Bromine- and Iodine-substituted 16alpha,17alpha-dioxolane Progestins for Breast Tumor Imaging and Radiotherapy: Synthesis and Receptor Binding Affinity.
From: Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Journal of medicinal chemistry
- Publish Date: Jul 2006
- ISSN: 0022-2623
- Volume: 49
- Issue: 15
- Pages: 4737-44
- Medium: Print
- Language: English
- Citation (JAMA): Zhou Dong, Carlson Kathryn E, Katzenellenbogen John A, et al. Bromine- and Iodine-substituted 16alpha,17alpha-dioxolane Progestins for Breast Tumor Imaging and Radiotherapy: Synthesis and Receptor Binding Affinity.. J. Med. Chem. Jul 2006;49:4737-44
Abstract
Progesterone receptors (PRs) are present in many breast tumors, and their levels are increased by certain endocrine therapies. We describe the synthesis and PR binding affinities of a series of bromine- and iodine-substituted 16alpha,17alpha-dioxolane progestins, some of which, when appropriately radiolabeled, are potential agents for diagnostic imaging of PR-positive breast tumors using positron emission tomography (PET) and for radiotherapy. These compounds were synthesized from halogenated furanyl, phenyl, and thiophenyl aldehydes and a progestin 16alpha,17alpha,21-triol (5) in the presence of HClO4 or Sc(OTf)3 in high yields under optimized conditions. A new reagent, perfluoro-1-butanesulfonyl fluoride (PBSF), was used to convert the C-21 OH to F in high yields. The relative binding affinities (RBAs) of the most promising compounds for the PR (RBA of R5020 = 100) were 16alpha,17alpha-[(R)-1’-alpha-(5-bromofurylmethylidene)dioxyl]-21-hydroxy-19-norpregn-4-ene-3,20-dione (endo-6; RBA = 65 and moderate lipophilicity), 21-fluoro-16alpha,17alpha-[(R)-1’-alpha-(5-iodofurylmethylidene)dioxyl]-19-norpregn-4-ene-3,20-dione (endo-14; RBA = 40) and 21-fluoro-16alpha,17alpha-[(S)-1’-beta-(4-iodophenylmethylidene)dioxyl]-19-norpregn-4-ene-3,20-dione (exo-16; RBA = 34).
Mesh Headings (Keywords): Animals, Binding, Competitive, Breast Neoplasms, Dioxolanes, Female, Neoplasms, Hormone-Dependent, Norpregnenes, Progestins, Radioligand Assay, Rats, Receptors, Progesterone, Stereoisomerism, Structure-Activity Relationship
Check for Full Text / PubMed Unique Identifier (PMID): 16854080
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