Synthesis of Aromatase Inhibitors and Dual Aromatase Steroid Sulfatase Inhibitors by Linking an Arylsulfamate Motif to 4-(4H-1,2,4-triazol-4-ylamino)benzonitrile: SAR, Crystal Structures, in vitro and in vivo Activities

ChemMedChem ◽  
2008 ◽  
Vol 3 (11) ◽  
pp. 1708-1730 ◽  
Author(s):  
Christian Bubert ◽  
L. W. Lawrence Woo ◽  
Oliver B. Sutcliffe ◽  
Mary F. Mahon ◽  
Surinder K. Chander ◽  
...  
Keyword(s):  
Crystal Structures ◽  
Aromatase Inhibitors ◽  
Steroid Sulfatase

Synthesis, in vitro and in vivo activity of benzophenone-based inhibitors of steroid sulfatase

2004 ◽  
Vol 12 (10) ◽  
pp. 2759-2772 ◽  
Author(s):  
Hatem A.M Hejaz ◽  
L.W.Lawrence Woo ◽  
Atul Purohit ◽  
Michael J Reed ◽  
Barry V.L Potter
Keyword(s):  
Steroid Sulfatase

scholarly journals Discovery of a dual inhibitor of NQO1 and GSTP1 for treating glioblastoma

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Kecheng Lei ◽  
Xiaoxia Gu ◽  
Alvaro G. Alvarado ◽  
Yuhong Du ◽  
Shilin Luo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Crystal Structures ◽  
Active Sites ◽  
Redox Homeostasis ◽  
Growth Factor Receptor ◽  
Quinone Oxidoreductase ◽  
Cancer Proliferation ◽  
Dual Inhibitor

Abstract Background Glioblastoma (GBM) is a universally lethal tumor with frequently overexpressed or mutated epidermal growth factor receptor (EGFR). NADPH quinone oxidoreductase 1 (NQO1) and glutathione-S-transferase Pi 1 (GSTP1) are commonly upregulated in GBM. NQO1 and GSTP1 decrease the formation of reactive oxygen species (ROS), which mediates the oxidative stress and promotes GBM cell proliferation. Methods High-throughput screen was used for agents selectively active against GBM cells with EGFRvIII mutations. Co-crystal structures were revealed molecular details of target recognition. Pharmacological and gene knockdown/overexpression approaches were used to investigate the oxidative stress in vitro and in vivo. Results We identified a small molecular inhibitor, “MNPC,” that binds to both NQO1 and GSTP1 with high affinity and selectivity. MNPC inhibits NQO1 and GSTP1 enzymes and induces apoptosis in GBM, specifically inhibiting the growth of cell lines and primary GBM bearing the EGFRvIII mutation. Co-crystal structures between MNPC and NQO1, and molecular docking of MNPC with GSTP1 reveal that it binds the active sites and acts as a potent dual inhibitor. Inactivation of both NQO1 and GSTP1 with siRNA or MNPC results in imbalanced redox homeostasis, leading to apoptosis and mitigated cancer proliferation in vitro and in vivo. Conclusions Thus, MNPC, a dual inhibitor for both NQO1 and GSTP1, provides a novel lead compound for treating GBM via the exploitation of specific vulnerabilities created by mutant EGFR.

Structural effects in chemistry and biology

2000 ◽  
Vol 04 (04) ◽  
pp. 382-385 ◽  
Author(s):  
JACK FAJER
Keyword(s):  
Excited State ◽  
Physicochemical Properties ◽  
Crystal Structures ◽  
Protein Complexes ◽  
Structural Effects ◽  
Conformational Variations ◽  
Prosthetic Groups ◽  
Skeletal Deformations

Conformationally designed, non-planar porphyrins afford new classes of structurally distinct chromophores with significantly altered optical, redox, magnetic, radical and excited state properties. The synthetic, non-planar porphyrins model and illustrate the consequences of the skeletal deformations and plasticity increasingly observed in crystal structures of protein complexes comprising porphyrinic chromophores and prosthetic groups. Conformational variations thus offer attractively simple mechanisms for modulating the physicochemical properties of porphyrins in vivo and in vitro.

