In vitro evaluation of amino acid prodrugs of novel antitumour 2-(4-amino-3-methylphenyl)benzothiazoles.
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.
Bradshaw
T D
TD
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, UK. rcztb@unix.nottingham.ac.uk
Chua
M-S
MS
Browne
H L
HL
Trapani
V
V
Sausville
E A
EA
Stevens
M F G
MF
D000588:Amines / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D052160:Benzothiazoles; D015153:Blotting, Western; D002455:Cell Division / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006801:Humans; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D011355:Prodrugs / Q000378:metabolism / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D013997:Time Factors; D014407:Tumor Cells, Cultured
D000588:Amines; D000596:Amino Acids; D000814:Aniline Compounds; D052160:Benzothiazoles; C122062:NSC 674495; D011355:Prodrugs; D013844:Thiazoles; D019363:Cytochrome P-450 CYP1A1