Antitumor Benzothiazoles. 26. 2-(3,4-Dimethoxyphenyl)-5-fluorobenzothiazole (GW 610, NSC 721648), a Simple Fluorinated 2-Arylbenzothiazole, Shows Potent and Selective Inhibitory Activity against Lung, Colon, and Breast Cancer Cell Lines

Abstract

A series of new 2-phenylbenzothiazoles has been synthesized on the basis of the discovery of the potent and selective in vitro antitumor properties of 2-(3,4-dimethoxyphenyl)-5-fluorobenzothiazole (8n; GW 610, NSC 721648). Synthesis of analogues substituted in the benzothiazole ring was achieved via the reaction of o-aminothiophenol disulfides with substituted benzaldehydes under reducing conditions. Compounds were evaluated in vitro in four human cancer cell lines, and compound 8n was found to possess exquisitely potent antiproliferative activity (GI(50) < 0.1 nM for MCF-7 and MDA 468). Potent and selective activity was also observed in the NCI 60 human cancer cell line panel. Structure-activity relationships established that the compound 8n stands on a pinnacle of potent activity, with most structural variations having a deactivating in vitro effect. Mechanistically, this new series of agents contrasts with the previously reported 2-(4-aminophenyl)benzothiazoles; compound 8n is not reliant on induction of CYP1A1 expression for antitumor activity.

Synthesis and antitumor activity evaluation of new 2-(4-aminophenyl)benzothiazole derivatives bearing different heterocyclic rings

“…Compounds 3,6,8,10,11,12,16,18 and 20 were selected by NCI for 60 human tumor cell lines' anticancer screening test at single dose assay. In vitro single-dose anticancer assay was performed in full NCI 60 cell panel representing L, NSCLC, CC, CNSC, M, OC, RC, PC, and BC.…”

“…This discovery was followed by the identification of the 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495) and 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) and the evaluation of the analogue compounds with more potent and diverse activities [8][9][10][11][12][13][14] . Phortress (NSC 710305, dihydrochloride salt of the lysylamide prodrug of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203)), the fluorinated water-soluble pro-drug, which has been synthesized to address formulation and bioavailability issues related to the desired parenteral administration [15][16][17][18][19] , was then chosen for phase 1 The mechanism of action involves formation of reactive intermediates that can bind covalently to DNA and can be metabolized only by sensitive cancer cell lines 21 . Conversely, in insensitive cell lines, neither retaining nor metabolization occurs, thereby selective antitumor properties appear due through to metabolism [22][23][24][25][26] .…”

Synthesis and Antimicrobial Evaluation of Some Tricyclic Substituted benzo[h]quinazolines, benzo[h]quinolines and naphthaleno[d]thiazoles

“…Moreover, benzothiazole fused heterocyclic scaffold has been reported to have a relatively variable pharmacological effects such as antimicrobial 34 , anticancer 35,36 , anti-inflammatory 37 , β-2 adrenoceptor agonist and antidepressant activities 38 . Figure 3 depicts some of benzothiazole-containing drugs like; the sulfonamide diuretic ethoxozolmide, the antiviral and immuno-suppressive frentizole, the glutamate receptor antagonist riluzole used in treatment of amyotrophic lateral sclerosis, the anti-diabetic zopolrestat and the amyloid imaging agent thioflavin T 38 .…”

The Genus Melodinus (Apocynaceae): Chemical and Pharmacological Perspectives

“…The assay measures cell respiration and the amount of formazan produced is proportional to the number of living cells present in culture which will result in lower optical density (OD) [58].…”