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

Lawrence B. Hendry, Chung K. Chu, John A. Copland, Virendra B. Mahesh

Research output: Contribution to journalArticle

6 Scopus citations

Abstract

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 accommodated 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.

Original languageEnglish (US)
Pages (from-to)495-505
Number of pages11
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume48
Issue number5-6
DOIs
StatePublished - Apr 1994

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Endocrinology
  • Clinical Biochemistry
  • Cell Biology

Fingerprint Dive into the research topics of 'Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes'. Together they form a unique fingerprint.

  • Cite this