ANTIESTROGENIC PIPERIDINEDIONES DESIGNED PROSPECTIVELY USING COMPUTER-GRAPHICS AND ENERGY CALCULATIONS OF DNA-LIGAND COMPLEXES

Drug design technology based upon DNA stereochemistry and now suppleme nted by computer modeling was used to design a novel compound to inhib it estrogen-induced tumor cell growth. A known compound 3-phenylacetyl amino-2,6-piperidinedione (PP) was accommodated in partially unwound D NA 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 calculat ions. 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 ant iestrogen than tamoxifen. Synthesis and subsequent evaluation of p-OH- PP as an inhibitor of estrogen stimulated MCF-7 (E3) human breast canc er cell growth demonstrated that p-OH-PP was more active than both PP and its hydrolysis product phenylacetylglutamine. As predicted, the or der of fit into DNA correlated with the relative ability to inhibit es trogen-induced growth of tumor cells suggesting that the evolving drug design technology will be valuable in developing new drugs for breast cancer.