Inhibitors of apoptosis in lymphocytes: synthesis and biological evaluation of compounds related to pifithrin-alpha.

The chemoprotection of cells from apoptosis induced by toxins or ionizing radiation could be important for biodefense and in the treatment of acute injuries. We describe a series of small heterocycles, including fused benzothiazoles, benzimidazoles, and related compounds, that abrogate thymocyte apoptosis induced by dexamethasone and gamma-irradiation. To optimize the protective activity of the previously reported pifithrin-alpha (PFT-alpha, 1), various derivatives and analogues of this and the corresponding ring-closed imidazobenzothiazole (IBT, 39) were synthesized.

Quinolinium salt as a potent inhibitor of lymphocyte apoptosis.

The synthesis of several quinolinium salts and related compounds and their ability to inhibit glucocorticoid-induced apoptosis in murine thymocytes are described. Interestingly, 1-[2-methoxyimino-2-(4-pyrrolidin-1-yl-phenyl)ethyl]quinolinium bromide (11) showed a potent protective effect with an EC(50) of 0.013 microM, which was at least 300-fold more potent than the reference compound pifithrin-alpha.