1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase

Mei Jung Lai, Ritu Ojha, Mei Hsiang Lin, Yi Min Liu, Hsueh Yun Lee, Tony Eight Lin, Kai Cheng Hsu, Chi Yen Chang, Mei Chuan Chen, Kunal Nepali, Jang-Yang Chang, Jing Ping Liou

Research output: Contribution to journalArticle

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Abstract

We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1 μM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR-positive cell lines with an IC50 value of 49 nM (KB), 79 nM (A549), 63 nM (MKN45), 64 nM (KB-VIN10), 43 nM (KB-S15), and 46 nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model.

Original languageEnglish
Pages (from-to)612-630
Number of pages19
JournalEuropean Journal of Medicinal Chemistry
Volume162
DOIs
Publication statusPublished - 2019 Jan 15

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Benzamides
Histone Deacetylases
Tubulin
Heterografts
Inhibitory Concentration 50
Cells
Amino Acids
B-Cell Lymphoma
Structure-Activity Relationship
Non-Small Cell Lung Carcinoma
Catalytic Domain
Neoplasms
Protein Isoforms
Cell Line
Molecular modeling
Tumors
indoline

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

Lai, Mei Jung ; Ojha, Ritu ; Lin, Mei Hsiang ; Liu, Yi Min ; Lee, Hsueh Yun ; Lin, Tony Eight ; Hsu, Kai Cheng ; Chang, Chi Yen ; Chen, Mei Chuan ; Nepali, Kunal ; Chang, Jang-Yang ; Liou, Jing Ping. / 1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase. In: European Journal of Medicinal Chemistry. 2019 ; Vol. 162. pp. 612-630.
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abstract = "We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1 μM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR-positive cell lines with an IC50 value of 49 nM (KB), 79 nM (A549), 63 nM (MKN45), 64 nM (KB-VIN10), 43 nM (KB-S15), and 46 nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model.",
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Lai, MJ, Ojha, R, Lin, MH, Liu, YM, Lee, HY, Lin, TE, Hsu, KC, Chang, CY, Chen, MC, Nepali, K, Chang, J-Y & Liou, JP 2019, '1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase', European Journal of Medicinal Chemistry, vol. 162, pp. 612-630. https://doi.org/10.1016/j.ejmech.2018.10.066

1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase. / Lai, Mei Jung; Ojha, Ritu; Lin, Mei Hsiang; Liu, Yi Min; Lee, Hsueh Yun; Lin, Tony Eight; Hsu, Kai Cheng; Chang, Chi Yen; Chen, Mei Chuan; Nepali, Kunal; Chang, Jang-Yang; Liou, Jing Ping.

In: European Journal of Medicinal Chemistry, Vol. 162, 15.01.2019, p. 612-630.

Research output: Contribution to journalArticle

TY - JOUR

T1 - 1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase

AU - Lai, Mei Jung

AU - Ojha, Ritu

AU - Lin, Mei Hsiang

AU - Liu, Yi Min

AU - Lee, Hsueh Yun

AU - Lin, Tony Eight

AU - Hsu, Kai Cheng

AU - Chang, Chi Yen

AU - Chen, Mei Chuan

AU - Nepali, Kunal

AU - Chang, Jang-Yang

AU - Liou, Jing Ping

PY - 2019/1/15

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N2 - We report structure-activity relationships of 1-arylsulfonyl indoline based benzamides. The benzamide (9) exhibits striking tubulin inhibition with an IC50 value of 1.1 μM, better than that of combretastain A-4 (3), and substantial antiproliferative activity against a variety of cancer cells, including MDR-positive cell lines with an IC50 value of 49 nM (KB), 79 nM (A549), 63 nM (MKN45), 64 nM (KB-VIN10), 43 nM (KB-S15), and 46 nM (KB-7D). Dual inhibitory potential of compound 9 was found as it demonstrated significant inhibitory potential against HDAC1, 2 and 6 in comparison to MS-275 (6). Some key interactions of 9 with the amino acid residues of the active site of tubulin and with amino acid residues of HDAC 1 isoform have been figured out by molecular modeling. Compound 9 also demonstrated significant in vivo efficacy in the human non-small cell lung cancer A549 xenograft model as well as B-cell lymphoma BJAB xenograft tumor model.

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