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

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

Research output: Contribution to journalArticle

6 Citations (Scopus)

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 - 1994
Externally publishedYes

Fingerprint

Computer Graphics
Computer graphics
Ligands
Estrogen Receptor Modulators
DNA
Estrogens
Drug Design
Cell growth
Tamoxifen
Hydroxyl Radical
Tumors
Substitution reactions
Growth
Pharmaceutical Preparations
Breast Neoplasms
Technology
Stereochemistry
glutarimide
Hydrogen
Hydrolysis

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology

Cite this

Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes. / Hendry, Lawrence B.; Chu, Chung K.; Copland, John A III; Mahesh, Virendra B.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 48, No. 5-6, 1994, p. 495-505.

Research output: Contribution to journalArticle

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