3,3′-Disubstituted bipolar biphenyls as inhibitors of nuclear receptor coactivator binding

Weiser, Patrick T.; Williams, Amber; Chang, Ching‐yi; McDonnell, Donald P.; Hanson, Robert N.

doi:10.1016/j.bmcl.2012.09.007

Cited by 9 publications

(7 citation statements)

References 27 publications

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“…Elemental analyses were performed by Atlantic Microlabs, Inc. High-resolution mass spectra were obtained at the NCSU Department of Chemistry Mass Spectrometry Facility and the Duke University Department of Chemistry Mass Spectrometry Facility. Compounds 1 , 2-Ph , 6 , 8 , 16 , 21 o -iodoxybenzoic acid ( IBX ), 2,3-dimethyl-2,3-bis(hydroxyamino)butane ( BHA ), and Tp Cum·Me Zn(OH) were synthesized as previously described. Compounds 3-Ph 2 , 4-T , and 5-T 2 were prepared as outlined below.…”

Section: Methodsmentioning

confidence: 99%

Superexchange Contributions to Distance Dependence of Electron Transfer/Transport: Exchange and Electronic Coupling in Oligo(para-Phenylene)- and Oligo(2,5-Thiophene)-Bridged Donor–Bridge–Acceptor Biradical Complexes

et al. 2013

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The preparation and characterization of three new donor-bridge-acceptor biradical complexes are described. Using variable-temperature magnetic susceptibility, EPR hyperfine coupling constants, and the results of X-ray crystal structures, we evaluate both exchange and electronic couplings as a function of bridge length for two quintessential molecular bridges: oligo(para-phenylene), β = 0.39 Å(-1) and oligo(2,5-thiophene), β = 0.22 Å(-1). This report represents the first direct comparison of exchange/electronic couplings and distance attenuation parameters (β) for these bridges. The work provides a direct measurement of superexchange contributions to β, with no contribution from incoherent hopping. The different β values determined for oligo(para-phenylene) and oligo(2,5-thiophene) are due primarily to the D-B energy gap, Δ, rather than bridge-bridge electronic couplings, H(BB). This is supported by the fact that the H(BB) values extracted from the experimental data for oligo(para-phenylene) (H(BB) = 11,400 cm(-1)) and oligo(2,5-thiophene) (12,300 cm(-1)) differ by <10%. The results presented here offer unique insight into the intrinsic molecular factors that govern H(DA) and β, which are important for understanding the electronic origin of electron transfer and electron transport mediated by molecular bridges.

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Section: Methodsmentioning

confidence: 99%

Superexchange Contributions to Distance Dependence of Electron Transfer/Transport: Exchange and Electronic Coupling in Oligo(para-Phenylene)- and Oligo(2,5-Thiophene)-Bridged Donor–Bridge–Acceptor Biradical Complexes

et al. 2013

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“…The results from this study were compared with those previously reported 11,13 and the comparison provides a clearer picture of the potential of the biphenyl scaffold as the basis for co-regulatory protein inhibition. The earlier study examined a limited set of 2,2′-,2,3′-, and 3,2′-disubstituted biphenyl derivatives from which 6 compounds demonstrated significant (low μM) activity against the CBP of ER- or AR-LBP.…”

Section: Resultsmentioning

confidence: 95%

“…Furthermore, the importance of substitution pattern on the dibenzyl, as well as the dimethyl, derivative was studied. 13 The objective of our current study was to incorporate larger hydrophobic sidechains into our scaffold in an attempt to make these compounds a better fit for the hydrophobic coactivator binding pocket (CBP). The synthetic approach that we envisioned relied upon the appropriate 2-substituted-4-bromophenols.…”

Section: Introductionmentioning

confidence: 99%

4,4′-Unsymmetrically substituted 3,3′-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors

Weiser

Chang

McDonnell

et al. 2014

Bioorganic & Medicinal Chemistry

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A series of unsymmetrically substituted biphenyl compounds was designed as alpha helical proteomimetics with the aim of inhibiting the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were synthesized in good overall yields in seven steps starting from 2-bromoanisole. The final products were evaluated using cotransfection reporter gene assays and mammalian two-hybrid competitive inhibition assays to demonstrate their effectiveness as competitive binding inhibitors. The results from this study indicate that these proteomimetics possess the ability to inhibit coactivator-receptor interactions, but via a mixed mode of inhibition.

