Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents

Mei Juan Wang, Ying Qian Liu, Ling Chu Chang, Chih Ya Wang, Yong Long Zhao, Xiao Bo Zhao, Keduo Qian, Xiang Nan, Liu Yang, Xiao Ming Yang, Hsin Yi Hung, Jai Sing Yang, Daih Huang Kuo, Masuo Goto, Susan L. Morris-Natschke, Shiow Lin Pan, Che Ming Teng, Sheng Chu Kuo, Tian Shung Wu, Yang Chang WuKuo Hsiung Lee

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.

Original languageEnglish
Pages (from-to)6008-6018
Number of pages11
JournalJournal of Medicinal Chemistry
Volume57
Issue number14
DOIs
Publication statusPublished - Jul 24 2014

Fingerprint

Camptothecin
Type I DNA Topoisomerase
irinotecan
Lethal Dose 50
Antineoplastic Agents
DNA Damage
Topoisomerase I Inhibitors
Tumor Cell Line
Heterografts
Clinical Trials

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents. / Wang, Mei Juan; Liu, Ying Qian; Chang, Ling Chu; Wang, Chih Ya; Zhao, Yong Long; Zhao, Xiao Bo; Qian, Keduo; Nan, Xiang; Yang, Liu; Yang, Xiao Ming; Hung, Hsin Yi; Yang, Jai Sing; Kuo, Daih Huang; Goto, Masuo; Morris-Natschke, Susan L.; Pan, Shiow Lin; Teng, Che Ming; Kuo, Sheng Chu; Wu, Tian Shung; Wu, Yang Chang; Lee, Kuo Hsiung.

In: Journal of Medicinal Chemistry, Vol. 57, No. 14, 24.07.2014, p. 6008-6018.

Research output: Contribution to journalArticle

Wang, MJ, Liu, YQ, Chang, LC, Wang, CY, Zhao, YL, Zhao, XB, Qian, K, Nan, X, Yang, L, Yang, XM, Hung, HY, Yang, JS, Kuo, DH, Goto, M, Morris-Natschke, SL, Pan, SL, Teng, CM, Kuo, SC, Wu, TS, Wu, YC & Lee, KH 2014, 'Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents', Journal of Medicinal Chemistry, vol. 57, no. 14, pp. 6008-6018. https://doi.org/10.1021/jm5003588
Wang, Mei Juan ; Liu, Ying Qian ; Chang, Ling Chu ; Wang, Chih Ya ; Zhao, Yong Long ; Zhao, Xiao Bo ; Qian, Keduo ; Nan, Xiang ; Yang, Liu ; Yang, Xiao Ming ; Hung, Hsin Yi ; Yang, Jai Sing ; Kuo, Daih Huang ; Goto, Masuo ; Morris-Natschke, Susan L. ; Pan, Shiow Lin ; Teng, Che Ming ; Kuo, Sheng Chu ; Wu, Tian Shung ; Wu, Yang Chang ; Lee, Kuo Hsiung. / Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents. In: Journal of Medicinal Chemistry. 2014 ; Vol. 57, No. 14. pp. 6008-6018.
@article{4a9073d586194f768074e9ac394ccc3f,
title = "Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents",
abstract = "Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.",
author = "Wang, {Mei Juan} and Liu, {Ying Qian} and Chang, {Ling Chu} and Wang, {Chih Ya} and Zhao, {Yong Long} and Zhao, {Xiao Bo} and Keduo Qian and Xiang Nan and Liu Yang and Yang, {Xiao Ming} and Hung, {Hsin Yi} and Yang, {Jai Sing} and Kuo, {Daih Huang} and Masuo Goto and Morris-Natschke, {Susan L.} and Pan, {Shiow Lin} and Teng, {Che Ming} and Kuo, {Sheng Chu} and Wu, {Tian Shung} and Wu, {Yang Chang} and Lee, {Kuo Hsiung}",
year = "2014",
month = "7",
day = "24",
doi = "10.1021/jm5003588",
language = "English",
volume = "57",
pages = "6008--6018",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "14",

}

TY - JOUR

T1 - Design, synthesis, mechanisms of action, and toxicity of novel 20(s)-sulfonylamidine derivatives of camptothecin as potent antitumor agents

AU - Wang, Mei Juan

AU - Liu, Ying Qian

AU - Chang, Ling Chu

AU - Wang, Chih Ya

AU - Zhao, Yong Long

AU - Zhao, Xiao Bo

AU - Qian, Keduo

AU - Nan, Xiang

AU - Yang, Liu

AU - Yang, Xiao Ming

AU - Hung, Hsin Yi

AU - Yang, Jai Sing

AU - Kuo, Daih Huang

AU - Goto, Masuo

AU - Morris-Natschke, Susan L.

AU - Pan, Shiow Lin

AU - Teng, Che Ming

AU - Kuo, Sheng Chu

AU - Wu, Tian Shung

AU - Wu, Yang Chang

AU - Lee, Kuo Hsiung

PY - 2014/7/24

Y1 - 2014/7/24

N2 - Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.

AB - Twelve novel 20-sulfonylamidine derivatives (9a-9l) of camptothecin (1) were synthesized via a Cu-catalyzed three-component reaction. They showed similar or superior cytotoxicity compared with that of irinotecan (3) against A-549, DU-145, KB, and multidrug-resistant (MDR) KBvin tumor cell lines. Compound 9a demonstrated better cytotoxicity against MDR cells compared with that of 1 and 3. Mechanistically, 9a induced significant DNA damage by selectively inhibiting Topoisomerase (Topo) I and activating the ATM/Chk related DNA damage-response pathway. In xenograft models, 9a demonstrated significant activity without overt adverse effects at 5 and 10 mg/kg, comparable to 3 at 100 mg/kg. Notably, 9a at 300 mg/kg (i.p.) showed no overt toxicity in contrast to 1 (LD50 56.2 mg/kg, i.p.) and 3 (LD50 177.5 mg/kg, i.p.). Intact 9a inhibited Topo I activity in a cell-free assay in a manner similar to that of 1, confirming that 9a is a new class of Topo I inhibitor. 20-Sulfonylamidine 1-derivative 9a merits development as an anticancer clinical trial candidate.

UR - http://www.scopus.com/inward/record.url?scp=84905014952&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84905014952&partnerID=8YFLogxK

U2 - 10.1021/jm5003588

DO - 10.1021/jm5003588

M3 - Article

C2 - 25003995

AN - SCOPUS:84905014952

VL - 57

SP - 6008

EP - 6018

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 14

ER -