Antitumor Benzothiazoles. 7. Synthesis of 2-(4-Acylaminophenyl)benzothiazoles and Investigations into the Role of Acetylation in the Antitumor Activities of the Parent Amines

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.

Aryl Hydrocarbon Receptor Mediates Sensitivity of MCF-7 Breast Cancer Cells to Antitumor Agent 2-(4-Amino-3-methylphenyl) Benzothiazole

“…2B). This dose-response relationship was concordant with the previously published (Bradshaw et al, 1998b;Chua et al, 1999) capacity of DF 203 to inhibit proliferation of MCF-7 cells in culture.…”

The role of fluorine in medicinal chemistry

“…breast MCF-7 and MDA 468 cells) in vitro but was negligible in insensitive cell lines (e.g. prostate PC 3 cells) [10]. The initial lead compound (DF 203), however, exhibited a distinctive biphasic doseresponse relationship in sensitive breast tumour lines, where cell kill occurs at low nanomolar concentrations, followed by a proliferative response at low micromolar concentrations, known as the second growth phase [11].…”

In Vitro Activities of Position 2 Substitution-Bearing 6-Nitro- and 6-Amino-Benzothiazoles and Their Corresponding Anthranilic Acid Derivatives againstLeishmania infantumandTrichomonas vaginalis

“…Since the 1990s, various pharmacological investigations of newly synthesized benzothiazole derivatives demonstrated interesting pharmacological activities and led to the development of new medications for treating human diseases. Among the most efficient compounds, riluzole, sulfathiazole, mercapto-2-benzothiazole, and 2-(phenylsulfonyl)-benzothiazole revealed neuroprotective (1,12), anticonvulsive (14), antiallergenic, and antimicrobial (7,11,19) activities, respectively, while other derivatives such as 2-(4-aminophenyl)-benzothiazoles exhibited potent antitumoral activity (3,5), probably due to their capacity to bind with tumor-specific proteins. In contrast to other anticancer drugs, such as acridines, that have been extensively studied for their antileishmanial (8) and trypanocidal activities (8), benzothiazoles have been poorly investigated.…”