11β-Alkyl-Δ<sup>9</sup>-19-Nortestosterone Derivatives:  High-Affinity Ligands and Potent Partial Agonists of the Androgen Receptor

Muddana, Smita S.; Price, Aimee M.; MacBride, Megan M.; Peterson, Blake R.

doi:10.1021/jm0342515

Cited by 9 publications

(4 citation statements)

References 34 publications

(67 reference statements)

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“…Studies by Muddana et al [29] have demonstrated that instead of using the steroidal core of mifepristone towards antiandrogen design, Δ 9 -19-nortestosterone chemical structure can be used as the core backbone, thereby eliminating antiglucocorticoid activity of the derivatives (Fig. 1D).…”

Section: Resultsmentioning

confidence: 99%

Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer

Singh¹,

Gurulingappa

Anchoori

et al. 2008

The Prostate

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BACKGROUND The standard hormonal therapy with currently available antiandrogens and the leutinizing hormone releasing hormone (LHRH) analogs is not effective in the hormone-refractory stage of prostate cancer due to changes in androgen receptor (AR) signaling axis. In this refractory stage, AR continues to play a significant role in the growth of cancer cells even though the cancer cells are no longer dependent on the level of circulating androgens. METHODS A series of 11β-Δ9-19 nortestosterone compounds were designed through structure-based rationale and tested for their binding affinity against AR and glucocorticoid receptor (GR) using fluorescence polarization assays, their agonistic ability to induce AR dependent transcription using PSA-driven report gene assays, and their growth inhibitory affects against a series of AR positive (LAPC4, LNCap, and CWR22R) and negative human prostate cancer cell lines (PC3) using MTT cell proliferation assays. RESULTS This study proposes the design of novel bifunctional antiandrogens based on the conjugation of 11β and/or 7α-Δ9-19 nortestosterone class of steroidal compounds to the synthetic ligand for FK506-binding proteins. As a critical step towards the development of bifunctional antiandrogens, highly potent and AR-specific lead compounds were identified using in vitro data. The lead compounds identified in this study possessed low binding affinity for GR, indicating the absence of undesirable antiglucocorticoid activity. CONCLUSIONS The results of this study validate our drug discovery rationale based on the structural biology of AR and pave the pay for future development of bifunctional compounds in order to block AR function in hormone refractory stage of prostate cancer.

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Section: Resultsmentioning

confidence: 99%

Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer

Singh¹,

Gurulingappa

Anchoori

et al. 2008

The Prostate

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“…Alcohols 1a , 1r , 1t , 1u , 1v , 1w , 3a – 3e , 3h and 3i were purchased from Aldrich Co., Kanto Kagaku Reagent Division, Tokyo Kasei Kogyo Co., and Wako Pure Chemical Industries. Other alcohols ( 1b , 1c , 1d , 1e , 1f , 1g , 1h , 1i , 1j , 1k , 1l , 1m , 1n , 1o , 1p , 1q , 1s , 1v , 1x , 1y , 1a‐D , 3f , 3g ) and diol 5 were prepared according to the literature methods. NMR spectra were recorded on JEOL JNM‐AL400 FT‐NMR spectrometer (400 MHz for 1 H NMR and 100 MHz for 13 C NMR) and JEOL ECZ‐500 (500 MHz for 1 H NMR, 125 MHz for 13 C NMR and 470 MHz for 19 F NMR).…”

Section: Methodsmentioning

confidence: 99%

Ruthenium‐Catalyzed Dehydrogenation of Alcohols with Carbodiimide via a Hydrogen Transfer Mechanism

et al. 2020

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“…7). Along this line, studies by Muddana et al (2004) have demonstrated that instead of using the mifepristone as the core steroid backbone, D 9 -19-nortestosterone can be used as the core backbone for such 11b position analogs and Endocrine-Related Cancer (2006) 13 653-666 www.endocrinology-journals.org thereby eliminate the anti-glucocorticoid activity of the derivatives. Thus, we have used the available structural biology data to design D 9 -19-nortestosterone analogs, which should have high (i.e.…”

Section: Rationale For Cart Therapymentioning

confidence: 99%

Combinatorial androgen receptor targeted therapy for prostate cancer

Singh¹,

Uzgare²,

Litvinov³

et al. 2006

Endocr Relat Cancer

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Prostatic carcinogenesis is associated with changes in the androgen receptor (AR) axis converting it from a paracrine dependence upon stromal signaling to an autocrine-initiated signaling for proliferation and survival of prostatic cancer cells. This malignant conversion is due to gain of function changes in which the AR activates novel genomic (i.e. transcriptional) and non-genomic signaling pathways, which are not present in normal prostate epithelial cells. During further progression, additional molecular changes occur which allow these unique malignancy-dependent AR signaling pathways to be activated even in the low androgen ligand environment present following androgen ablation therapy. These signaling pathways are the result of partnering the AR with a series of other genomic (e.g. transcriptional co-activators) or non-genomic (e.g. steroid receptor co-activator (Src) kinase) signaling molecules. Thus, a combinatorial androgen receptor targeted therapy (termed CART therapy) inhibiting several points in the AR signaling cascade is needed to prevent the approximately 30,000 US males per year dying subsequent to failure of standard androgen ablation therapy. To develop such CART therapy, a series of agents targeted at specific points in the AR cascade should be used in combination with standard androgen ablative therapy to define the fewest number of agents needed to produce the maximal therapeutic antiprostate cancer effect. As an initial approach for developing such CART therapy, a variety of new agents could be combined with luteinizing hormone-releasing hormone analogs. These include: (1) 5a-reductase inhibitors to inhibit the conversion of testosterone to the more potent androgen, dihydrotestosterone; (2) geldanamycin analogs to downregulate AR protein in prostate cancer cells, (3) 'bulky' steroid analogs, which can bind to AR and prevent its partnering with other co-activators/signaling molecules, and (4) small molecule kinase inhibitors to inhibit MEK, which is activated as part of the malignant AR signaling cascade.

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11β-Alkyl-Δ⁹-19-Nortestosterone Derivatives: High-Affinity Ligands and Potent Partial Agonists of the Androgen Receptor

Cited by 9 publications

References 34 publications

Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer

Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer

Ruthenium‐Catalyzed Dehydrogenation of Alcohols with Carbodiimide via a Hydrogen Transfer Mechanism

Combinatorial androgen receptor targeted therapy for prostate cancer

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11β-Alkyl-Δ9-19-Nortestosterone Derivatives: High-Affinity Ligands and Potent Partial Agonists of the Androgen Receptor

Cited by 9 publications

References 34 publications

Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer

Rational design of novel antiandrogens for neutralizing androgen receptor function in hormone refractory prostate cancer

Ruthenium‐Catalyzed Dehydrogenation of Alcohols with Carbodiimide via a Hydrogen Transfer Mechanism

Combinatorial androgen receptor targeted therapy for prostate cancer

Contact Info

Product

Resources

About

11β-Alkyl-Δ⁹-19-Nortestosterone Derivatives: High-Affinity Ligands and Potent Partial Agonists of the Androgen Receptor