Chemicals

SKI-178 is a selective inhibitor of sphingosine kinase 1 which is active in vitro and in vivo. SKI-178 is a competitive inhibitor of sphingosine binding to SPHK1 (Ki = 1.3 uM) and shows no inhibition of SPHK2 up to 25 uM. SKI-178 is cytotoxic to numerous cancer cell lines (MCF-7 A549 Panc-1 etc) at low to sub-micromolar concentrations.

THI is a trace component present in the industrially produced food colorant caramel color III. It acts as an immunosuppressant by inhibiting the enzyme sphingosine 1-phosphate lyase (S1PL) which fragments S1P to hexadecenal and phosphoethanolamine. Administration of THI in drinking water to mice (50 μg/mL) resulted in decreased S1PL activity increased S1P levels in lymphoid tissues and reduced egress of CD4+ and CD8+ T cells (lymphopenia).

1-Methylhistamine (N-Tau-MethylHistamine:2HCl) is a histamine metabolite that has been used as a biomarker of Alzheimer's disease and other neurological disorders. It is a formed by histamine 1-methyltransferase in the histidine metabolism pathway.

NVP-231 is a potent specific and reversible Ceramide kinase (CerK) inhibitor (IC50= 12 nM in vitro) which competitively inhibits binding of ceramide. CerK is a key enzyme for controlling ceramide levels.ReferencesGraf C. et al. Targeting Ceramide Metabolism with a Potent and Specific Ceramide Kinase Inhibitor; Molecular Pharmacology 2008 74(4): 925-932

Acid ceramidase (aCDase) is a lysosomal amidase which hydrolyzes the acyl chain from ceramides forming sphingosine which is subsequently phosphorylated to the bioactive lipid sphingosine 1-phosphate. aCDase is upregulated in many cancer types such as melanoma prostate head neck and colon cancers. ARN14988 is a potent inhibitor of aCDase in vitro (IC50 = 12 nM) and in A375 melanoma cells (IC50 = 1.5uM). ARN14988 is weakly cytotoxic by itself but shows a synergystic effect with some common anti-cancer drugs (5-Fluorouracil vemurafinib and taxol) in proliferative G361 cells.

Ceramides are bioactive sphingolipids which induce apoptosis in cells. Ceramidases which hydrolyze the fatty acid chain keep ceramide levels in check and have been proposed as a target for small-molecule inhibitors for anti-cancer therapy. B13 (or D-NMAPPD) is a potent ceramidase inhibitor which causes aopotosis in a number of cell lines including colorectal HL60 melanoma and keratinocyes.References1) A. Bielawska C.M. Linardic Y. Hannun "Ceramide-mediated biology. Determination of structural and stereospecific requirements through the use of N-acyl-phenylaminoalcohol analogs" J. Biol. Chem. 1992 267 18493-7. 2) M. Raisova G. Goltz et al. "Bcl-2 overexpression prevents apoptosis induced by ceramidase inhibitors in malignant melanoma and HaCaT keratinocytes" FEBS Letters 2002 516 47-52. 3) Bhabak Krishna P.; Kleuser Burkhard "Effective inhibition of acid and neutral ceramidases by novel B-13 and LCL-464 analogues" Bioorganic & Medicinal Chemistry 2013 21 874-882.

Ceramides are bioactive sphingolipids which induce apoptosis in cells. Ceramidases (CDase) which hydrolyze the fatty acid chain keep ceramide levels in check and have been proposed as a target for small-molecule inhibitors for anti-cancer therapy. Ceranib-2 inhibits cellular CDase activity with an IC50 = 28 uM in SKOV3 cells and does not show significant cytotoxity up to 100uM. Incubations of SKOV3 cells with Ceranib-2 resulted in an increase in all ceramide species and a dose-dependant decrease in sphingosine and S1P. Ceranib-2 suppressed tumor growth in a mouse model with subcutaneous JC cell tumors.References1) J.M Draper et al. "Discovery and Evaluation of Inhibitors of Human Ceramidase" Mol. Cancer Ther. 2011 10 2052-20612) H.S. Vethakanraj et al. "Targeting ceramide metabolic pathway induces apoptosis in human breast cancer cell lines" Biophys. Biochem. Res. Commun. 2015 464 833-839.

Benzo[a]pyrene (BaP 3 4-Benzopyrene 3 4-Benzpyrene Benzo[def]chrysene) is a procarcinogenic polyaromatic hydrocarbon (PAH) found in coal tar and other byproducts from the combustion of organic material. It is metabolized by cytochrome P450 1A1 (CYP1A1) to benzo[a]pyrene-7 8-dihydrodiol-9 10-epoxide which is carcinogenic. This metabolite intercalates DNA thus disrupting DNA copying and inducing mutations. Benzo[a]pyrene is used as a chemical carcinogen in cancer models.

CYM50308 is a potent and selective S1P4 receptor agonist with EC50 of 37.7 nM - 79.1nM. It is inactive against the S1P1 S1P2 and S1P3 receptors up to 25 μM and the S1P5 receptor up to 2.1 μM.References1) Urbano et al. Discovery synthesis and SAR analysis of novel selective small molecule S1P4-R agonists based on a (2Z 5Z)-5-((pyrrol-3-yl)methylene)-3-alkyl-2- (alkylimino)thiazolidin-4-one chemotype Bioorganic & Medicinal Chemistry Letters 2011 6739-6745.2) Guerrero et al. Identification of a novel agonist of the sphingosine 1-phosphate receptor 4 (S1P4) Probe Reports from the NIH Molecular Libraries Program. http://www.ncbi.nlm.nih.gov/books/NBK143556/