title: Design, synthesis, and biological evaluation of ellipticine-estradiol conjugates.
abstract: 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 17 alpha 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 microM), while 4 and 5 were inactive. Conjugate 3 was consistently more cytotoxic (GI50 values 1-10 microM) than compounds 4 and 5 (GI50 values 10-100 microM) 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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: R
authors.initials: R
authors.lastname: Devraj
authors.forename: J F
authors.initials: JF
authors.lastname: Barrett
authors.forename: J A
authors.initials: JA
authors.lastname: Fernandez
authors.forename: J A
authors.initials: JA
authors.lastname: Katzenellenbogen
authors.forename: M
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D001943:Breast Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D002470:Cell Survival / Q000187:drug effects*; D016543:Central Nervous System Neoplasms; D015195:Drug Design; D004611:Ellipticines / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D004958:Estradiol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000633:toxicity; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D007938:Leukemia; D008175:Lung Neoplasms; D008297:Male; D008545:Melanoma; D010051:Ovarian Neoplasms; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D011471:Prostatic Neoplasms; D011960:Receptors, Estrogen / Q000378:metabolism*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004611:Ellipticines; D011960:Receptors, Estrogen; D059005:Topoisomerase II Inhibitors; C034192:ellipticine; D004958:Estradiol