The Experts below are selected from a list of 84 Experts worldwide ranked by ideXlab platform
Xianzhong Zhang - One of the best experts on this subject based on the ideXlab platform.
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18f labeled Ethisterone derivative for progesterone receptor targeted pet imaging of breast cancer
Nuclear Medicine and Biology, 2019Co-Authors: Chenyu Peng, Rongqiang Zhuang, Lumei Huang, Hua Li, Duo Xu, Jianyang Fang, Xianzhong ZhangAbstract:Abstract Purpose A novel radiolabeled probe 1‑(17‑[ 18 F]fluoro‑3,6,9,12,15‑pentaoxaheptadecyl‑1H‑1,2,3‑triazole testosterone ([ 18 F]FPTT) was synthesized and evaluated for PET imaging of progesterone receptor (PR)-positive breast cancer. Methods The ethinyl group of Ethisterone, a PR targeting pharmacophore, was coupled with azide modified PEG-OTs by click chemistry to obtain the labeling precursor. The final [ 18 F]FPTT was synthesized by a one-step nucleophilic substitution reaction with 18 F. The in vitro stabilities of [ 18 F]FPTT in saline or rat serum were determined after 2 h incubation. Then the in vitro cell binding, ex vivo biodistribution and in vivo imaging of [ 18 F]FPTT were further investigated to evaluate the PR targeting ability and feasibility for the diagnosis of PR-positive breast cancer with PET imaging. Results [ 18 F]FPTT was obtained in high decay-corrected radiochemical yield (78 ± 9%) at the end of synthesis. It had high radiochemical purity (>98%) after HPLC purification and good in vitro stability. The molar activity of [ 18 F]FPTT was calculated as 17 GBq/μmol. The microPET imaging of [ 18 F]FPTT in tumor-bearing mice showed much higher tumor uptake in PR-positive MCF-7 tumor (3.9 ± 0.20%ID/g) than that of PR-negative MDA-MB-231 tumor (1.3 ± 0.08%ID/g). The high MCF-7 tumor uptake could be specifically inhibited by blocking with Ethisterone (1.3 ± 0.11%ID/g) or [ 19 F]FPTT (2.20 ± 0.17%ID/g), respectively. The biodistribution in estrogen-primed female SD rats of [ 18 F]FPTT showed high uterus and ovary uptakes (8.31 ± 1.74%ID/g and 3.79 ± 0.82%ID/g at 1 h post-injection). The specific uptakes of uterus and ovary in normal rats were 3.52 ± 0.29%ID/g and 3.22 ± 0.50%ID/g respectively and could be inhibited by co-injecting of Ethisterone. Conclusion A novel [ 18 F]FPTT probe based on Ethisterone modification could be a potential diagnostic agent for PR-positive breast cancer.
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synthesis and preliminary evaluation of a 18f labeled Ethisterone derivative 18f eaef for progesterone receptor targeting
Chemical Biology & Drug Design, 2017Co-Authors: Xiaowei Wu, Rongqiang Zhuang, Lumei Huang, Duo Xu, Deliang Zhang, Zijing Li, Pu Zhang, Hua Wu, Xianzhong ZhangAbstract:: To develop a novel progesterone receptor-targeting probe for positron emission tomography imaging, an Ethisterone derivative [18 F]EAEF was designed and prepared in high decay-corrected radiochemical yield (30-35%) with good radiochemical purity (>98%). [18 F]EAEF is a lipophilic tracer (logP = 0.53 ± 0.06) with very good stability in saline and serum. In the biodistribution study, high radioactivity accumulation of [18 F]EAEF were found in uterus (5.73 ± 1.83% ID/g) and ovary (4.05 ± 0.73% ID/g) at 2 hr postinjection (p.i.), which have high progesterone receptor expression after treated with estradiol, while the muscle background has very low uptake (0.50 ± 0.17% ID/g). For positron emission tomography imaging, [18 F]EAEF showed high uptake in progesterone receptor-positive MCF-7 tumor (3.15 ± 0.07% ID/g at 2 hr p.i.) with good tumor to muscle ratio (2.90), and obvious lower tumor uptakes were observed in MCF-7 with EAEF blocking (1.84 ± 0.05% ID/g at 2 hr p.i.) or in progesterone receptor-negative MDA-MB-231 tumor (1.80 ± 0.03% ID/g at 2 hr p.i.). Based on the good stability and specificity of [18 F]EAEF, it may be a good candidate for imaging progesterone receptor and worth further investigation.
