Lb. Hendry et al., ANTIESTROGENIC PIPERIDINEDIONES DESIGNED PROSPECTIVELY USING COMPUTER-GRAPHICS AND ENERGY CALCULATIONS OF DNA-LIGAND COMPLEXES, Journal of steroid biochemistry and molecular biology, 48(5-6), 1994, pp. 495-505
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.