Synthesis of selective inhibitors of sphingosine kinase 1 (original) (raw)
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Design, synthesis and biological activity of sphingosine kinase 2 selective inhibitors
Bioorganic & Medicinal Chemistry, 2012
Sphingosine kinase (SphK) has emerged as an attractive target for cancer therapeutics due to its role in cell survival. SphK phosphorylates sphingosine to form sphingosine 1-phosphate (S1P), which has been implicated in cancer growth and survival. SphK exists as two different isotypes, namely SphK1 and SphK2, which play different roles inside the cell. In this report, we describe SphK inhibitors based on the immunomodulatory drug, FTY720, which is phosphorylated by SphK2 to generate a S1P mimic. Structural modification of FTY720 provided a template for synthesizing new inhibitors. A diversity-oriented synthesis generated a library of SphK inhibitors with a novel scaffold and headgroup. We have discovered subtype selective inhibitors with K i 's in the low micromolar range. This is the first report describing quaternary ammonium salts as SphK inhibitors.
Synthesis and evaluation of sphingoid analogs as inhibitors of sphingosine kinases
Bioorganic & Medicinal Chemistry, 2005
Sphingosine 1-phosphate (S1P), a product of sphingosine kinases (SphK), mediates diverse biological processes such as cell differentiation, proliferation, motility and apoptosis. In an effort to search and identify specific inhibitors of human SphK, the inhibitory effects of synthetic sphingoid analogs on kinase activity were examined.
Sphingosine Kinase 1: A Potential Therapeutic Target in Pulmonary Arterial Hypertension?
Trends in Molecular Medicine
Sphingosine kinase 1 (SphK1) knockout mice are protected against pulmonary hypertension and expression levels of the enzyme are increased in the lungs of pulmonary arterial hypertensive (PAH) patients. Moreover, sphingosine 1-phosphate can promote vascular remodeling/vasoconstriction in rodent and human pulmonary arterial smooth muscle cell models. Therefore, SphK1 might be a novel target for treatment of PAH. However, in our opinion more refined strategies to target SphK1 are needed because this enzyme is protective against endothelial dysfunction and can become resistant to SphK1 inhibitors in vascular smooth muscle, thereby potentially limiting effectiveness in PAH. In addition, SphK1 is involved in maladaptive hypertrophy and we propose that heart failure might be an additional direct target for therapeutic intervention with SphK1 inhibitors. Pulmonary Arterial Hypertension and Sphingosine 1-Phosphate Pulmonary arterial hypertension (PAH) affects 15-50 people/million and is characterised by elevated mean arterial blood pressure, shortness of breath, fatigue, dizziness, chest pain and edema. PAH can lead to reduced blood flow to the heart, cardiac hypertrophy and heart failure. PAH affects small pre-capillary arteries in the lung where there is enhanced vasoconstriction and vascular remodelling (see Glossary) with an underlying inflammation [1]. Treatment is aimed at enhancing pulmonary hemodynamics, exercise tolerance and life quality. Drugs used to treat PAH are vasodilators including prostacyclin analogues, endothelin receptor antagonists and phosphodiesterase 5 inhibitors. Combination therapies with these agents has significantly improved life expectancy from ~ 3 years at diagnosis to 5-7 years [1]. Nevertheless progressive vascular and ventricular remodeling still occurs leading to cardiac hypertrophy/heart failure and death. Therefore, there is still an unmet medical need and recent findings suggest that sphingosine 1-phosphate (S1P) might be a potential novel target for clinical intervention in PAH. This is exemplified by the role of sphingosine kinase 1 (SphK1, which catalyses the formation of S1P) and the S1P 2 receptor (which is specifically activated by binding of S1P) in vascular remodeling and vasoconstriction in rodent models (Figure 1). In addition, SphK1 and S1P are linked with signaling networks that involve gene products that are significantly up-regulated in human PAH, such as the Receptor for Advanced Glycation End products (RAGE) [2] and Signal Transducer Activator of Transcription 3 (STAT3) [3]. The enzyme is also potentially linked with down-regulation of Bone Morphogenetic Protein Receptor type II (BMPR2) [4], where inactivating mutations in the BMPR2 gene are associated with familial hypertension [5]. The overlap of SphK1 signaling with known PAH susceptibility gene products provides additional support for the idea that the enzyme could be considered as a novel target for
Sphingosine Kinase Inhibitors and Cancer: Seeking the Golden Sword of Hercules
Cancer Research, 2011
There is considerable evidence that sphingosine kinases play a key role in cancer progression, which might involve positive selection of cancer cells that have been provided with a survival and growth advantage as a consequence of overexpression of the enzyme. Therefore, inhibitors of sphingosine kinase represent a novel class of compounds that have potential as anticancer agents. Poor inhibitor potency is a major issue that has precluded successful translation of these compounds into the clinic. However, recent discoveries have shown that sphingosine kinase 1 is an allosteric enzyme and that some inhibitors offer improved effectiveness by inducing proteasomal degradation of the enzyme or having nanomolar potency. Herein, we provide a perspective about these recent developments and highlight the importance of translating basic pharmacologic and biochemical findings on sphingosine kinase into new drug discovery programs for treatment of cancer. Cancer Res; 71(21); 6576-82. Ó2011 AACR.
