Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents

Jing Ping Liou, Yi Ling Chang, Fu Ming Kuo, Chun Wei Chang, Huan Yi Tseng, Chiung Chiu Wang, Yung Ning Yang, Jang Yang Chang, Shiow Ju Lee, Hsing Pang Hsieh

Research output: Contribution to journalArticle

161 Citations (Scopus)

Abstract

The synthesis and study of the structure-activity relationships of two new classes of synthetic antitubulin compounds based on 1-aroylindole and 3-aroylindole skeletons are described. Lead compounds 3, 10, and 14 displayed potent cytotoxicities with IC50 = 0.9-26 nM against human NUGC3 stomach, MKN45 stomach, MESSA uterine, A549 lung, and MCF-7 breast carcinoma cell lines. The inhibition of proliferation correlated with in vitro polymerization inhibitory activities. Structure-activity relationships revealed that 6-methoxy substitution of 3-aroylindoles and 5-methoxy substitution of 1-aroylindoles contribute to a significant extent for maximal activity by mimicking the para substitution of the methoxy group to the carbonyl group in the case of aminobenzophenones. Addition of a methyl group at the C-2 position on the indole ring exerts an increased potency. The 3,4,5-trimethoxybenzoyl moiety was necessary for better activity but not essential and can be replaced by 3,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzyl moieties. We conclude that 1- and 3-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.

Original languageEnglish
Pages (from-to)4247-4257
Number of pages11
JournalJournal of Medicinal Chemistry
Volume47
Issue number17
DOIs
Publication statusPublished - Aug 12 2004
Externally publishedYes

Fingerprint

Structure-Activity Relationship
Stomach
Substitution reactions
Skeleton
Polymerization
Inhibitory Concentration 50
Lead compounds
Oncology
Cytotoxicity
Breast Neoplasms
Cell Line
Lung
Thermodynamic properties
Cells
Neoplasms
fosbretabulin
In Vitro Techniques
Lead
indole

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents. / Liou, Jing Ping; Chang, Yi Ling; Kuo, Fu Ming; Chang, Chun Wei; Tseng, Huan Yi; Wang, Chiung Chiu; Yang, Yung Ning; Chang, Jang Yang; Lee, Shiow Ju; Hsieh, Hsing Pang.

In: Journal of Medicinal Chemistry, Vol. 47, No. 17, 12.08.2004, p. 4247-4257.

Research output: Contribution to journalArticle

Liou, Jing Ping ; Chang, Yi Ling ; Kuo, Fu Ming ; Chang, Chun Wei ; Tseng, Huan Yi ; Wang, Chiung Chiu ; Yang, Yung Ning ; Chang, Jang Yang ; Lee, Shiow Ju ; Hsieh, Hsing Pang. / Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 17. pp. 4247-4257.
@article{20f4fb12627d4a00a994746e8d41f6a3,
title = "Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents",
abstract = "The synthesis and study of the structure-activity relationships of two new classes of synthetic antitubulin compounds based on 1-aroylindole and 3-aroylindole skeletons are described. Lead compounds 3, 10, and 14 displayed potent cytotoxicities with IC50 = 0.9-26 nM against human NUGC3 stomach, MKN45 stomach, MESSA uterine, A549 lung, and MCF-7 breast carcinoma cell lines. The inhibition of proliferation correlated with in vitro polymerization inhibitory activities. Structure-activity relationships revealed that 6-methoxy substitution of 3-aroylindoles and 5-methoxy substitution of 1-aroylindoles contribute to a significant extent for maximal activity by mimicking the para substitution of the methoxy group to the carbonyl group in the case of aminobenzophenones. Addition of a methyl group at the C-2 position on the indole ring exerts an increased potency. The 3,4,5-trimethoxybenzoyl moiety was necessary for better activity but not essential and can be replaced by 3,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzyl moieties. We conclude that 1- and 3-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.",
author = "Liou, {Jing Ping} and Chang, {Yi Ling} and Kuo, {Fu Ming} and Chang, {Chun Wei} and Tseng, {Huan Yi} and Wang, {Chiung Chiu} and Yang, {Yung Ning} and Chang, {Jang Yang} and Lee, {Shiow Ju} and Hsieh, {Hsing Pang}",
year = "2004",
month = "8",
day = "12",
doi = "10.1021/jm049802l",
language = "English",
volume = "47",
pages = "4247--4257",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "17",

}

TY - JOUR

T1 - Concise synthesis and structure-activity relationships of combretastatin A-4 analogues, 1-aroylindoles and 3-aroylindoles, as novel classes of potent antitubulin agents

AU - Liou, Jing Ping

AU - Chang, Yi Ling

AU - Kuo, Fu Ming

AU - Chang, Chun Wei

AU - Tseng, Huan Yi

AU - Wang, Chiung Chiu

AU - Yang, Yung Ning

AU - Chang, Jang Yang

AU - Lee, Shiow Ju

AU - Hsieh, Hsing Pang

PY - 2004/8/12

Y1 - 2004/8/12

N2 - The synthesis and study of the structure-activity relationships of two new classes of synthetic antitubulin compounds based on 1-aroylindole and 3-aroylindole skeletons are described. Lead compounds 3, 10, and 14 displayed potent cytotoxicities with IC50 = 0.9-26 nM against human NUGC3 stomach, MKN45 stomach, MESSA uterine, A549 lung, and MCF-7 breast carcinoma cell lines. The inhibition of proliferation correlated with in vitro polymerization inhibitory activities. Structure-activity relationships revealed that 6-methoxy substitution of 3-aroylindoles and 5-methoxy substitution of 1-aroylindoles contribute to a significant extent for maximal activity by mimicking the para substitution of the methoxy group to the carbonyl group in the case of aminobenzophenones. Addition of a methyl group at the C-2 position on the indole ring exerts an increased potency. The 3,4,5-trimethoxybenzoyl moiety was necessary for better activity but not essential and can be replaced by 3,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzyl moieties. We conclude that 1- and 3-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.

AB - The synthesis and study of the structure-activity relationships of two new classes of synthetic antitubulin compounds based on 1-aroylindole and 3-aroylindole skeletons are described. Lead compounds 3, 10, and 14 displayed potent cytotoxicities with IC50 = 0.9-26 nM against human NUGC3 stomach, MKN45 stomach, MESSA uterine, A549 lung, and MCF-7 breast carcinoma cell lines. The inhibition of proliferation correlated with in vitro polymerization inhibitory activities. Structure-activity relationships revealed that 6-methoxy substitution of 3-aroylindoles and 5-methoxy substitution of 1-aroylindoles contribute to a significant extent for maximal activity by mimicking the para substitution of the methoxy group to the carbonyl group in the case of aminobenzophenones. Addition of a methyl group at the C-2 position on the indole ring exerts an increased potency. The 3,4,5-trimethoxybenzoyl moiety was necessary for better activity but not essential and can be replaced by 3,5-dimethoxybenzoyl and 3,4,5-trimethoxybenzyl moieties. We conclude that 1- and 3-aroylindoles constitute an interesting new class of antitubulin agents with the potential to be clinically developed for cancer treatment.

UR - http://www.scopus.com/inward/record.url?scp=3843136376&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=3843136376&partnerID=8YFLogxK

U2 - 10.1021/jm049802l

DO - 10.1021/jm049802l

M3 - Article

C2 - 15293996

AN - SCOPUS:3843136376

VL - 47

SP - 4247

EP - 4257

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 17

ER -