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synthesis and preliminary evaluation of a 18 f labeled Ethisterone derivative 18 f eaef for progesterone receptor targeting
Chemical Biology & Drug Design, 2017Co-Authors: Linyi You, Rongqiang Zhuang, Lumei Huang, Deliang Zhang, Pu Zhang, Mengna Gao, Xianzhong ZhangAbstract:To develop a novel progesterone receptor-targeting probe for positron emission tomography imaging, an Ethisterone derivative [18 F]EAEF was designed and prepared in high decay-corrected radiochemical yield (30-35%) with good radiochemical purity (>98%). [18 F]EAEF is a lipophilic tracer (logP = 0.53 ± 0.06) with very good stability in saline and serum. In the biodistribution study, high radioactivity accumulation of [18 F]EAEF were found in uterus (5.73 ± 1.83% ID/g) and ovary (4.05 ± 0.73% ID/g) at 2 hr postinjection (p.i.), which have high progesterone receptor expression after treated with estradiol, while the muscle background has very low uptake (0.50 ± 0.17% ID/g). For positron emission tomography imaging, [18 F]EAEF showed high uptake in progesterone receptor-positive MCF-7 tumor (3.15 ± 0.07% ID/g at 2 hr p.i.) with good tumor to muscle ratio (2.90), and obvious lower tumor uptakes were observed in MCF-7 with EAEF blocking (1.84 ± 0.05% ID/g at 2 hr p.i.) or in progesterone receptor-negative MDA-MB-231 tumor (1.80 ± 0.03% ID/g at 2 hr p.i.). Based on the good stability and specificity of [18 F]EAEF, it may be a good candidate for imaging progesterone receptor and worth further investigation.
Miguel A Garciagaribay - One of the best experts on this subject based on the ideXlab platform.
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synthesis and solid state characterization of molecular rotors with steroidal stators Ethisterone and norEthisterone
Organic and Biomolecular Chemistry, 2010Co-Authors: Braulio Rodriguezmolina, Arturo Pozos, Ricardo Cruz, Margarita Romero, Blas Flores, Noberto Farfan, Rosa Santillan, Miguel A GarciagaribayAbstract:In this article we describe the synthesis and dynamic behavior of two new molecular rotors with 1,4-diethynylphenylene rotators axially linked to two conformationally rigid steroidal norEthisterone acetate or Ethisterone frames. The resulting 1,4-bis(19-nor-17α-ethynyltestosterone-17β-acetate)benzene (1) and 1,4-bis(17α-ethynyltestosterone)benzene (2) were fully characterized in solution and in the solid state, and the rotational dynamics of the central phenylene were explored with the help of 13C NMR with cross polarization and magic angle spinning (CPMAS), and with quadrupolar echo variable temperature (VT) 2H NMR in the case of 1. Splitting of signals from the aromatic ring on the 13C CPMAS NMR and a broad quadrupolar spin echo 2H spectrum of polycrystalline samples indicated that the rotation of the central aromatic ring in these compounds was limited at ambient temperature in the solid state. Variable temperature 2H NMR experiments at 350 K in the case of 1-d4 suggested a 2-fold rotational exchange with upper frequency limit of ca. 10 kHz. Single crystal X-ray analysis of this compound revealed that a crowded environment around the prospective phenylene rotator is responsible of the restricted rotation in the solid state.
