title: Antiestrogenic piperidinediones designed prospectively using computer graphics and energy calculations of DNA-ligand complexes.
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 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.
authors.affiliation: Department of Physiology and Endocrinology CLW3134, Medical College of Georgia, Augusta 30912.
authors.forename: L B
authors.initials: LB
authors.lastname: Hendry
authors.forename: C K
authors.initials: CK
authors.lastname: Chu
authors.forename: J A
authors.initials: JA
authors.lastname: Copland
authors.forename: V B
authors.initials: VB
authors.lastname: Mahesh
mesh_terms: D044482:Benzeneacetamides; D001943:Breast Neoplasms / Q000473:pathology; D017076:Computer-Aided Design; D004273:DNA, Neoplasm / Q000187:drug effects*; D015195:Drug Design; D004965:Estrogen Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D010881:Piperidones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics; D014407:Tumor Cells, Cultured
chemical_list: D044482:Benzeneacetamides; D004273:DNA, Neoplasm; D004965:Estrogen Antagonists; D008024:Ligands; D010881:Piperidones; C052091:antineoplaston A10