Antitumor Benzothiazoles. 14. Synthesis and in Vitro Biological Properties of Fluorinated 2-(4-Aminophenyl)benzothiazoles

Abstract

Synthetic routes to a series of mono- and difluorinated 2-(4-amino-3-substituted-phenyl)benzothiazoles have been devised. Whereas mixtures of regioisomeric 5- and 7-fluoro-benzothiazoles were formed from the established Jacobsen cyclization of precursor 3-fluoro-thiobenzanilides, two modifications to this general process have allowed the synthesis of pure samples of these target compounds. Fluorinated 2-(4-aminophenyl)benzothiazoles were potently cytotoxic (GI(50) < 1 nM) in vitro in sensitive human breast MCF-7 (ER+) and MDA 468 (ER-) cell lines but inactive (GI(50) > 10 microM) against PC 3 prostate, nonmalignant HBL 100 breast, and HCT 116 colon cells. The biphasic dose-response relationship characteristically shown by the benzothiazole series against sensitive cell lines was exhibited by the 4- and 6-fluoro-benzothiazoles (10b,d) but not by the 5- and 7-fluoro-benzothiazoles (10h,i). The most potent broad spectrum agent in the NCI cell panel was 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (10h) which, unlike the 6-fluoro isomer (10d), produces no exportable metabolites in the presence of sensitive MCF-7 cells. Induction of cytochrome P450 CYP1A1, a crucial event in determining the antitumor specificity of this series of benzothiazoles, was not compromised. 10h is currently the focus of pharmaceutical and preclinical development.

Helical Arrangement of 2-(4-hydroxy-3-methoxyphenyl)-Benzothiazole in Crystal Formation and Biological Evaluation on HeLa Cells

“…However, the potency of the compound was higher in HeLa cells than in MDA-MB-231 cells, because our assay lasted half the time that was reported for breast cancer cells. Likewise, our results are consistent with the antitumor effect for other benzothiazole-containing compounds such as fluorinated 2-phenylbenzothiazole derivatives with IC 50 values between 50 to 0.0001 µM [10], as well as 2-(4-Amino-3-methylphenyl) benzothiazole derivatives showed IC 50 values between 100 nM to 100 µM [13,14]. According to these data, the relative potency of this type of compound depends on the origin of the cancer cell line.…”

“…Recent studies showed that this compound and its analogues promote signaling and nuclear translocation of Aryl hydrocarbon Receptor (AhR) and induce the carboxyl terminus of Hsp70-interacting protein (CHIP) expression through recruitment of AhR upstream of the CHIP gene. This mechanism has potential application in the suppression of tumor progression in breast cancer cells [13][14][15][16][17]. The synthesis of the title compound has been recently improved by using several catalysts such as LiBr [18], ZnO [19] and CdS [20], silica [21], nanoparticles, clays [22,23], and transition metals [24,25].…”

Retracted: Synthesis and Cytotoxic Activity of 2‐Anilinopyridine‐3‐Acrylamides as Tubulin Polymerization Inhibitors

“…[9] Benzothiazoles are well known to exhibit various biological properties including antimicrobial, anticancer, anti-amyloid, antirheumatic, and antiglutamate activities. [10][11][12][13] Various modified arylbenzothiazoles and substituted 2-aminobenzothiazoles are also known to possess significant anticancer activity both in vitro and in vivo. [14][15][16][17][18] Phenylcinnamide derivative 4 [19] induced G 2 /M-phase cell-cycle arrest and cell death in cancer cell lines at low micromolar concentrations.…”

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.…”

“…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] . Motivated by the above observations and extending our previous study 27 , we planned to synthesize new 2-(4-aminophenyl)benzothiazole derivatives including (benz)imidazole/benzoxazole/benzothiazole heterocyclic ring systems and to evaluate their antitumor activity against nine cancer types comprised of approximately 60 cell lines.…”