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John A Katzenellenbogen - One of the best experts on this subject based on the ideXlab platform.

  • selenophenes introducing a new element into the core of Non Steroidal Estrogen receptor ligands
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang, Haibing Zhou
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for Estrogen receptor (ER) has been well recognized. Here, we expand the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene-core and the nature of these substituents having in a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most of selenophenes exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2b), bis(4-fluoro-3-hydroxyphenyl) 3-bromoselenophene (6f), 2,3,5-tris(hydroxyphenyl)-thiophenes (8b and 8d) profiling as superagonists for ERα, but several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8c showing antiproliferative effects comparable to that of 4OHT in breast cancer MCF-7 cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.

  • Selenophenes: Introducing a New Element into the Core of Non-Steroidal Estrogen Receptor Ligands.
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the Estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2 b), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene (6 f), and 2,3,5-tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being Nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.

  • Determination of the absolute configuration of the NonSteroidal contraceptive agent centchroman by X-ray crystallography on its N-methyl iodide salt
    Bioorganic & Medicinal Chemistry Letters, 1996
    Co-Authors: Neeta Srivastava, Indra Dwivedy, Scott R. Wilson, John A Katzenellenbogen
    Abstract:

    X-ray crystallographic analysis of the N-methyl iodide salt of the d-enantiomer of the Non-Steroidal Estrogen contraceptive agent centchroman (less active) indicates that the more active l-centchroman enantiomer has a 3R,4R configuration. This confirms a prediction made by us earlier and suggests that this ligand is bound to the Estrogen receptor in a chroman/AB ring orientation relative to d-estradiol.

  • Estrogen platinum diamine complexes preparation of a Non Steroidal Estrogen platinum diamine complex labeled with platinum 191 and a study of its binding to the Estrogen receptor in vitro and its tissue distribution in vivo
    The Journal of Steroid Biochemistry and Molecular Biology, 1992
    Co-Authors: James P Dizio, Kathryn E Carlson, C J Bannochie, Michael J Welch, E Von Angerer, John A Katzenellenbogen
    Abstract:

    Abstract We have prepared in radiolabeled form (platinum-191) a Non-Steroidal Estrogen platinum—diamine complex (Pt—diamine complex) that is reported to have selective cytostatic activity in Estrogen receptor positive mouse mammary tumors. We then studied the interaction of this metal radiolabeled complex with the Estrogen receptor in vitro and its distribution in immature rats in vivo. The radiolabeled complex was prepared by incubation of the Non-Steroidal Estrogen diamine with [ 191 Pt ]( II)Cl 4 −2 (t 1 2 = 2.96 days, sp. act. 7.54 Ci/mmol ) in dimethylformamide (DMF)/H2O, followed by purification by HPLC. The final radiolabeled product coeluted with an authentic standard of the unlabeled Pt—diamine complex, with a retention time distinct from those of the precursor diamine and chloroplatinate. In competitive radiometric receptor binding assays with rat uterine Estrogen receptor, samples of the unlabeled diamine and Pt—diamine complex have apparent binding affinities of 53±3% and 32 ± 11%, respectively, relative to estradiol (RBA = 100% as standard). However, attempts to observe the binding of the 191Pt—diamine complex with the Estrogen receptor were complicated by a very high level of Non-receptor binding, an irreversible binding to proteins in the receptor preparation, and a degradation of the platinum complex that, in part, releases the diamine. As a result, it is difficult to be certain whether the binding affinity measured for the Pt—diamine complex in the competitive binding assays is due to the complex itself, or whether it arises from diamine released upon degradation of the complex. In tissue distribution studies in immature female rats, much of the 191Pt—diamine complex was deposited in the liver; there was no evidence of selective uptake of this compound by Estrogen target tissues. Thus, it is not clear, from these studies, that the observed bioactivity of this complex arises from the interaction of the Pt complex or the diamine ligand with the Estrogen receptor.

Kathryn E Carlson - One of the best experts on this subject based on the ideXlab platform.

  • selenophenes introducing a new element into the core of Non Steroidal Estrogen receptor ligands
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang, Haibing Zhou
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for Estrogen receptor (ER) has been well recognized. Here, we expand the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene-core and the nature of these substituents having in a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most of selenophenes exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2b), bis(4-fluoro-3-hydroxyphenyl) 3-bromoselenophene (6f), 2,3,5-tris(hydroxyphenyl)-thiophenes (8b and 8d) profiling as superagonists for ERα, but several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8c showing antiproliferative effects comparable to that of 4OHT in breast cancer MCF-7 cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.

  • Selenophenes: Introducing a New Element into the Core of Non-Steroidal Estrogen Receptor Ligands.
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the Estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2 b), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene (6 f), and 2,3,5-tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being Nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.

  • Estrogen platinum diamine complexes preparation of a Non Steroidal Estrogen platinum diamine complex labeled with platinum 191 and a study of its binding to the Estrogen receptor in vitro and its tissue distribution in vivo
    The Journal of Steroid Biochemistry and Molecular Biology, 1992
    Co-Authors: James P Dizio, Kathryn E Carlson, C J Bannochie, Michael J Welch, E Von Angerer, John A Katzenellenbogen
    Abstract:

    Abstract We have prepared in radiolabeled form (platinum-191) a Non-Steroidal Estrogen platinum—diamine complex (Pt—diamine complex) that is reported to have selective cytostatic activity in Estrogen receptor positive mouse mammary tumors. We then studied the interaction of this metal radiolabeled complex with the Estrogen receptor in vitro and its distribution in immature rats in vivo. The radiolabeled complex was prepared by incubation of the Non-Steroidal Estrogen diamine with [ 191 Pt ]( II)Cl 4 −2 (t 1 2 = 2.96 days, sp. act. 7.54 Ci/mmol ) in dimethylformamide (DMF)/H2O, followed by purification by HPLC. The final radiolabeled product coeluted with an authentic standard of the unlabeled Pt—diamine complex, with a retention time distinct from those of the precursor diamine and chloroplatinate. In competitive radiometric receptor binding assays with rat uterine Estrogen receptor, samples of the unlabeled diamine and Pt—diamine complex have apparent binding affinities of 53±3% and 32 ± 11%, respectively, relative to estradiol (RBA = 100% as standard). However, attempts to observe the binding of the 191Pt—diamine complex with the Estrogen receptor were complicated by a very high level of Non-receptor binding, an irreversible binding to proteins in the receptor preparation, and a degradation of the platinum complex that, in part, releases the diamine. As a result, it is difficult to be certain whether the binding affinity measured for the Pt—diamine complex in the competitive binding assays is due to the complex itself, or whether it arises from diamine released upon degradation of the complex. In tissue distribution studies in immature female rats, much of the 191Pt—diamine complex was deposited in the liver; there was no evidence of selective uptake of this compound by Estrogen target tissues. Thus, it is not clear, from these studies, that the observed bioactivity of this complex arises from the interaction of the Pt complex or the diamine ligand with the Estrogen receptor.

Haibing Zhou - One of the best experts on this subject based on the ideXlab platform.

  • selenophenes introducing a new element into the core of Non Steroidal Estrogen receptor ligands
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang, Haibing Zhou
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for Estrogen receptor (ER) has been well recognized. Here, we expand the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene-core and the nature of these substituents having in a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most of selenophenes exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2b), bis(4-fluoro-3-hydroxyphenyl) 3-bromoselenophene (6f), 2,3,5-tris(hydroxyphenyl)-thiophenes (8b and 8d) profiling as superagonists for ERα, but several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8c showing antiproliferative effects comparable to that of 4OHT in breast cancer MCF-7 cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.

Silong Zhang - One of the best experts on this subject based on the ideXlab platform.

  • selenophenes introducing a new element into the core of Non Steroidal Estrogen receptor ligands
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang, Haibing Zhou
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for Estrogen receptor (ER) has been well recognized. Here, we expand the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene-core and the nature of these substituents having in a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most of selenophenes exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2b), bis(4-fluoro-3-hydroxyphenyl) 3-bromoselenophene (6f), 2,3,5-tris(hydroxyphenyl)-thiophenes (8b and 8d) profiling as superagonists for ERα, but several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8c showing antiproliferative effects comparable to that of 4OHT in breast cancer MCF-7 cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.

  • Selenophenes: Introducing a New Element into the Core of Non-Steroidal Estrogen Receptor Ligands.
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the Estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2 b), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene (6 f), and 2,3,5-tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being Nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.

Jian Huang - One of the best experts on this subject based on the ideXlab platform.

  • selenophenes introducing a new element into the core of Non Steroidal Estrogen receptor ligands
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang, Haibing Zhou
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for Estrogen receptor (ER) has been well recognized. Here, we expand the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene-core and the nature of these substituents having in a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most of selenophenes exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2b), bis(4-fluoro-3-hydroxyphenyl) 3-bromoselenophene (6f), 2,3,5-tris(hydroxyphenyl)-thiophenes (8b and 8d) profiling as superagonists for ERα, but several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8c showing antiproliferative effects comparable to that of 4OHT in breast cancer MCF-7 cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.

  • Selenophenes: Introducing a New Element into the Core of Non-Steroidal Estrogen Receptor Ligands.
    ChemMedChem, 2017
    Co-Authors: Silong Zhang, Kathryn E Carlson, John A Katzenellenbogen, Zhiyong Wang, Zhiye Hu, Changhao Li, Chu Tang, Chune Dong, Jian Huang
    Abstract:

    The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the Estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2 b), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene (6 f), and 2,3,5-tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being Nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the Estrogen receptor.