DESIGN, SYNTHESIS, AND BIOLOGICAL EVALUATION OF ELLIPTICINE-ESTRADIOLCONJUGATES

Three ellipticine-estradiol conjugates were synthesized in an effort t o target the cytotoxicity of ellipticine to estrogen-receptor positive cells. The three conjugates were prepared with linker chains extendin g from the 17 alpha position of the estradiol to N-2 (compound 3), N-6 (compound 4), and C-9 (compound 5) positions of ellipticine. The elli pticine-estradiol conjugates were evaluated for their abilities to bin d to estrogen receptors, to inhibit topoisomerase II, and for their cy totoxicities in human cancer cell lines. Conjugates 3 and 5 displayed weak binding affinities of 0.132 and 0.303 for the estrogen receptor ( relative to estradiol = 100), while conjugate 4 did not show any detec table binding to the estrogen receptor. Compound 3 was a moderate inhi bitor of topoisomerase II (IC50 24.1 mu M), while 4 and 5 were inactiv e. Conjugate 3 was consistently more cytotoxic (GI(50) values 1-10 mu M) than compounds 4 and 5 (GI(50) values 10-100 mu M) in a variety of human cancer cell lines, None of the compounds displayed any selectivi ty for estrogen-receptor positive cell lines, which probably reflects their weak affinities for estrogen receptors.