Fluorinated 2-(4-Amino-3-Methylphenyl)benzothiazoles Induce Cyp1a1 Expression, Become Metabolized, and Bind to Macromolecules in Sensitive Human Cancer Cells

Abstract

ABSTRACT:Fluorinated 2-(4-amino-3-methylphenyl)benzothiazoles possess potent antiproliferative activity against certain cancer cells, similar to the unfluorinated 2-(4-amino-3-methylphenyl)benzothiazole (DF 203, NSC 674495). In "sensitive" cancer cells, DF 203 is metabolized by, can induce expression of, and binds covalently to CYP1A1. Metabolism appears to be essential for its antiproliferative activity through DNA adduct formation. However, a biphasic dose-response relationship compromises its straightforward development as a chemotherapeutic agent. We investigated whether fluorinated benzothiazoles inhibit cancer cell growth without the biphasic dose-response, and whether the fluorinated benzothiazoles are also metabolized into Benzothiazoles contain a benzene ring fused to a thiazole ring (Shi et al., 1996). These small molecules display antitumor properties that are modulated by substitutions at specific positions on the benzothiazole pharmacophore Kashiyama et al., 1999;Wells et al., 2000;Hutchinson et al., 2001Hutchinson et al., , 2002. 2-(4-Amino-3-methylphenyl)benzothiazole (DF 203) represents the lead compound for a recently explored series, and possesses potent antitumor properties in select breast, ovarian, and renal cancer cell lines of the 60-cell line, disease-oriented NCI Anticancer Drug Screen . DF 203 displays a unique biphasic dose-response relationship, with more potent activity at concentrations below 1 M but reduced antiproliferative activity at concentrations ranging from 1 to 100 M. The precise mechanism by which DF 203 and similar benzothiazoles display their antiproliferative effects has not been fully elucidated. Recent studies, however, suggest that their ability to become metabolized and covalently bind to subcellular targets contributes to their anticancer effects (Kashiyama et al., 1999;Chua et al., 2000;Hutchinson et al., 2001). Metabolism and covalent binding to subcellular This is part 25 of the series "Antitumor 2-(4-aminophenyl)

The role of fluorine in medicinal chemistry

“…Various fluorine analogues of DF 230 were synthesised to circumvent this deactivating metabolism in order to eliminate this biphasic dose-response relationship. 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203) was one such fluorine analogue that potently inhibited the growth of MCF-7 cells without the characteristic biphasic dose-response relationship [12,13]. 5F 203 was metabolically stable and had no exportable metabolite in sensitive MCF-7 cells which confirms that oxidative metabolism in the 6-position is essentially completely blocked by 5-fluorination.…”

“…Compared to other imaging techniques available, it offers the best combination of selectivity, specificity, and sensitivity when used with appropriate radiopharmaceuticals [56]. The radiopharmaceuticals are labelled with positron emitting radionuclides such as 11 C, 13 N, 15 O and 18 F. Positrons (b þ ) are formed during the decay of nuclides that have an excess of protons in the nucleus compared to the number of neutrons. PET is based on the simultaneous detection of two g-rays of 511 keV each, emitted during positron annihilation.…”

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

“…Furthermore, compounds 9-15 vary from compounds 3-9 due to including chlorine atom on phenyl ring at second position of the benzothiazole structure. Imidazole including compounds namely N-[4-(benzothiazole-2-yl)phenyl]-2-[(1,5-diphenyl-1H-imidazole-2-yl)thio]acetamide derivatives (16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) have methyl, methoxy and fluoro substituents on phenyl groups at the first and fifth positions of the imidazole ring. Among the nine tested compounds, imidazole and non-substituted benzimidazole including compounds (3, 10 and 16) possessed higher activity.…”

“…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] .…”

2-(4-Amino-3-methylphenyl)-5-fluorobenzothiazole is a ligand and shows species-specific partial agonism of the aryl hydrocarbon receptor

“…The ability of 5F 203 to act as an antagonist of TCDD at inducing CYP1A1 in human cells was investigated; MCF-7 cells were used since these showed inducibility of CYP1A1 by TCDD (Christou et al, 1994) and 5F 203 (Brantley et al, 2004). CYP1A1 mRNA was highly induced by 5F 203 and TCDD (~1600-and ~1700-fold above vehicle control, respectively).…”