title: Discovery of medium ring thiophosphorus based heterocycles as antiproliferative agents.
abstract: Hydrogen sulfide (H2S) has been investigated for its potential in therapy. Recently, we reported novel H2S donor molecules based on a thiophosphorus core, which slowly release H2S and have improved anti-proliferative activity in cancer cell lines compared to the most widely studied H2S donor GYY4137 (1). Herein, we have prepared new thiophosphorus organic H2S 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 IC50sin breast (0.76μM) and ovarian (0.76μM) cancer cell lines. No significant H2S release was detected in aqueous solution for this compound. However, confocal imaging showed that H2S was released from 17 inside cells at a similar level to the widely studied H2S donor GYY4137, which was shown to release 10μM H2S 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 H2S. Additional mechanism(s) appear to be responsible for the observed activity, hence more detailed studies are required to better understand the role of H2S in cancer with potent thiophosphorus agents.
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Feng
authors.affiliation: Department of Biochemistry, Block MD7 #04-06, 8 Medical Drive, National University of Singapore, 117596, Singapore.
authors.forename: Wisna
authors.initials: W
authors.lastname: Novera
authors.affiliation: Department of Pharmacy, Block S4A Level 3, 18 Science Drive 4, National University of Singapore, 117543, Singapore.
authors.forename: Kaye
authors.initials: K
authors.lastname: Peh
authors.affiliation: Department of Pharmacy, Block S4A Level 3, 18 Science Drive 4, National University of Singapore, 117543, Singapore.
authors.forename: Donavan
authors.initials: D
authors.lastname: Neo
authors.affiliation: 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.
authors.forename: Pondy Murugappan
authors.initials: PM
authors.lastname: Ramanujulu
authors.affiliation: Life Sciences Institute, Centre for Life Sciences Level 5, 28 Medical Drive, National University of Singapore, 117456, Singapore; Department of Pharmacology, UHL Level 5-02R, Lee Kong Chian Wing, 21 Lower Kent Ridge Road, National University of Singapore, 119077, Singapore.
authors.forename: Philip K
authors.initials: PK
authors.lastname: Moore
authors.affiliation: Department of Biochemistry, Block MD7 #04-06, 8 Medical Drive, National University of Singapore, 117596, Singapore.
authors.forename: Lih-Wen
authors.initials: LW
authors.lastname: Deng
authors.affiliation: Department of Pharmacy, Block S4A Level 3, 18 Science Drive 4, National University of Singapore, 117543, Singapore. Electronic address: phadbw@nus.edu.sg.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Dymock
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D055808:Drug Discovery; D005260:Female; D006571:Heterocyclic Compounds / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D006862:Hydrogen Sulfide / Q000378:metabolism / Q000494:pharmacology; D010758:Phosphorus / Q000737:chemistry*
chemical_list: D006571:Heterocyclic Compounds; D010758:Phosphorus; D006862:Hydrogen Sulfide
keywords: Anti-proliferative agents; Hydrogen sulfide; Medium sized rings; Organic synthesis; Thiophosphorus