Journal of Medicinal Chemistry, 2015
Sphingosine 1-phosphate (S1P) is a pleiotropic signaling molecule that acts as a ligand for five Gprotein coupled receptors (S1P 1-5) whose downstream effects are implicated in a variety of important pathologies including sickle cell disease, cancer, inflammation, and fibrosis. The synthesis of S1P is catalyzed by sphingosine kinase (SphK) isoforms 1 and 2, and hence, inhibitors of this phosphorylation step are pivotal in understanding the physiological functions of SphKs. To date, SphK1 and 2 inhibitors with the potency, selectivity, and in vivo stability necessary to determine the potential of these kinases as therapeutic targets are lacking. Herein, we report the design, synthesis, and structure-activity relationship studies of guanidine-based SphK inhibitors bearing an oxadiazole ring in the scaffold. Our studies demonstrate that SLP120701, a SphK2-selective inhibitor (K i = 1 μM), decreases S1P levels in histiocytic lymphoma (U937) cells. Surprisingly, homologation with a single methylene unit between the oxadiazole and heterocyclic *
European Journal of Medicinal Chemistry, 2010
Sphingosine kinase (SphK) is a lipid kinase with oncogenic activity, and SphK inhibitors (SKIs) are known for their anti-cancer activity. Here, we report highly efficient syntheses of SKIs and their aspirinyl (Asp) analogs. Both SKIs and their Asp analogs were highly cytotoxic towards multiple human cancer cell lines; in several cases the Asp analogs were up to three times more effective. Furthermore, they were equally potent inhibitors of SphK. The pharmacokinetic study indicated that SKI-I-Asp cleaved efficiently to form SKI-I and the half-life of SKI-I was increased from w7 h in SKI-I to w10 h in SKI-I-Asp injected mice, thereby prolonging its effect. In summary, the Asp-conjugated SKIs seem to be promising prodrugs of SKIs where delivery in vivo remains a problem.
Structure-activity relationship of short-chain sphingoid bases as inhibitors of sphingosine kinase
Bioorganic & Medicinal Chemistry Letters, 1999
Short-chain sphinganine analogues 8, 9, 18, and 19, as well as 3-fluoro-sphingosine analogues 25 and 26 were synthesized. Their potential as sphingosine kinase inhibitors was investigated, in combination with previously synthesized sphingosine and fluorinated sphinganine analogues. De Jonghe et al. /Bioorg. Med. Chem. Lett. 9 (1999) 3175-3180 D,L-threo-dihydrosphingosine (or D,L-threo-sphinganine) 8 and N,N-dimethylsphingosine 9 are known competitive inhibitors of sphingosine kinase ). To further explore the structural requirements, necessary for inhibition of sphingosine kinase, we previously synthesized sphingosine analogues 9 and fluorinated sphinganine analogues, t° We have now prepared a new series of sphinganine derivatives and 3fluoro-sphingosine analogues in order to comparatively assess these compounds as potential inhibitors of
A selective ATP-competitive sphingosine kinase inhibitor demonstrates anti-cancer properties
Oncotarget, 2015
The dynamic balance of cellular sphingolipids, the sphingolipid rheostat, is an important determinant of cell fate, and is commonly deregulated in cancer. Sphingosine 1-phosphate is a signaling molecule with anti-apoptotic, pro-proliferative and pro-angiogenic effects, while conversely, ceramide and sphingosine are pro-apoptotic. The sphingosine kinases (SKs) are key regulators of this sphingolipid rheostat, and are attractive targets for anti-cancer therapy. Here we report a first-in-class ATP-binding site-directed small molecule SK inhibitor, MP-A08, discovered using an approach of structural homology modelling of the ATP-binding site of SK1 and in silico docking with small molecule libraries. MP-A08 is a highly selective ATP competitive SK inhibitor that targets both SK1 and SK2. MP-A08 blocks pro-proliferative signalling pathways, induces mitochondrial-associated apoptosis in a SK-dependent manner, and reduces the growth of human lung adenocarcinoma tumours in a mouse xenograft ...