Novel silicon-containing drugs derived from the indomethacin scaffold: Synthesis, characterization and evaluation of biological activity

Synthesis, spectroscopic characterization and in vitro pharmacological and cancer cell growth inhibitory activity studies of new silicon-containing compounds based on the indomethacin scaffold are now reported. Amidation of the indomethacin carboxylate group using amino-functional silanes generated a series of novel lipophilic derivatives of indomethacin. The pharmacological activity of these derivatives tested against human recombinant cyclooxygenase-1 and 2 demonstrated that the silicon-containing derivatives are cyclooxygenase-2 (COX-2) selective. The silicon-containing amides of indomethacin demonstrated in vitro growth inhibitory activity against human MiaPaCa-2 pancreatic carcinoma cells at low μM concentrations. The 3a and 3c derivatives exhibited the most potent in vitro antiproliferative activity, with IC₅₀ <6.0 μM, compared to unmodified indomethacin having an IC₅₀100 μM. We dedicate this paper to Prof. Mitsuo Kira, outstanding organosilicon chemist and valued friend.