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synthesis and solid state characterization of molecular rotors with steroidal stators Ethisterone and norEthisterone
Organic and Biomolecular Chemistry, 2010Co-Authors: Braulio Rodriguezmolina, Arturo Pozos, Margarita Romero, Blas Flores, Noberto Farfan, Rosa Santillan, Ricardo Alcantarade La Cruz, Miguel A GarciagaribayAbstract:In this article we describe the synthesis and dynamic behavior of two new molecular rotors with 1,4-diethynylphenylene rotators axially linked to two conformationally rigid steroidal norEthisterone acetate or Ethisterone frames. The resulting 1,4-bis(19-nor-17alpha-ethynyltestosterone-17beta-acetate)benzene (1) and 1,4-bis(17alpha-ethynyltestosterone)benzene (2) were fully characterized in solution and in the solid state, and the rotational dynamics of the central phenylene were explored with the help of (13)C NMR with cross polarization and magic angle spinning (CPMAS), and with quadrupolar echo variable temperature (VT) (2)H NMR in the case of 1. Splitting of signals from the aromatic ring on the (13)C CPMAS NMR and a broad quadrupolar spin echo (2)H spectrum of polycrystalline samples indicated that the rotation of the central aromatic ring in these compounds was limited at ambient temperature in the solid state. Variable temperature (2)H NMR experiments at 350 K in the case of 1-d(4) suggested a 2-fold rotational exchange with upper frequency limit of ca. 10 kHz. Single crystal X-ray analysis of this compound revealed that a crowded environment around the prospective phenylene rotator is responsible of the restricted rotation in the solid state.
Kent Kirshenbaum - One of the best experts on this subject based on the ideXlab platform.
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981 targeting androgen receptor dependent prostate cancer with multivalent Ethisterone conjugates
The Journal of Urology, 2013Co-Authors: Kent Kirshenbaum, Paul M Levine, Eugine Lee, Keren Imbergkazdan, Susan K Logan, Michael J GarabedianAbstract:INTRODUCTION AND OBJECTIVES: Prostate cells are dependent on androgens for growth and survival and thus the androgen receptor (AR) is the major therapeutic target in prostate cancer. While prostate cancers are treated with agents that inhibit androgen synthesis and modulate AR activity, the aggressive disease state called castration resistant prostate cancer (CRPC) is resistant to treatment. Studies indicate that AR itself promotes treatment resistance. Men with CRPC have a poor prognosis, suggesting that the AR directs alternate programs of gene transcription. To circumvent drug resistance, new therapeutic agents for prostate cancer should possess mechanisms of action that are distinct from those of current approaches. Our objective is to test whether multiple Ethisterone ligands conjugated to peptoid oligomers will inhibit AR activity and repress prostate cancer growth. METHODS: Using an N-substituted glycine oligomer scaffold, termed a “peptoid,” we conjugated Ethisterone, a 17 -ethynyl homologue of DHT, to peptoid side chains, and generated a set of multivalent conjugates that differed in valency, spacing and conformational ordering. Multivalent pharmacological strategies are advantageous because they enhance binding to target receptors through avidity effects. We tested these compounds for effects on AR transcriptional activity and cellular proliferation using LNCaP-abl cells, a model for CRPC. RESULTS: We identified a linear and a cyclic peptoid divalent conjugate (Fig 1) that exhibit potent and distinct anti-proliferative effects in LNCaP-abl cells. The linear compound blocks AR action by competing for androgen binding, deterring AR translocation into the nucleus, and preventing AR?s ability to activate a pro-cancer gene signature. In contrast, the cyclic conjugate, despite its inability to compete for androgen binding to AR, promotes AR nuclear localization but alters the cell cycle, causing cancer cell death. CONCLUSIONS: Our studies show that the multivalent conjugates exhibit promise as potential therapeutic agents for treatmentresistant prostate cancer.
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androgen receptor antagonism by divalent Ethisterone conjugates in castrate resistant prostate cancer cells
ACS Chemical Biology, 2012Co-Authors: Paul M Levine, Eugine Lee, Susan K Logan, Michael J Garabedian, Alex Greenfield, Richard Bonneau, Kent KirshenbaumAbstract:Sustained treatment of prostate cancer with androgen receptor (AR) antagonists can evoke drug resistance, leading to castrate-resistant disease. Elevated activity of the AR is often associated with this highly aggressive disease state. Therefore, new therapeutic regimens that target and modulate AR activity could prove beneficial. We previously introduced a versatile chemical platform to generate competitive and non-competitive multivalent peptoid oligomer conjugates that modulate AR activity. In particular, we identified a linear and a cyclic divalent Ethisterone conjugate that exhibit potent anti-proliferative properties in LNCaP-abl cells, a model of castrate-resistant prostate cancer. Here, we characterize the mechanism of action of these compounds utilizing confocal microscopy, time-resolved fluorescence resonance energy transfer, chromatin immunoprecipitation, flow cytometry, and microarray analysis. The linear conjugate competitively blocks AR action by inhibiting DNA binding. In addition, the line...
