Design, Synthesis, and Biological Evaluation of Doxorubicin−Formaldehyde Conjugates Targeted to Breast Cancer Cells

• Published in: Journal of medicinal chemistry 2004-02, Vol.47 (5), p.1193-1206
• Main Authors: Burke, Patrick J, Koch, Tad H
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Binding, Competitive; Biological and medical sciences; Breast Neoplasms; Cell Division - drug effects; Cell Line; Cell Line, Tumor; Doxorubicin - chemistry; Drug Design; Drug Screening Assays, Antitumor; Drug Stability; Estrogen Receptor Modulators - chemical synthesis; Estrogen Receptor Modulators - chemistry; Estrogen Receptor Modulators - pharmacology; Female; Formaldehyde - chemistry; General aspects; Humans; Hydrolysis; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Polyethylene Glycols - chemistry; Receptors, Estrogen - drug effects; Receptors, Estrogen - metabolism; Stereoisomerism; Structure-Activity Relationship; Tamoxifen - analogs & derivatives; Tamoxifen - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm030352r

The anthracycline antitumor drug doxorubicin (DOX) has been utilized for decades as a broad-spectrum chemotherapeutic. Recent literature evidence documents the role of formaldehyde in the cytotoxic mechanism, and anthracycline−formaldehyde conjugates possess substantially enhanced activity in vitro and in vivo. Targeting a doxorubicin−formaldehyde conjugate specifically to cancer cells may provide a more efficacious chemotherapeutic. The design and 11-step synthesis of doxorubicin−formaldehyde conjugates targeted to the estrogen receptor, which is commonly overexpressed in breast cancer cells, are reported. The formaldehyde is incorporated in a masked form as an N-Mannich linkage between doxorubicin and salicylamide. The salicylamide triggering molecule, previously developed to release the doxorubicin−formaldehyde active metabolite, is tethered via derivatized ethylene glycols to an E and Z mixture of 4-hydroxytamoxifen. The targeting group, E/Z-4-hydroxytamoxifen, was selected for its ability to tightly bind the estrogen receptor and antiestrogen binding sites. The targeted doxorubicin−formaldehyde conjugates' estrogen receptor binding and in vitro growth inhibition were evaluated as a function of tether length. The lead compound, DOX-TEG-TAM, bearing a triethylene glycol tether, binds the estrogen receptor with a binding affinity of 2.5% relative to E/Z-4-hydroxytamoxifen and inhibits the growth of four breast cancer cell lines with 4-fold up to 140-fold enhanced activity relative to doxorubicin.