title: Design, synthesis, and initial biological evaluation of a steroidal anti-estrogen-doxorubicin bioconjugate for targeting estrogen receptor-positive breast cancer cells.
abstract: As part of our program to develop breast cancer specific therapeutic agents, we have synthesized a conjugate agent that is a conjugate of the steroidal anti-estrogen and the potent cytotoxin doxorubicin. In this effort, we employed a modular assembly approach to prepare a novel 11β-substituted steroidal anti-estrogen functionalized with an azido-tetraethylene glycol moiety, which could be coupled to a complementary doxorubicin benzoyl hydrazone functionalized with a propargyl tetraethylene glycol moiety. Huisgen [3 + 2] cycloaddition chemistry gave the final hybrid that was evaluated for selective uptake and cytotoxicity in ER(+)-MCF-7 and ER(-)-MDA-MB-231 breast cancer cell lines. The results demonstrated that the presence of the anti-estrogenic component in the hybrid compound was critical for selectivity and cytotoxicity in ER(+)-MCF-7 human breast cancer cells as the hybrid was ~70-fold more potent than doxorubicin in inhibition of cell proliferation and promoting cell death.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115-5000, USA.
authors.forename: Kinh-Luan
authors.initials: KL
authors.lastname: Dao
authors.forename: Rupa R
authors.initials: RR
authors.lastname: Sawant
authors.forename: J Adam
authors.initials: JA
authors.lastname: Hendricks
authors.forename: Victoria
authors.initials: V
authors.lastname: Ronga
authors.forename: Vladimir P
authors.initials: VP
authors.lastname: Torchilin
authors.forename: Robert N
authors.initials: RN
authors.lastname: Hanson
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D004965:Estrogen Antagonists / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D058990:Molecular Targeted Therapy; D011960:Receptors, Estrogen / Q000378:metabolism*; D013256:Steroids / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D004965:Estrogen Antagonists; D011960:Receptors, Estrogen; D013256:Steroids; D004317:Doxorubicin