Array-based structure and gene expression relationship study of antitumor sulfonamides including N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide and N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide.

doi:10.1021/JM0201060

Paper

Array-based structure and gene expression relationship study of antitumor sulfonamides including N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide and N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide.

Published Sep 24, 2002 · T. Owa, A. Yokoi, K. Yamazaki

Journal of medicinal chemistry

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67

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1

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Abstract

Compounds from sulfonamide-focused libraries have been evaluated in cell-based antitumor screens using the COMPARE analysis with a panel of 39 human cancer cell lines and flow cytometric cell cycle analysis. Thus far, 2 (N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide (E7010)) and 3 (N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide (E7070)) have been selected from the collections as potent cell cycle inhibitors, which have progressed to clinical trials. Compound 2 is an orally active antimitotic agent disrupting tubulin polymerization, whereas compound 3 belongs to a novel class of antiproliferative agents causing a decrease in the S phase fraction along with G1 and/or G2 accumulation in various cancer cell lines. Because both compounds exhibited preliminary clinical activities in the phase I setting, we decided to examine further this series of oncolytic small molecules, particularly by using high-density oligonucleotide microarray analysis. The array data have enabled us to characterize these two classes of antitumor sulfonamides on the basis of gene expression changes, illuminating the essential pharmacophore structure and drug-sensitive cellular pathways for each class. Moreover, the dual character of 5 (N-(3-chloro-7-indolyl)-4-methoxybenzenesulfonamide (ER-67880)), resembling both 2 and 3, was revealed by array-based transcription profiling, though the 3-type profile of this molecule had not been apparent in the cell-based phenotypic screens. These results provide an example of the utility of structure and gene expression relationship studies in medicinal genomics.

In Vitro Study

Study Snapshot

Antitumor sulfonamides 2 and 3 show promising clinical activity, with structure and gene expression studies revealing essential pharmacophore structures and drug-sensitive pathways.

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

Array-based structure and gene expression relationship study of antitumor sulfonamides including N-[2-[(4-hydroxyphenyl)amino]-3-pyridinyl]-4-methoxybenzenesulfonamide and N-(3-chloro-7-indolyl)-1,4-benzenedisulfonamide.

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References

Citations

Directing group assisted rhodium-catalyzed formal C−H arylation and carbonylative arylation of arenes with aryl halides in the presence of CO

Rhodium-catalyzed formal C-H arylation and carbonylative arylation of arenes with aryl halides under 1 atm of CO provides efficient access to various bi(hetero)aryls and 7-aroyl indolines.

Identification of Novel β-Tubulin Inhibitors Using a Combined In Silico/In Vitro Approach

This study identified 11 active tubulin polymerization inhibitors using a combined in silico/in vitro approach, with two novel inhibitors showing potential as cancer therapeutic agents.

Palladium-Catalyzed Direct C-H Allylation of Indoles Derivatives with Allyltrimethylsilanes

Palladium-catalyzed cross-coupling between 2-substituted indole and allyltrimethylsilanes can produce benzindoles with allyl groups in good to high yields without fluoride anion source.

Overlaid Transcriptional and Proteome Analyses Identify Mitotic Kinesins as Important Targets of Arylsulfonamide-Mediated RBM39 Degradation

Arylsulfonamide-mediated RBM39 degradation leads to upregulation of RSRP1 and downregulation of key kinesin motor proteins KIF20A and KIF20B, potentially aiding in the assessment of potential cancer drug candidates targeting splicing factors.

Design, synthesis and biological evaluation of conformationnally-restricted analogues of E7010 as inhibitors of tubulin assembly (ITA) and vascular disrupting agents (VDA).

Indole 4j shows potential as a vascular-disrupting agent with potency against HUVEC and HIG-82 cells, and shows a vascular disrupting activity comparable to Combretastatin A4.