Treating cancer with hydrogen sulfide

02 Feb 2016 NUS scientists have discovered new molecules which release small amounts of hydrogen sulfide (H2S) gas resulting in potent anti-cancer effects

H2S is well-known as a malodorous gas but in small amounts it behaves as a physiologically important gasotransmitter, comparable to carbon monoxide and nitric oxide. H2S plays many roles in the body, such as protecting the heart and mediating inflammation. In cancer, H2S is known to trigger cell death. However, treatment with H2S itself is not practical since the gas is toxic in large amounts and is short-lived in the body. New molecules which can release H2S slowly and in a controlled manner inside cancer cells are therefore highly sought after and may have useful therapeutic applications (see Figure).

A team led by Prof Brian DYMOCK from the Department of Pharmacy in NUS has designed and constructed several new molecular series of novel small organic compounds. These are stable as solids at room temperature but when added to aqueous solutions, such as cultures of living cells, they release H2S gas slowly into the solution. These compounds have been synthesised from commercially available materials in an efficient manner and in high yields. H2S release profiles were established in the first published example of the application of a dansyl azide fluorescent probe to measure H2S release from novel small molecules.

Treatment of a wide range of cancer cells with the new compounds revealed a broad range of activity across solid tumours (IC50s down to 6μM with preferred compound FW1256), while being less toxic towards normal cells. The best compounds from each series were further studied and shown to have increased the levels of H2S inside the cancer cells, indicating that the drugs can enter cancer cells and release their H2S where most needed. Reduced internal pH of cancer cells was also shown as well as an apoptotic mechanism of cell death. FW1256 was able to almost completely stop the growth of breast cancer spheroids growing in a three-dimensional matrix.

The next step is to develop these molecules into in vivo active agents. Further development of new H2S anti-cancer therapeutics could bring much needed hope to patients.

Feb 16  dymock feb16

Figure shows (A) evolution of starting compound GYY4137 through to compound 14 then cyclisation to compound 22 (FW1256). (B) Single crystal structure of a derivative of 14. (C) Confocal microscopy showing H2S released inside MCF7 breast cancer cells with 14. (D) Inhibition of MCF7 tumour spheroid growth by 22 (FW1256). [Image credit: Brian W Dymock]



Feng W, Teo XY, Novera W, Ramanujulu PM, Liang D, Huang D, Moore PK, Deng LW, Dymock BW. "Discovery of New H2S Releasing Phosphordithioates and 2,3-Dihydro-2-phenyl-2-sulfanylenebenzo[d][1,3,2]oxazaphospholes with Improved Antiproliferative Activity." Journal of Medicinal Chemistry. 58 (2015) 6456.