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Rational Design and Synthesis of Androgen Receptor-Targeted Nonsteroidal Anti-Androgen Ligands for the Tumor-Specific Delivery of a Doxorubicin−Formaldehyde Conjugate

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Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado 80309-0215, and Department of Pharmaceutical Sciences, University of Colorado Health Sciences Center, Denver, Colorado 80262
Cite this: J. Med. Chem. 2003, 46, 24, 5258–5270
Publication Date (Web):October 18, 2003
https://doi.org/10.1021/jm0303305
Copyright © 2003 American Chemical Society

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    Abstract

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    The synthesis and preliminary evaluation of a doxorubicin−formaldehyde conjugate tethered to the nonsteroidal antiandrogen, cyanonilutamide (RU 56279), for the treatment of prostate cancer are reported. The relative ability of the targeting group to bind to the human androgen receptor was studied as a function of tether. The tether served to attach the antiandrogen to the doxorubicin−formaldehyde conjugate via an N-Mannich base of a salicylamide derivative. The salicylamide was selected to serve as a trigger release mechanism to separate the doxorubicin−formaldehyde conjugate from the targeting group after it has bound to the androgen receptor. The remaining part of the tether consisted of a linear group that spanned from the 5-position of the salicylamide to the 3‘-position of cyanonilutamide. The structures explored for the linear region of the tether were derivatives of di(ethylene glycol), tri(ethylene glycol), N,N‘-disubstituted-piperazine, and 2-butyne-1,4-diol. Relative binding affinity of the tethers bound to the targeting group for human androgen receptor were measured using a 3H-Mibolerone competition assay and varied from 18% of nilutamide binding for the butynediol-based linear region to less than 1% for one of the piperazine derivatives. The complete targeted drug with the butynediol-based linear region has a relative binding affinity of 10%. This relative binding affinity is encouraging in light of the cocrystal structure of human androgen receptor ligand binding domain bound to the steroid Metribolone which predicts very limited space for a tether connecting the antiandrogen on the inside to the cytotoxin on the outside.

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     University of Colorado Health Sciences Center.

    *

     Corresponding author. Phone 303-492-6193, fax 303-492-5894, e-mail [email protected].

     University of Colorado.

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    1H NMR spectra for all products and isolated intermediates; semilogarithmic IC50 determinations. This material is available free of charge via the Internet at http://pubs.acs.org.

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