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In vitro evaluation of amino acid prodrugs of novel antitumour 2-(4-amino-3-methylphenyl)benzothiazoles.
- Source :
-
British journal of cancer [Br J Cancer] 2002 Apr 22; Vol. 86 (8), pp. 1348-54. - Publication Year :
- 2002
-
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.<br /> (Copyright 2002 Cancer Research UK)
- Subjects :
- Amines metabolism
Amino Acids metabolism
Benzothiazoles
Blotting, Western
Cell Division drug effects
Cytochrome P-450 CYP1A1 metabolism
Dose-Response Relationship, Drug
Drug Evaluation, Preclinical
Humans
Neoplasms enzymology
Neoplasms metabolism
Neoplasms pathology
Prodrugs metabolism
Time Factors
Tumor Cells, Cultured
Amino Acids pharmacology
Aniline Compounds pharmacology
Prodrugs pharmacology
Thiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 0007-0920
- Volume :
- 86
- Issue :
- 8
- Database :
- MEDLINE
- Journal :
- British journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 11953897
- Full Text :
- https://doi.org/10.1038/sj.bjc.6600225