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multivalent peptidomimetic conjugates a versatile platform for modulating androgen receptor activity
Journal of the American Chemical Society, 2012Co-Authors: Paul M Levine, Michael J Garabedian, Keren Imberg, Kent KirshenbaumAbstract:We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive Ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non-competitive AR modulators with potential therapeutic significance.
Braulio Rodriguezmolina - One of the best experts on this subject based on the ideXlab platform.
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synthesis and solid state characterization of molecular rotors with steroidal stators Ethisterone and norEthisterone
Organic and Biomolecular Chemistry, 2010Co-Authors: Braulio Rodriguezmolina, Arturo Pozos, Ricardo Cruz, Margarita Romero, Blas Flores, Noberto Farfan, Rosa Santillan, Miguel A GarciagaribayAbstract:In this article we describe the synthesis and dynamic behavior of two new molecular rotors with 1,4-diethynylphenylene rotators axially linked to two conformationally rigid steroidal norEthisterone acetate or Ethisterone frames. The resulting 1,4-bis(19-nor-17α-ethynyltestosterone-17β-acetate)benzene (1) and 1,4-bis(17α-ethynyltestosterone)benzene (2) were fully characterized in solution and in the solid state, and the rotational dynamics of the central phenylene were explored with the help of 13C NMR with cross polarization and magic angle spinning (CPMAS), and with quadrupolar echo variable temperature (VT) 2H NMR in the case of 1. Splitting of signals from the aromatic ring on the 13C CPMAS NMR and a broad quadrupolar spin echo 2H spectrum of polycrystalline samples indicated that the rotation of the central aromatic ring in these compounds was limited at ambient temperature in the solid state. Variable temperature 2H NMR experiments at 350 K in the case of 1-d4 suggested a 2-fold rotational exchange with upper frequency limit of ca. 10 kHz. Single crystal X-ray analysis of this compound revealed that a crowded environment around the prospective phenylene rotator is responsible of the restricted rotation in the solid state.
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synthesis and solid state characterization of molecular rotors with steroidal stators Ethisterone and norEthisterone
Organic and Biomolecular Chemistry, 2010Co-Authors: Braulio Rodriguezmolina, Arturo Pozos, Margarita Romero, Blas Flores, Noberto Farfan, Rosa Santillan, Ricardo Alcantarade La Cruz, Miguel A GarciagaribayAbstract:In this article we describe the synthesis and dynamic behavior of two new molecular rotors with 1,4-diethynylphenylene rotators axially linked to two conformationally rigid steroidal norEthisterone acetate or Ethisterone frames. The resulting 1,4-bis(19-nor-17alpha-ethynyltestosterone-17beta-acetate)benzene (1) and 1,4-bis(17alpha-ethynyltestosterone)benzene (2) were fully characterized in solution and in the solid state, and the rotational dynamics of the central phenylene were explored with the help of (13)C NMR with cross polarization and magic angle spinning (CPMAS), and with quadrupolar echo variable temperature (VT) (2)H NMR in the case of 1. Splitting of signals from the aromatic ring on the (13)C CPMAS NMR and a broad quadrupolar spin echo (2)H spectrum of polycrystalline samples indicated that the rotation of the central aromatic ring in these compounds was limited at ambient temperature in the solid state. Variable temperature (2)H NMR experiments at 350 K in the case of 1-d(4) suggested a 2-fold rotational exchange with upper frequency limit of ca. 10 kHz. Single crystal X-ray analysis of this compound revealed that a crowded environment around the prospective phenylene rotator is responsible of the restricted rotation in the solid state.
Michael J Garabedian - One of the best experts on this subject based on the ideXlab platform.
