nsc-674495 and 2-(4-aminophenyl)benzothiazole

The development of a series of potent and selective antitumour agents, the 2-(4-aminophenyl)benzothiazoles, is described. The original lead compound in this series, CJM 126, exhibits nanomolar in vitro activity against certain human breast cancer cell lines. Structure-activity relationship studies within this simple antitumour benzothiazole pharmacophore revealed that 2-(4-aminophenyl) benzothiazoles bearing a 3'- methyl, 3'-bromo, 3'-iodo or 3'-chloro substituent are especially potent, extending the spectrum of in vitro antitumour activity to ovarian, lung, renal and colon carcinoma cell lines with a remarkable selectivity profile (NCI analysis). Other interesting features of this series include the highly unusual transient biphasic dose response relationship and possible unique mechanism of action (NCI COMPARE analysis). 2-(4-Amino-3-methylphenyl)benzothiazole (DF 203) has been selected as the lead compound in this series on the basis of superior in vivo results

Topics: Aniline Compounds; Animals; Antineoplastic Agents; Benzothiazoles; Humans; Prodrugs; Structure-Activity Relationship; Thiazoles

Photodynamic therapy (PDT) employing exogenous photosensitizers is currently being approved for treatment of basal cell carcinoma (BCC). 2-(4-Aminophenyl)benzothiazoles (6) consist of chromophoric structure and absorb light in the UVA (315-400 nm). These results encouraged us to design and synthesize a diversity of 2-phenylbenzothiazoles (6). Studies on the apoptotic mechanism involved in photosensitive effects induced by UVA-activated 6 in BCC cells are carried out in the present article. 6-UVA-treated cells displayed several features of apoptosis, including an increase in the sub-G1 population, a significantly increased annexin V binding, and activation of caspase-3. 6-UVA induced a decrease in mitochondrial membrane potential (Deltapsi(mt)) and ATP via enhanced ROS generation and promoted phosphorylation of extracellular signal-regulated kinase (ERK) and p38 MAPK expression. These results suggest that 6-UVA elicits photosensitive effects in mitochondria processes which involve ERK and p38 activation, and ultimately lead to BCC cell apoptosis.

Topics: Apoptosis; Benzothiazoles; Carcinoma, Basal Cell; Cell Line, Tumor; Cell Survival; Humans; MAP Kinase Signaling System; Mitochondria; Photochemotherapy; Photosensitizing Agents; Ultraviolet Rays

A series of sulfamate salt derivatives of the potent and selective 2-(4-aminophenyl)benzothiazole antitumour agents has been prepared and their evaluation as potential prodrugs for parenteral administration carried out. The salts were sparingly soluble under aqueous conditions (pH 4-9), and degradation to the active free amine was shown to occur under strongly acidic conditions. The salts were found to be markedly less active than their parent amines against sensitive human tumour cell lines in vitro.

Topics: Amines; Antineoplastic Agents; Benzothiazoles; Breast Neoplasms; Drug Stability; Enzyme Activators; Female; Guanylate Cyclase; Humans; Hydrogen-Ion Concentration; Inhibitory Concentration 50; Platelet Aggregation Inhibitors; Prodrugs; Solubility; Sulfonic Acids; Thiazoles; Tumor Cells, Cultured