Structure and Serotonin 5-HT2C Receptor Activity of ortho- and meta-Substituted Phenylpiperazines

1997 ◽  
Vol 53 (6) ◽  
pp. 976-983 ◽  
Author(s):  
M. L. Verdonk ◽  
J. W. Voogd ◽  
J. A. Kanters ◽  
J. Kroon ◽  
R. den Besten ◽  
...  
Keyword(s):  
Molecular Mechanics ◽  
Crystal Structures ◽  
Phenyl Ring ◽  
Structural Characteristics ◽  
Molecular Mechanics Calculations ◽  
Piperazine Ring ◽  
Energy Profiles ◽  
Nitrogen Bond

The structural characteristics of ortho- and meta-substituted phenylpiperazines have been investigated in order to understand their actions at the serotonin 5-HT2c receptor. The crystal structures of the 4-methylated analogues of two phenylpiperazines that are already known as 5-HT2c ligands, 1-(1-naphthyl)-4-methylpiperazine (1NMP) and 1-[(3-trifluoromethyl)phenyl]-4-methylpiperazine (TFMPMP), and those of two novel 5-HT2c ligands, 1-(2-methoxyphenyl)piperazine (oMPP) and 1-(3-methoxyphenyl)piperazine (mMPP), are determined. Molecular mechanics calculations are performed to calculate the energy profiles of six phenylpiperazines for rotation about the central phenyl–nitrogen bond. The activities of several phenylpiperazines, in combination with their crystal structures and conformational characteristics, lead to the hypothesis that the conformation for which the piperazine ring and the phenyl ring are approximately co-planar should be the 5-HT2c receptor `activating' conformation. This hypothesis is then used to predict the activities of the two novel 5-HT2c ligands oMPP and mMPP. oMPP is predicted to be an antagonist at this receptor, whereas mMPP is predicted to be an agonist. As this prediction was confirmed by in vitro and in vivo tests, the proposed conformation is very likely to be responsible for the activation of the 5-HT2c receptor.

Current perspectives on aromatase inhibitors in breast cancer.

1994 ◽  
Vol 12 (11) ◽  
pp. 2460-2470 ◽  
Author(s):  
P E Goss ◽  
K M Gwyn
Keyword(s):  
Breast Cancer ◽  
Aromatase Inhibitors ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Future Application ◽  
In Vivo Experiments ◽  
Estrogen Production ◽  
New Generation

PURPOSE AND DESIGN: One way to deprive hormone-dependent breast cancer of estrogen is to prevent its synthesis. This is achievable by inhibiting the aromatase cytochrome P-450 (P-450arom) enzyme complex responsible for the ultimate step in estrogen production. A new generation of specific and selective aromatase inhibitors is currently under investigation. The purpose of this review is to outline the preclinical test systems for screening these inhibitors, to summarize the preclinical and clinical data published to date, and to discuss the future application of these inhibitors in the management of breast cancer. RESULTS AND CONCLUSION: Disadvantages to the use of earlier inhibitors are described. In vitro and in vivo experiments that reflect the potency and selectivity of new inhibitors are highlighted. From preliminary clinical trials, these inhibitors appear to have excellent pharmacokinetic profiles and produce few side effects when administered orally. Activity against postmenopausal metastatic breast cancer has been demonstrated for the agents reviewed. They are all now in phase III testing to determine their relative efficacy in this setting. Their application in combination with both hormone therapy and chemotherapy, in premenopausal metastatic disease, and in the adjuvant setting in both premenopausal and postmenopausal women remains to be defined.

scholarly journals Crystal Structures of Poly(ADP-ribose) Polymerase-1 (PARP-1) Zinc Fingers Bound to DNA

