SAR studies of 4-pyridyl heterocyclic anilines that selectively induce autophagic cell death in von Hippel-Lindau-deficient renal cell carcinoma cells

Bonnet, Muriel; Flanagan, Jack U.; Chan, Denise A.; Lai, Edwin W.; Nguyen, Pauline; Giaccia, Amato J.; Hay, Michael P.

doi:10.1016/j.bmc.2011.04.042

Cited by 21 publications

(9 citation statements)

References 24 publications

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“…Moreover, the mean accuracy (AUC) of the CMap approach validated on an independent set is approximately 0.61 for antineoplastic drugs [ 28 ]. The most published QSAR-based methods for the prediction of chemical tumour cell line cytotoxicity aimed to create QSAR models for calculating the IC50 or IG50 values for the single cell line [ 13 ], cell lines belonging to an appropriate tissue [ 11 , 12 ] or without the determination of the particular cell line [ 10 ]. Only Menden and co-authors created QSAR models for 608 tumour cell lines from different tissues.…”

Section: Introductionmentioning

confidence: 99%

CLC-Pred: A freely available web-service for in silico prediction of human cell line cytotoxicity for drug-like compounds

et al. 2018

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In silico methods of phenotypic screening are necessary to reduce the time and cost of the experimental in vivo screening of anticancer agents through dozens of millions of natural and synthetic chemical compounds. We used the previously developed PASS (Prediction of Activity Spectra for Substances) algorithm to create and validate the classification SAR models for predicting the cytotoxicity of chemicals against different types of human cell lines using ChEMBL experimental data. A training set from 59,882 structures of compounds was created based on the experimental data (IG50, IC50, and % inhibition values) from ChEMBL. The average accuracy of prediction (AUC) calculated by leave-one-out and a 20-fold cross-validation procedure during the training was 0.930 and 0.927 for 278 cancer cell lines, respectively, and 0.948 and 0.947 for cytotoxicity prediction for 27 normal cell lines, respectively. Using the given SAR models, we developed a freely available web-service for cell-line cytotoxicity profile prediction (CLC-Pred: Cell-Line Cytotoxicity Predictor) based on the following structural formula: http://way2drug.com/Cell-line/.

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Section: Introductionmentioning

confidence: 99%

CLC-Pred: A freely available web-service for in silico prediction of human cell line cytotoxicity for drug-like compounds

et al. 2018

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“…14 In this instance, Click reaction of acetylene 13 with 20-azido-3,6,9,12,15,18-hexaoxaeicosan-1-amine using CuSO 4 ·5H 2 O and sodium ascorbate at room temperature, or at 40 °C, gave no product. However, addition of tris(benzyltriazolyl)amine (TBTA) ligand 18 and increased reaction temperature (60 °C) gave the triazole PAT derivative 16 in 20% yield.…”

Section: Resultsmentioning

confidence: 93%

“…2, green volume) adjacent to the pyridine ring as a potential feature for further analogue development and this feature was further explored, along with the orientation of the thiazole B-ring and the roles of the heteroatom substituents, in a subsequent study. 14 We used Suzuki–Miyaura and Sonogashira Pd-mediated cross coupling reactions and nucleophilic displacement reactions to prepare series of aryl-, alkynyl-, alkoxy- and alkylamino-substituted pyridines, respectively, to explore the steric and electronic contours adjacent to the pyridyl ring. Although we failed to improve the predictivity of the CoMFA model, we did identify several analogues with increased potency and/or selectivity to 1 .…”

Section: Molecular Designmentioning

confidence: 99%

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Identifying novel targets in renal cell carcinoma: Design and synthesis of affinity chromatography reagents

Bonnet

Flanagan

Chan

et al. 2014

Bioorganic & Medicinal Chemistry

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Two novel scaffolds, 4-pyridylanilinothiazoles (PAT) and 3-pyridylphenylsulfonyl benzamides (PPB), previously identified as selective cytotoxins for von Hippel–Lindau-deficient Renal Carcinoma cells, were used as templates to prepare affinity chromatography reagents to aid the identification of the molecular targets of these two classes. Structure–activity data and computational models were used to predict possible points of attachment for linker chains. In the PAT class, Click coupling of long chain azides with 2- and 3-pyridylanilinothiazoleacetylenes gave triazole-linked pyridylanilinothiazoles which did not retain the VHL-dependent selectivity of parent analogues. For the PPB class, Sonagashira coupling of 4-iodo-(3-pyridylphenylsulfonyl)benzamide with a propargyl hexaethylene glycol carbamate gave an acetylene which was reduced to the corresponding alkyl 3-pyridylphenylsulfonylbenzamide. This reagent retained the VHL-dependent selectivity of the parent analogues and was successfully utilized as an affinity reagent.

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“…The tert ‐butyl thioether moiety shall serve as a precursor for a sulfo group. The cross coupling proceeded smoothly under standard conditions furnishing biaryl compound 3 in 74 % yield. The thiol function was then deprotected with BBr 3 in the presence of AcCl for ease of purification.…”

Section: Resultsmentioning

confidence: 99%

Pyridine and Pyrimidine Functionalized Benzene Sulfonic and Disulfonic Acids as New Linker Compounds for Coordination Polymers

et al. 2018

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Sulfonic acids serve as interesting, yet not intensively studied alternatives to carboxylic acids as linker units in coordination polymers. In this study, we present the synthesis of hybrid sulfonic acids with pyridine and pyrimidine units as additional nitrogen donor moieties. Four biaryl compounds consisting of a 4‐mono‐ or 3,5‐disulfophenyl ring and a 4‐pyridyl or 5‐pyrimidyl residue were prepared by Suzuki coupling reaction. In these cases, tert‐butylthio groups were utilized as precursor functions for the sulfonic acid residues. The tert‐butyl residues were cleaved with BBr3, the intermediate thiols trapped with acetyl chloride and then oxidized with H2O2. Furthermore, two pyrimidine derivatives with 5‐ethynyl linkers and 4‐mono‐ and 3,5‐disulfophenyl moieties were prepared by Sonogashira coupling. In these cases, the sulfonic acids were applied as neopentyl esters. Finally, the neopentyl groups were simply cleaved by thermolysis.

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SAR studies of 4-pyridyl heterocyclic anilines that selectively induce autophagic cell death in von Hippel-Lindau-deficient renal cell carcinoma cells

Cited by 21 publications

References 24 publications

CLC-Pred: A freely available web-service for in silico prediction of human cell line cytotoxicity for drug-like compounds

CLC-Pred: A freely available web-service for in silico prediction of human cell line cytotoxicity for drug-like compounds

Identifying novel targets in renal cell carcinoma: Design and synthesis of affinity chromatography reagents

Pyridine and Pyrimidine Functionalized Benzene Sulfonic and Disulfonic Acids as New Linker Compounds for Coordination Polymers

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