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 - Jan 15 2019

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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

Keywords

  • Benzamide
  • Cancer
  • HDAC
  • Indoline
  • Tubulin

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Cite this

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title = "1-Arylsulfonyl indoline-benzamides as a new antitubulin agents, with inhibition of histone deacetylase",
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.",
keywords = "Benzamide, Cancer, HDAC, Indoline, Tubulin",
author = "Lai, {Mei Jung} and Ritu Ojha and Lin, {Mei Hsiang} and Liu, {Yi Min} and Lee, {Hsueh Yun} and Lin, {Tony Eight} and Hsu, {Kai Cheng} and Chang, {Chi Yen} and Chen, {Mei Chuan} and Kunal Nepali and Chang, {Jang Yang} and Liou, {Jing Ping}",
year = "2019",
month = "1",
day = "15",
doi = "10.1016/j.ejmech.2018.10.066",
language = "English",
volume = "162",
pages = "612--630",
journal = "European Journal of Medicinal Chemistry",
issn = "0223-5234",
publisher = "Elsevier Masson SAS",

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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

Y1 - 2019/1/15

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.

AB - 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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KW - Cancer

KW - HDAC

KW - Indoline

KW - Tubulin

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