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

doi:10.1016/j.ejmech.2018.10.066

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

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41 Citations (Scopus)

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 language	English
Pages (from-to)	612-630
Number of pages	19
Journal	European Journal of Medicinal Chemistry
Volume	162
DOIs	https://doi.org/10.1016/j.ejmech.2018.10.066
Publication status	Published - Jan 15 2019

Keywords

Benzamide
Cancer
HDAC
Indoline
Tubulin

ASJC Scopus subject areas

Pharmacology
Drug Discovery
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.ejmech.2018.10.066

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@article{b165987ce366440e9ca720ade9aa379c,

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}",

note = "Funding Information: This research were supported by the Ministry of Science and Technology, Taiwan (grant no. MOST 103-2113-M-038-001-MY3 , 107-2113-M-038-001 ). Publisher Copyright: {\textcopyright} 2018",

year = "2019",

month = jan,

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 s.r.l.",

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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.

KW - Benzamide

KW - Cancer

KW - HDAC

KW - Indoline

KW - Tubulin

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ER -

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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