Design, synthesis, and biological evaluation of ellipticine-estradiol conjugates

Three ellipticine-estradiol conjugates were synthesized in an effort to target the cytotoxicity of ellipticine to estrogen-receptor positive cells. The three conjugates were prepared with linker chains extending from the 17α position of the estradiol to N-2 (compound 3), N-6 (compound 4), and C- 9 (compound 5) positions of ellipticine. The ellipticine-estradiol conjugates were evaluated for their abilities to bind to estrogen receptors, to inhibit topoisomerase II, and for their cytotoxicities 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 detectable binding to the estrogen receptor. Compound 3 was a moderate inhibitor of topoisomerase II (IC₅₀ 24.1 μM), while 4 and 5 were inactive. Conjugate 3 was consistently more cytotoxic (GI₅₀ values 1-10 μM) than compounds 4 and 5 (GI₅₀ values 10-100 μM) in a variety of human cancer cell lines. None of the compounds displayed any selectivity for estrogen-receptor positive cell lines, which probably reflects their weak affinities for estrogen receptors.