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981 targeting androgen receptor dependent prostate cancer with multivalent Ethisterone conjugates
The Journal of Urology, 2013Co-Authors: Kent Kirshenbaum, Paul M Levine, Eugine Lee, Keren Imbergkazdan, Susan K Logan, Michael J GarabedianAbstract:INTRODUCTION AND OBJECTIVES: Prostate cells are dependent on androgens for growth and survival and thus the androgen receptor (AR) is the major therapeutic target in prostate cancer. While prostate cancers are treated with agents that inhibit androgen synthesis and modulate AR activity, the aggressive disease state called castration resistant prostate cancer (CRPC) is resistant to treatment. Studies indicate that AR itself promotes treatment resistance. Men with CRPC have a poor prognosis, suggesting that the AR directs alternate programs of gene transcription. To circumvent drug resistance, new therapeutic agents for prostate cancer should possess mechanisms of action that are distinct from those of current approaches. Our objective is to test whether multiple Ethisterone ligands conjugated to peptoid oligomers will inhibit AR activity and repress prostate cancer growth. METHODS: Using an N-substituted glycine oligomer scaffold, termed a “peptoid,” we conjugated Ethisterone, a 17 -ethynyl homologue of DHT, to peptoid side chains, and generated a set of multivalent conjugates that differed in valency, spacing and conformational ordering. Multivalent pharmacological strategies are advantageous because they enhance binding to target receptors through avidity effects. We tested these compounds for effects on AR transcriptional activity and cellular proliferation using LNCaP-abl cells, a model for CRPC. RESULTS: We identified a linear and a cyclic peptoid divalent conjugate (Fig 1) that exhibit potent and distinct anti-proliferative effects in LNCaP-abl cells. The linear compound blocks AR action by competing for androgen binding, deterring AR translocation into the nucleus, and preventing AR?s ability to activate a pro-cancer gene signature. In contrast, the cyclic conjugate, despite its inability to compete for androgen binding to AR, promotes AR nuclear localization but alters the cell cycle, causing cancer cell death. CONCLUSIONS: Our studies show that the multivalent conjugates exhibit promise as potential therapeutic agents for treatmentresistant prostate cancer.
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androgen receptor antagonism by divalent Ethisterone conjugates in castrate resistant prostate cancer cells
ACS Chemical Biology, 2012Co-Authors: Paul M Levine, Eugine Lee, Susan K Logan, Michael J Garabedian, Alex Greenfield, Richard Bonneau, Kent KirshenbaumAbstract:Sustained treatment of prostate cancer with androgen receptor (AR) antagonists can evoke drug resistance, leading to castrate-resistant disease. Elevated activity of the AR is often associated with this highly aggressive disease state. Therefore, new therapeutic regimens that target and modulate AR activity could prove beneficial. We previously introduced a versatile chemical platform to generate competitive and non-competitive multivalent peptoid oligomer conjugates that modulate AR activity. In particular, we identified a linear and a cyclic divalent Ethisterone conjugate that exhibit potent anti-proliferative properties in LNCaP-abl cells, a model of castrate-resistant prostate cancer. Here, we characterize the mechanism of action of these compounds utilizing confocal microscopy, time-resolved fluorescence resonance energy transfer, chromatin immunoprecipitation, flow cytometry, and microarray analysis. The linear conjugate competitively blocks AR action by inhibiting DNA binding. In addition, the line...
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multivalent peptidomimetic conjugates a versatile platform for modulating androgen receptor activity
Journal of the American Chemical Society, 2012Co-Authors: Paul M Levine, Michael J Garabedian, Keren Imberg, Kent KirshenbaumAbstract:We introduce a family of multivalent peptidomimetic conjugates that modulate the activity of the androgen receptor (AR). Bioactive Ethisterone ligands were conjugated to a set of sequence-specific peptoid oligomers. Certain multivalent peptoid conjugates enhance AR-mediated transcriptional activation. We identify a linear and a cyclic conjugate that exhibit potent anti-proliferative activity in LNCaP-abl cells, a model of therapy-resistant prostate cancer. The linear conjugate blocks AR action by competing for ligand binding. In contrast, the cyclic conjugate is active despite its inability to compete against endogenous ligand for binding to AR in vitro, suggesting a non-competitive mode of action. These results establish a versatile platform to design competitive and non-competitive AR modulators with potential therapeutic significance.