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“…Selected diarylhydrazide derivatives were found to inhibit AR coactivator recruitment by TR-FRET assay with IC 50 In another approach, Weiser et al used biaryl scaffolds to replicate the -helical rotation of the LXXLL motif backbone and display the i and i + 4 leucine side chains in the appropriate arrangement [90]. Supported by theoretical data and promising results in the design of ER CBIs using biaryl scaffolds, they designed 3,3′-disubstituted bis-4,4′oxybiphenyls to mimic the hydrophobic side chains arrangement and also the electronic interactions with the charge clamp to lock the inhibitors in place (Fig 3. 4a-d) [90][91][92][93][94].…”

Section: <Insert Figure 3 (Double Column)>mentioning

confidence: 98%

“…Supported by theoretical data and promising results in the design of ER CBIs using biaryl scaffolds, they designed 3,3′-disubstituted bis-4,4′oxybiphenyls to mimic the hydrophobic side chains arrangement and also the electronic interactions with the charge clamp to lock the inhibitors in place (Fig 3. 4a-d) [90][91][92][93][94]. A series 3,3′-disubstituted biphenyls including 4,4′-asymmetrical phenolic-ester, amino-ester and amino-acid derivatives was prepared and their ability to disrupt ER-and AR-coactivator binding evaluated in respective cell-based transactivation assays.…”

Section: <Insert Figure 3 (Double Column)>mentioning

confidence: 99%

Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

Biron

Bédard

2016

The Journal of Steroid Biochemistry and Molecular Biology

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The androgen receptor (AR) is a key regulator for the growth, differentiation and survival of prostate cancer cells. Identified as a primary target for the treatment of prostate cancer, many therapeutic strategies have been developed to attenuate AR signaling in prostate cancer cells. While frontline androgen-deprivation therapies targeting either the production or action of androgens usually yield favorable responses in prostate cancer patients, a significant number acquire treatment resistance. Known as the castration-resistant prostate cancer (CRPC), the treatment options are limited for this advanced stage. It has been shown that AR signaling is restored in CRPC due to many aberrant mechanisms such as AR mutations, amplification or expression of constitutively active splice-variants. Coregulator recruitment is a crucial regulatory step in AR signaling and the direct blockade of coactivator binding to AR offers the opportunity to develop therapeutic agents that would remain effective in prostate cancer cells resistant to conventional endocrine therapies. Structural analyses of the AR have identified key surfaces involved in protein-protein interaction with coregulators that have been recently used to design and develop promising AR-coactivator binding inhibitors. In this review we will discuss the design and development of small-molecule inhibitors targeting the AR-coactivator interactions for the treatment of prostate cancer.

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3,3′-Disubstituted bipolar biphenyls as inhibitors of nuclear receptor coactivator binding

Cited by 9 publications

References 27 publications

Superexchange Contributions to Distance Dependence of Electron Transfer/Transport: Exchange and Electronic Coupling in Oligo(para-Phenylene)- and Oligo(2,5-Thiophene)-Bridged Donor–Bridge–Acceptor Biradical Complexes

Superexchange Contributions to Distance Dependence of Electron Transfer/Transport: Exchange and Electronic Coupling in Oligo(para-Phenylene)- and Oligo(2,5-Thiophene)-Bridged Donor–Bridge–Acceptor Biradical Complexes

4,4′-Unsymmetrically substituted 3,3′-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors

Recent progress in the development of protein–protein interaction inhibitors targeting androgen receptor–coactivator binding in prostate cancer

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