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Synthesis of irreversibly binding bicalutamide analogs for imaging studies

Publication Type : Journal Article

Publisher : Elsevier

Source : Tetrahedron Letters, 2005

Campus : Amritapuri

School : School of Biotechnology

Verified : No

Year : 2005

Abstract : Proper management of prostate cancer patients is highly dependent on the spread of the disease. High expression levels of the androgen receptor (AR) in prostate tumor offer a target for identifying cancer metastasis. We investigated the use of nonsteroidal AR ligands for receptor-mediated imaging as a diagnostic tool for prostate cancer staging. Compound S-26 [S-3-(4-fluorophenoxy)-2-hydroxy-2-methyl-N-(4-cyano-3-iodophenyl)-propionamide]was identified from a series of iodinated ether-linked derivatives of bicalutamide due to its high-AR binding affinity of 3.3 nM (which is similar to testosterone and ∼25% of the binding affinity of dihydrotestosterone) in an in vitro competitive binding assay using rat prostate cytosol. Furthermore, S-26 exhibited a greater binding affinity (Ki = 4.4 nM) in a whole-cell binding assay using COS-7 cells transfected with human AR than testosterone (Ki = 32.9 nM) and dihydrotestosterone (Ki = 45.4 nM). We also confirmed that sex hormone-binding globulin (SHBG), a plasma protein that binds steroids with high affinity, does not bind with S-26. Cotransfection studies with the estrogen, progesterone, and glucocorticoid receptor indicated that S-26 does not cross-react with other members of the steroid hormone receptor family. The nonsteroidal structure, high-AR binding affinity, specificity, and lack of binding to SHBG indicate that S-26 exhibits favorable properties for further development as an imaging agent for prostate cancer.

Cite this Research Publication : Vipin A. Nair, Suni M. Mustafa, Michael L. Mohler, Jun Yang, Leonid I. Kirkovsky, James T. Dalton and Duane D. Miller, "", Tetrahedron Letters 2005, 46, 4821-4823

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