Discovery of medium ring thiophosphorus based heterocycles as antiproliferative agents.

Hydrogen sulfide (H2 S) has been investigated for its potential in therapy. Recently, we reported novel H2 S donor molecules based on a thiophosphorus core, which slowly release H2 S and have improved anti-proliferative activity in cancer cell lines compared to the most widely studied H2 S donor GYY4137 (1). Herein, we have prepared new thiophosphorus organic H2 S donors with different ring sizes and evaluated them in two solid tumor cell lines and one normal cell line. A seven membered ring compound, 17, was found to be the most potent with sub-micromolar IC50s in breast (0.76μM) and ovarian (0.76μM) cancer cell lines. No significant H2 S release was detected in aqueous solution for this compound. However, confocal imaging showed that H2 S was released from 17 inside cells at a similar level to the widely studied H2 S donor GYY4137, which was shown to release 10μM H2 S after 12h at a concentration of 400μM. Comparison of 17 with its non-sulfur oxygen analogue, 26, provided evidence that the sulfur atom is important for its potency. However, the significant potency observed for 26 (5.94-11.0μM) indicates that the high potency of 17 is not entirely due to release of H2 S. Additional mechanism(s) appear to be responsible for the observed activity, hence more detailed studies are required to better understand the role of H2 S in cancer with potent thiophosphorus agents.