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

• Published in: British journal of cancer Vol. 86; no. 8; pp. 1348 - 1354
• Main Authors: BRADSHAW, T. D, CHUA, M.-S, BROWNE, H. L, TRAPANI, V, SAUSVILLE, E. A, STEVENS, M. F. G
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing Group 22-04-2002
• Subjects: Amines - metabolism; Amino acids; Amino Acids - metabolism; Amino Acids - pharmacology; Aniline Compounds - pharmacology; Antineoplastic agents; Benzothiazoles; Bioavailability; Biological and medical sciences; Blotting, Western; Cancer research; Cell Division - drug effects; Cytochrome P-450 CYP1A1 - metabolism; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Experimental Therapeutics; General aspects; Humans; Medical research; Medical sciences; Metabolism; Metabolites; Neoplasms - enzymology; Neoplasms - metabolism; Neoplasms - pathology; Ovaries; Oxidation; Pharmaceuticals; Pharmacology. Drug treatments; Prodrugs - metabolism; Prodrugs - pharmacology; Protein expression; Thiazoles - pharmacology; Time Factors; Tumor Cells, Cultured; Adenocarcinoma; Antineoplastic agent; Human; Isozyme; Cytochrome P450; Malignant tumor; Prodrug; Benzothiazole derivatives; In vitro; Biological activity; Mammary gland diseases; Aminoacid; Established cell line; Mammary gland
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6600225

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.