Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Heat Shock Protein 90

Gopalsamy, Ariamala; Shi, Mengxiao; Golas, Jennifer M.; Vogan, Erik; Jacob, Jaison; Johnson, Matthew; Lee, Frederick; Nilakantan, Ramaswamy; Petersen, Roseann; Svenson, Kristin; Chopra, Rajiv; Tam, May; Wen, Yingxia; Ellingboe, John W.; Arndt, Kim; Boschelli, Frank

doi:10.1021/jm701385c

Cited by 85 publications

(53 citation statements)

References 18 publications

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“…QSAR modeling commenced by selecting a subset of 67 compounds from the total list of inhibitors [39][40][41] (1-83, Figure A, Table B under Supplementary Materials) as a training set for QSAR modeling; the remaining 16 molecules (ca. 20% of the dataset) were employed as an external test subset for validating the QSAR models.…”

Section: Qsar Modelingmentioning

confidence: 99%

Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation

Al-Sha’er

Mansi

Khanfar

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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The pharmacophoric features of the virtual cocrystallized protein of 178 Hsp90 proteins were obtained from the protein data bank and explored to generate 1260 pharmacophores evaluated using the decoy list composed of 1022 compounds. Accordingly, 51 pharmacophores were selected with high receiver operating characteristic (ROC) value for further processing. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors capable of accessing a self-consistent quantitative structure-activity relationship (QSAR) of optimal predictive potential (R The fifth generated pharmacophoric model from Hsp90 protein 2XJX (2XJX_2_05), and the forth generated cocrystallized pharmacophoric model from Hsp90 protein 4LWF (4LWF_2_04) with area under the curve AUC-ROC values 0.812 and 0.876, respectively were selected to be used as a searching tool sequentially of the National Cancer Institute (NCI) database. The captured hits were mapped based on successful hypotheses and the best predicted hits were selected. Twenty-four hits showed Hsp90 inhibition, 15 hits were measured with low micromolar IC 50 ranged from 5.0 mM to 77.1 mM

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Section: Qsar Modelingmentioning

confidence: 99%

Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation

Al-Sha’er

Mansi

Khanfar

et al. 2016

Journal of Enzyme Inhibition and Medicinal Chemistry

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show abstract

“…Chalcone is one of the major classes of natural products. It possess several biological activities such as antibacterial [1][2] , anti-fungal [3][4] and anti-tumour activities [5][6] . The pyrimidine derivatives are also known to exhibit diverse pharmacological properties such as effective bactericides and fungicides 7 .…”

Section: Introductionmentioning

confidence: 99%

Synthesis, Spectral Characterization and Antimicrobial Activities of Ethyl-2-(4-(naphthalene-1-yl)-6-phenyl- pyrimidin-2-yl amino)acetate Derivatives

2017

Chem Sci Trans

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Abstract:The novel series of ethyl-2-(4-naphthalene-1-yl)-6-phenyl pyrimidin-2-yl amino)acetate derivatives were synthesised by the condensation reactions of 4-(naphthalene-1-yl)-6-phenyl pyrimidin-2-amines reacted with chloroethyl acetate and K 2 CO 3 as a catalyst. The 4-(naphthalene-1-yl)-6-phenyl pyrimidin-2-amines were occurred by the reaction between naphthalene chalcones and guanidine nitrate in the presence of ethanolic sodium hydroxide solution. The naphthalene chalcones were synthesised from substituted aldehydes treated with 1-acetyl naphthalene. Finally the synthesised compounds were determined by elemental analysis and spectral characterizations such as FT-IR, 1 H NMR and 13 C NMR. The antimicrobial activities of the new synthesised heterocyclic compound are evaluated against gram positive, gram negative bacterial and fungal strains. The electron withdrawing chloro substituted derivative have an excellent zone of inhibition against bacterial strains.

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“…They are also useful intermediates for synthesis of natural products and biologically active compounds [4][5][6][7][8][9][10]. A variety of synthetic methods has been developed for preparation of cyclic compounds, of which the most convenient and attractive route is probably the cycloaddition of diene or dipole to alkenes [10][11].…”

Section: Introductionmentioning

confidence: 99%

Understanding the Regioselective and Molecular Mechanism of the TCE in Cycloaddtion Reaction (TCE+Cp) and Addition Reaction (TCE+HCl) using DFT calculation

Zeroual¹,

Hajbi²

2016

Can Chem Trans

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Abstract:The polar Diels-Alder (P-DA) reaction of TCE (2,3-Dicyano-but-2-enedinitrile), diene Cp, toward Bicyclo[2. 2. 1]hept-5-ene-2, 2, 3, 3-tetracarbonitrile , was theoretically studied using DFT methods at the B3LYP/ 6-31G(d) level and 6-31G(d,p) in the presence of water. Calculated relative enthalpy associated with the two feasible reactive channels indicate that this P-DA cycloaddition takes place via C2-C3 regioselectivity, furnishing a formal [4+2] P1 in excellent agreement with experimental outcomes. In the considered P-DA reaction, while C2-C3 regioselectivity can be explained using calculated Parr functions at the interacting sites of reagents. In addition, Hydrochloric acid does not react with the TCE (2,3-Dicyano-but-2-enedinitrile) due to the high activation energy of this reaction.

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Discovery of Benzisoxazoles as Potent Inhibitors of Chaperone Heat Shock Protein 90

Cited by 85 publications

References 18 publications

Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation

Discovery of new heat shock protein 90 inhibitors using virtual co-crystallized pharmacophore generation

Synthesis, Spectral Characterization and Antimicrobial Activities of Ethyl-2-(4-(naphthalene-1-yl)-6-phenyl- pyrimidin-2-yl amino)acetate Derivatives

Understanding the Regioselective and Molecular Mechanism of the TCE in Cycloaddtion Reaction (TCE+Cp) and Addition Reaction (TCE+HCl) using DFT calculation

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