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.