r transcription factors.