Discovery of New H2S Releasing Phosphordithioates and 2,3-Dihydro-2-phenyl-2-sulfanylenebenzo[d][1,3,2]oxazaphospholes with Improved Antiproliferative Activity.

Abstract

Hydrogen sulfide (H2S) is now recognized as a physiologically important gasotransmitter. Compounds which release H2S slowly are sought after for their potential in therapy. Herein the synthesis of a series of phosphordithioates based on 1 (GYY4137) are described. Their H2S release profiles are characterized using 2,6-dansyl azide (2), an H2S specific fluorescent probe. Most compounds have anticancer activity in several solid tumor cell lines and are less toxic in a normal human lung fibroblast, WI38. A preferred compound, 14, with 10-fold greater anticancer activity than 1, was shown to release H2S in MCF7 cells using a cell active probe, 21. Both permeability and intracellular pH (pHi) were found to be significantly improved for 14 compared to 1. Furthermore, 14 was also negative in the AMES test for genotoxicity. Cyclization of these initial structures gave a series of 2,3-dihydro-2-phenyl-2-sulfanylenebenzo[d][1,3,2]oxazaphospholes, of which the simplest member, compound 22 (FW1256), was significantly more potent in cells. The improved therapeutic window of 22 in WI38 cells was compared with three other cell types. Potency of 22 was superior to 1 in MCF7 tumor spheroids and the mechanism of cell death was shown to be via apoptosis with an increase in cleaved PARP and activated caspase-7. Evidence of H2S release in cells is also presented. This work provides a "toolbox" of slow-release H2S donors useful for studies of H2S in biology and as potential therapeutics in cancer, inflammation, and cardiovascular disease.

• Authors: Wei Feng, Xin-Yi Teo, Wisna Novera, Pondy Murugappan Ramanujulu, Dong Liang, Dejian Huang, Philip K Moore, Lih-Wen Deng, Brian W Dymock
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 16 Pg. 6456-80 (Aug 27 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 26147240 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2-phenyl-2,3-dihydrobenzo(d)(1,3,2)oxazaphosphole 2-sulfide
• Antineoplastic Agents
• Organothiophosphorus Compounds
• Hydrogen Sulfide

Topics

• Antineoplastic Agents (chemical synthesis, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• Cyclization
• Drug Discovery
• Drug Screening Assays, Antitumor
• Fibroblasts (drug effects)
• Humans
• Hydrogen Sulfide (metabolism)
• Models, Molecular
• Molecular Conformation
• Mutagenicity Tests
• Organothiophosphorus Compounds (chemical synthesis, pharmacology)
• Structure-Activity Relationship