In vitro evaluation of amino acid prodrugs of novel antitumour 2-(4-amino-3-methylphenyl)benzothiazoles

Abstract

Novel 2-(4-aminophenyl)benzothiazoles possess highly selective, potent antitumour properties in vitro and in vivo. They induce and are biotransformed by cytochrome P450 (CYP) 1A1 to putative active as well as inactive metabolites. Metabolic inactivation of the molecule has been thwarted by isosteric replacement of hydrogen with fluorine atoms at positions around the benzothiazole nucleus. The lipophilicity of these compounds presents limitations for drug formulation and bioavailability. To overcome this problem, water soluble prodrugs have been synthesised by conjugation of alanyl-and lysyl-amide hydrochloride salts to the exocyclic primary amine function of 2-(4-aminophenyl)benzothiazoles. The prodrugs retain selectivity with significant in vitro growth inhibitory potency against the same sensitive cell lines as their parent amine, but are inactive against cell lines inherently resistant to 2-(4-aminophenyl)benzothiazoles. Alanyl and lysyl prodrugs rapidly and quantitatively revert to their parent amine in sensitive and insensitive cell lines in vitro. Liberated parent compounds are sequestered and metabolised by sensitive cells only; similarly, CYP1A1 activity and protein expression are selectively induced in sensitive carcinoma cells. Amino acid prodrugs meet the criteria of aqueous solubility, chemical stability and quantitative reversion to parent molecule, and thus are suitable for in vivo preclinical evaluation.

Antitumour 2-(4-aminophenyl)benzothiazoles generate DNA adducts in sensitive tumour cells in vitro and in vivo

“…Thus, tumour sensitivity has been predicted accurately: in antitumour tests, the growth of MCF-7 xenografts was significantly retarded whereas MDA-MB-435 tumours transplanted in the opposite flank continued to grow (Bradshaw et al, 2002a). Thus, we propose that the evaluation of DNA adduct formation may provide a valuable pharmacodynamic (PD) end point predictive of tumour sensitivity.…”

“…Significant DNA adducts were detected in MCF-7 tumour xenografts 24 h after treatment of mice with a concentration of Phortress known to elicit antitumour activity (Bradshaw et al, 2002a). Phortress (2 Â 20 mg kg À1 , i.p.…”

“…Guided by in vitro data (Figure 4) and the knowledge that CYP1A1 protein can clearly be detected within sensitive xenografts 24 h post-treatment (Bradshaw et al, 2002a), tumours were recovered 24 h after animals were treated and DNA extracted. HPLC detection of 32 Ppostlabelled adducts clearly distinguished one major and a number of minor Phortress-derived adducts in the DNA of MCF-7 xenografts ( Figure 6).…”

“…Thus, 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (5F 203, NSC 703786) is the favoured analogue for clinical consideration possessing enhanced efficacy in vitro and superior potency in vivo against human breast and ovarian tumour xenografts implanted in nude mice (Hutchinson et al, 2001;Bradshaw et al, 2002a). The lysylamide dihydrochloride salt of 5F 203 (Phortress, NSC 710305) has been derivatised at the exocyclic primary amine function fulfilling the criteria for a suitable prodrug.…”

Imino-4-Methoxyphenol Thiazole Derived Schiff Base Ligands: Synthesis, Spectral Characterization and Antimicrobial Activity

“…These Schiff bases are well known to have biological activities such as antimicrobial [8,9], antifungal [10,11], antitumor [12,13] and as herbicides [14]. In particular, thiazole and derivatives have been found number of applications in medicopharmaceutical fields and also some of them were depicted to have antitumor activity [15]. Especially, benzothiazole have shown significant effect against cancer [16].…”