2-(4-Aminophenyl)benzothiazoles: novel agents with selective profiles of in vitro anti-tumour activity

Abstract

Summary 2-(4-Aminophenyl)benzothiazole (CJM 126) elicits biphasic growth-inhibitory effects against a panel of oestrogen receptor-positive (ER+) and oestrogen receptor-negative (ER-) human mammary carcinoma cell lines in vitro, yielding IC50 values in the nm range. Substitutions adjacent to the amino group in the 2-phenyl ring with a halogen atom or methyl group enhance potency in sensitive breast lines (pM IC50 values). Transient biphasic dose responses were induced but rapidly eradicated after specific drug exposure periods. Two human prostate carcinoma cell lines were refractory to the growth-inhibitory properties of 2-(4-aminophenyl)benzothiazoles; IC50 values > 30 ,UM were obtained.Potency and selectivity were confirmed when compounds were examined in the National Cancer Institute's Developmental Therapeutics screen; the spectrum of activity included specific ovarian, renal, colon as well as breast carcinoma cell lines. Moreover, comparing 6-day and 48-h incubations, the exposure time-dependent nature of the biphasic response was corroborated. Differential perturbation of cell cycle distribution followed treatment of MCF-7 and MDA 468 cells with substituted 2-(4-aminophenyl)benzothiazoles. In MDA 468 populations only, accumulation of events in G/M phase was observed. Two MCF-7 cell lines were established with acquired resistance to CJM 126 (IC50 values > 20 gM), which exhibit cross-resistance to substituted benzothiazoles, but equal sensitivity to tamoxifen and doxorubicin. Compared with standard anti-tumour agents evaluated in the National Cancer Institute in vitro cell panel, benzothiazoles revealed unique profiles of growth inhibition, suggesting a mode(s) of action shared with no known clinically active class of chemotherapeutic agents.

Influence of 2-(4-aminophenyl)benzothiazoles on growth of human ovarian carcinoma cells in vitro and in vivo

“…The initial mean doubling time of control tumours was 2.9 days. A maximum-tolerated dose was not (Tables I and 2) in addition to breast (Shi et al, 1996) (Bradshaw et al, 1998 (Bradshaw et al, 1998). Therefore, a shared mechanism(s) of resistance is implied.…”

“…GI50 values within the pM range were obtained in human breast carcinoma cell lines including MCF-7 oestrogen receptor-positive (ER+) and MDA 468 oestrogen receptor-negative (ER-) cell lines. In contrast, GI50 values > 30 gm were obtained when activity of the same compounds was examined in PC3 and DU 145 human prostate cell lines (Bradshaw et al, 1998).…”

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.…”

“…Unexpectedly, it was found that, 2-(4-aminophenyl)benzothiazole derivatives inhibit cancer cell growth with nanomolar scale against a large panel of human cancer cell lines particularly against breast, colon and ovarian cell lines in in vitro anticancer screening program of the National Cancer Institute (NCI) with a characteristic biphasic doseresponse relationship 6,7 . Up to present, scientists Shi and Bradshaw have a series of studies on antitumor activity of some benzothiazole derivatives [8][9][10][11][12][13][14] . First, the original lead compound 2-(4-aminophenyl)benzothiazole (CJM 126, NSC34445), which was originally prepared as a synthetic intermediate in a program of screening for tyrosine-kinase inhibitors, was found to possess selective in vitro activity against MCF-7 breast carcinoma cell line.…”

“…First, the original lead compound 2-(4-aminophenyl)benzothiazole (CJM 126, NSC34445), which was originally prepared as a synthetic intermediate in a program of screening for tyrosine-kinase inhibitors, was found to possess selective in vitro activity against MCF-7 breast carcinoma cell line. 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 .…”