Feng Wei, Novera Wisna, Peh Kaye, Neo Donavan, Ramanujulu Pondy Murugappan, Moore Philip K, Deng Lih-Wen, Dymock Brian W
Department of Pharmacy, Block S4A Level 3, 18 Science Drive 4, National University of Singapore, 117543, Singapore; Life Sciences Institute, Centre for Life Sciences Level 5, 28 Medical Drive, National University of Singapore, 117456, Singapore.
Department of Biochemistry, Block MD7 #04-06, 8 Medical Drive, National University of Singapore, 117596, Singapore.
Bioorg Med Chem Lett. 2017 Feb 15;27(4):967-972. doi: 10.1016/j.bmcl.2016.12.079. Epub 2017 Jan 2.
Hydrogen sulfide (HS) has been investigated for its potential in therapy. Recently, we reported novel HS donor molecules based on a thiophosphorus core, which slowly release HS and have improved anti-proliferative activity in cancer cell lines compared to the most widely studied HS donor GYY4137 (1). Herein, we have prepared new thiophosphorus organic HS 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 IC in breast (0.76μM) and ovarian (0.76μM) cancer cell lines. No significant HS release was detected in aqueous solution for this compound. However, confocal imaging showed that HS was released from 17 inside cells at a similar level to the widely studied HS donor GYY4137, which was shown to release 10μM HS 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 HS. Additional mechanism(s) appear to be responsible for the observed activity, hence more detailed studies are required to better understand the role of HS in cancer with potent thiophosphorus agents.
