Bradshaw Tracey D, Bibby Michael C, Double John A, Fichtner Iduna, Cooper Patricia A, Alley Michael C, Donohue Susan, Stinson Sherman F, Tomaszewjski Joseph E, Sausville Edward A, Stevens Malcolm F G
Cancer Research Laboratories, School of Pharmaceutical Sciences, University of Nottingham, Nottingham NG7 2RD, United Kingdom.
Mol Cancer Ther. 2002 Feb;1(4):239-46.
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.
新型2-(4-氨基苯基)苯并噻唑（例如化合物1和2）在体外和体内均具有高度选择性和强效的抗肿瘤特性。在选择候选临床药物的同时，对这类结构简单的化合物的作用机制也进行了阐明。抗肿瘤苯并噻唑可诱导细胞色素P 450 1A1并被其生物转化为推定的活性及非活性代谢产物。通过在苯并噻唑核周围位置用氟原子等排取代氢原子，阻碍了该分子的代谢失活。2-(4-氨基苯基)苯并噻唑的环外伯胺官能团与氨基酸共轭，已被用于克服药物亲脂性带来的限制。水溶性、化学稳定的前药在小鼠、大鼠和犬体内能迅速且定量地还原为其母体胺。从赖氨酰胺前药（2b）再生的2-(4-氨基-3-甲基苯基)-5-氟苯并噻唑（2）的血浆浓度足以引发对ZR-75-1和T47D人乳腺癌细胞系的杀细胞活性，并持续>6小时。2b可显著抑制乳腺（MCF-7）和卵巢（IGROV-1）异种移植肿瘤的生长。临床前有效剂量的2b报告的毒性副作用可控。在用2b（20mg/kg）处理小鼠24小时后，在MCF-7和IGROV-1肿瘤中检测到在敏感癌细胞中选择性诱导的细胞色素P 450 1A1蛋白表达。2-(4-氨基-3-甲基苯基)-5-氟苯并噻唑的赖氨酰胺前药可能适合进行临床评估。