2011 ◽  
Vol 286 (12) ◽  
pp. 10690-10701 ◽  
Author(s):  
Marie-France Langelier ◽  
Jamie L. Planck ◽  
Swati Roy ◽  
John M. Pascal
Keyword(s):  
Crystal Structures ◽  
Zinc Fingers ◽  
Dna Interaction ◽  
Strand Break ◽  
Structural Basis ◽  
Dna Structures ◽  
Parp 1 ◽  
Nucleotide Bases

Poly(ADP-ribose) polymerase-1 (PARP-1) has two homologous zinc finger domains, Zn1 and Zn2, that bind to a variety of DNA structures to stimulate poly(ADP-ribose) synthesis activity and to mediate PARP-1 interaction with chromatin. The structural basis for interaction with DNA is unknown, which limits our understanding of PARP-1 regulation and involvement in DNA repair and transcription. Here, we have determined crystal structures for the individual Zn1 and Zn2 domains in complex with a DNA double strand break, providing the first views of PARP-1 zinc fingers bound to DNA. The Zn1-DNA and Zn2-DNA structures establish a novel, bipartite mode of sequence-independent DNA interaction that engages a continuous region of the phosphodiester backbone and the hydrophobic faces of exposed nucleotide bases. Biochemical and cell biological analysis indicate that the Zn1 and Zn2 domains perform distinct functions. The Zn2 domain exhibits high binding affinity to DNA compared with the Zn1 domain. However, the Zn1 domain is essential for DNA-dependent PARP-1 activity in vitro and in vivo, whereas the Zn2 domain is not strictly required. Structural differences between the Zn1-DNA and Zn2-DNA complexes, combined with mutational and structural analysis, indicate that a specialized region of the Zn1 domain is re-configured through the hydrophobic interaction with exposed nucleotide bases to initiate PARP-1 activation.

scholarly journals Steroid sulfatase inhibitors for estrogen- and androgen-dependent cancers

2011 ◽  
Vol 212 (2) ◽  
pp. 99-110 ◽  
Author(s):  
Atul Purohit ◽  
Paul A Foster
Keyword(s):  
Clinical Trials ◽  
Dehydroepiandrosterone Sulfate ◽  
Biologically Active ◽  
Steroid Sulfatase ◽  
Developmental History ◽  
Estrone Sulfate ◽  
Therapy Targets ◽  
History Of

Estrogens and androgens are instrumental in the maturation of many hormone-dependent cancers. Consequently, the enzymes involved in their synthesis are cancer therapy targets. One such enzyme, steroid sulfatase (STS), hydrolyses estrone sulfate, and dehydroepiandrosterone sulfate to estrone and dehydroepiandrosterone respectively. These are the precursors to the formation of biologically active estradiol and androstenediol. This review focuses on three aspects of STS inhibitors: 1) chemical development, 2) biological activity, and 3) clinical trials. The aim is to discuss the importance of estrogens and androgens in many cancers, the developmental history of STS inhibitor synthesis, the potency of these compounds in vitro and in vivo and where we currently stand in regards to clinical trials for these drugs. STS inhibitors are likely to play an important future role in the treatment of hormone-dependent cancers. Novel in vivo models have been developed that allow pre-clinical testing of inhibitors and the identification of lead clinical candidates. Phase I/II clinical trials in postmenopausal women with breast cancer have been completed and other trials in patients with hormone-dependent prostate and endometrial cancer are currently active. Potent STS inhibitors should become therapeutically valuable in hormone-dependent cancers and other non-oncological conditions.

Inhibition of Aromatase in Vitro and in Vivo by Aromatase Inhibitors

1990 ◽  
Vol 4 (2) ◽  
pp. 179-186 ◽  
Author(s):  
A. S. Bhatnagar ◽  
A. Häusler ◽  
K. Schieweck
Keyword(s):  
Aromatase Inhibitors
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