Antitumor benzothiazoles. 7. Synthesis of 2-(4-acylaminophenyl)benzothiazoles and investigations into the role of acetylation in the antitumor activities of the parent amines

Chua, Mei-Sze, Shi, Dong-Fang, Wrigley, Samantha, Bradshaw, Tracey D., Hutchinson, Ian, Shaw, P. Nicholas, Barrett, David A., Stanley, Lesley A. and Stevens, Malcolm F. G. (1999) Antitumor benzothiazoles. 7. Synthesis of 2-(4-acylaminophenyl)benzothiazoles and investigations into the role of acetylation in the antitumor activities of the parent amines. Journal of Medicinal Chemistry, 42 3: 381-392. doi:10.1021/jm981076x


Author Chua, Mei-Sze
Shi, Dong-Fang
Wrigley, Samantha
Bradshaw, Tracey D.
Hutchinson, Ian
Shaw, P. Nicholas
Barrett, David A.
Stanley, Lesley A.
Stevens, Malcolm F. G.
Title Antitumor benzothiazoles. 7. Synthesis of 2-(4-acylaminophenyl)benzothiazoles and investigations into the role of acetylation in the antitumor activities of the parent amines
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 1999-02
Sub-type Article (original research)
DOI 10.1021/jm981076x
Volume 42
Issue 3
Start page 381
End page 392
Total pages 12
Place of publication Washington, DC, United States
Publisher American Chemical Society
Language eng
Abstract 2-(4-Aminophenyl)benzothiazoles display potent and selective antitumor activity against inter alia breast, ovarian, colon, and renal cell lines, but their mechanism of action, though yet to be defined, may be novel. Metabolism is suspected to play a central role in the mode of action of these benzothiazoles since drug uptake and biotransformation were observed in sensitive cell lines (e.g., breast MCF-7 and MDA 468 cells) in vitro, whereas insensitive cell lines (e.g., prostate PC 3 cells) showed negligible uptake and biotransformation. N-Acyl derivatives of the arylamines have been synthesized, and in vitro studies confirm N-acetylation and oxidation as the main metabolic transformations of 2-(4-aminophenyl)benzothiazoles. With the predominant process being dictated by the nature of the 3'-substituent. The prototype amine 3 underwent mainly N-acetylation in vitro, while 3'- substituted analogues 4 and 5 were primarily oxidized. N-Acetylation of 4 to 11 exerts a drastic dyschemotherapeutic effect in vitro, but acetylation of the halogeno congeners 5-7 gave acetylamines 12-14 which substantially retain selective antitumor activity. In vivo pharmacokinetic studies in rats confirmed rapid and exclusive N-acetylation of the 3'-methyl analogue 4, but less acetylation with the 3'-chloro analogue 5. Distinct expression patterns of N-acetyltransferase NAT1 and NAT2 have been demonstrated in our panel of cell lines.
Keyword Estrogen-receptor affinity
Tumor inhibiting activity
In-vitro
Cancer
Activation
Arylamines
Bladder
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Pharmacy Publications
 
Versions
Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 98 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 113 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Mon, 20 Dec 2010, 14:05:30 EST