Preclinical evaluation of amino acid prodrugs of novel antitumor 2-(4-amino-3-methylphenyl)benzothiazoles.

Abstract

Novel 2-(4-aminophenyl)benzothiazoles (e.g., compounds 1 and 2) possess highly selective, potent antitumor properties in vitro and in vivo. Elucidation of the mechanism of action of this structurally simple class of compounds has occurred in parallel with selection of a candidate clinical agent. Antitumor benzothiazoles induce and are biotransformed by cytochrome P 450 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. Amino acid conjugation to the exocyclic primary amine function of 2-(4-aminophenyl)benzothiazoles has been used to overcome limitations posed by drug lipophilicity. Water soluble, chemically stable prodrugs rapidly and quantitatively revert to their parent amine in mice, rats, and dogs in vivo. Plasma concentrations of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole (2) regenerated from the lysylamide prodrug (2b), sufficient to elicit cytocidal activity against ZR-75-1 and T47D human mammary carcinoma cell lines persist > 6 h. The growth of breast (MCF-7) and ovarian (IGROV-1) xenograft tumors is significantly retarded by 2b. Manageable toxic side effects are reported from preclinically efficacious doses of 2b. Cytochrome P 450 1A1 protein expression, selectively induced in sensitive carcinoma cells, was detected in MCF-7 and IGROV-1 tumors 24 h after treatment of mice with 2b (20 mg/kg). The lysyl amide prodrug of 2-(4-amino-3-methylphenyl)-5-fluorobenzothiazole is potentially suitable for clinical evaluation.

• Authors: Tracey D Bradshaw, Michael C Bibby, John A Double, Iduna Fichtner, Patricia A Cooper, Michael C Alley, Susan Donohue, Sherman F Stinson, Joseph E Tomaszewjski, Edward A Sausville, Malcolm F G Stevens
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 4 Pg. 239-46 (Feb 2002) ISSN: 1535-7163 [Print] United States
• PMID: 12467219 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Amino Acids
• Aniline Compounds
• Antineoplastic Agents
• Benzothiazoles
• NSC 674495
• Prodrugs
• Thiazoles
• Cytochrome P-450 CYP1A1

Topics

• Amino Acids (metabolism)
• Aniline Compounds (pharmacokinetics, therapeutic use)
• Animals
• Antineoplastic Agents (pharmacokinetics, therapeutic use)
• Benzothiazoles
• Blotting, Western
• Cell Division (drug effects)
• Cytochrome P-450 CYP1A1 (metabolism)
• Dogs
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• Female
• Humans
• Male
• Mammary Neoplasms, Experimental (drug therapy, enzymology)
• Mice
• Mice, Nude
• Ovarian Neoplasms (drug therapy, enzymology)
• Prodrugs
• Rats
• Rats, Sprague-Dawley
• Thiazoles (pharmacokinetics, therapeutic use)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays