ABSTRACT
CONTEXT: Resistance to conventional antiestrogens is a major cause of treatment failure and, ultimately, death in breast cancer. OBJECTIVE: The objective of the study was to identify small-molecule estrogen receptor (ER)-α antagonists that work differently from tamoxifen and other selective estrogen receptor modulators. DESIGN: Based on in silico screening of a pharmacophore database using a computed model of the BRCA1-ER-α complex (with ER-α liganded to 17ß-estradiol), we identified a candidate group of small-molecule compounds predicted to bind to a BRCA1-binding interface separate from the ligand-binding pocket and the coactivator binding site of ER-α. Among 40 candidate compounds, six inhibited estradiol-stimulated ER-α activity by at least 50% in breast carcinoma cells, with IC50 values ranging between 3 and 50 µM. These ER-α inhibitory compounds were further studied by molecular and cell biological techniques. RESULTS: The compounds strongly inhibited ER-α activity at concentrations that yielded little or no nonspecific toxicity, but they produced only a modest inhibition of progesterone receptor activity. Importantly, the compounds blocked proliferation and inhibited ER-α activity about equally well in antiestrogen-sensitive and antiestrogen-resistant breast cancer cells. Representative compounds disrupted the interaction of BRCA1 and ER-α in the cultured cells and blocked the interaction of ER-α with the estrogen response element. However, the compounds had no effect on the total cellular ER-α levels. CONCLUSIONS: These findings suggest that we have identified a new class of ER-α antagonists that work differently from conventional antiestrogens (eg, tamoxifen and fulvestrant).
Subject(s)
Estrogen Antagonists/pharmacology , Estrogen Receptor Modulators/pharmacology , Estrogen Receptor alpha/antagonists & inhibitors , Ubiquitin-Protein Ligases/metabolism , Cell Line, Tumor , Humans , Protein Binding , Selective Estrogen Receptor Modulators/pharmacology , Surface Plasmon Resonance , Tamoxifen/pharmacologyABSTRACT
A series of palmarumycin prodrugs and water-soluble analogs has been synthesized and assayed for inhibition of the thioredoxin-thioredoxin reductase system. Increased aqueous solubility led to an improved in vivo activity profile.
Subject(s)
Antineoplastic Agents/chemical synthesis , Prodrugs/chemical synthesis , Thioredoxin-Disulfide Reductase/antagonists & inhibitors , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Humans , Naphthalenes/chemistry , Naphthalenes/pharmacology , Prodrugs/pharmacology , Solubility , Spiro Compounds/chemistry , Spiro Compounds/pharmacology , Structure-Activity Relationship , Thioredoxins/antagonists & inhibitorsABSTRACT
[reaction: see text] Efficient modular synthesis of conformationally preorganized, C(3)-symmetric trilactams is reported. The allyl acetate cyclization substrate was synthesized in five steps from Garner's L-serine-derived aldehyde. After chiral ligand-mediated palladium cyclization, the resulting vinyl hydropyran was transformed into the orthogonally protected amino acids for iterative coupling. The final macrolactamization was accomplished using EDCI/HOBt or HATU/HOAt under high dilution conditions.
