Rational design of multitargeted tyrosine kinase inhibitors: a novel approach.

The non-receptor Src tyrosine kinase is known to cooperate with the epidermal growth factor receptor in a mechanism leading to invasion and metastasis of solid tumours. With the purpose of developing agents targeted to both epidermal growth factor receptor and Src or related kinases, we embarked on the design of chimeric molecules termed combi-molecules capable of blocking both Src and epidermal growth factor receptor. To this end, we have chosen to design molecules containing a quinazoline moiety (directed at epidermal growth factor receptor) and a 7-phenyl-pyrazolopyrimidine (directed at Src).

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.