Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes

J Steroid Biochem Mol Biol. 1994 Apr;48(5-6):495-505. doi: 10.1016/0960-0760(94)90199-6.


Drug design technology based upon DNA stereochemistry and now supplemented by computer modeling was used to design a novel compound to inhibit estrogen-induced tumor cell growth. A known compound 3-phenylacetylamino-2,6-piperidinedione (PP) was accommodated in partially unwound DNA in a manner consistent with criteria for antiestrogens. Examination of the PP-DNA complex revealed that substitution of a hydroxyl group at the para position (p-OH-PP) would provide a stereospecific hydrogen bond and a substantial increase in fit as assessed by energy calculations. The antiestrogen tamoxifen could also be accomodated within the site; analogous substitution of a hydroxyl at the 4 position resulted in a better fitting molecule. 4-Hydroxytamoxifen is a more potent antiestrogen than tamoxifen. Synthesis and subsequent evaluation of p-OH-PP as an inhibitor of estrogen stimulated MCF-7 (E3) human breast cancer cell growth demonstrated that p-OH-PP was more active than both PP and its hydrolysis product phenylacetylglutamine. As predicted, the order of fit into DNA correlated with the relative ability to inhibit estrogen-induced growth of tumor cells suggesting that the evolving drug design technology will be valuable in developing new drugs for breast cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Benzeneacetamides*
  • Breast Neoplasms / pathology
  • Computer-Aided Design*
  • DNA, Neoplasm / drug effects*
  • Drug Design*
  • Estrogen Antagonists / chemical synthesis*
  • Estrogen Antagonists / pharmacology
  • Humans
  • Ligands
  • Piperidones / chemical synthesis*
  • Piperidones / chemistry
  • Piperidones / pharmacology
  • Thermodynamics
  • Tumor Cells, Cultured


  • Benzeneacetamides
  • DNA, Neoplasm
  • Estrogen Antagonists
  • Ligands
  • Piperidones
  • antineoplaston A10