The dynamic balance of sphingolipids plays a crucial role in diverse biological processes such as mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SKs) including SK1 and SK2 phosphorylate sphingosine to sphingosine 1-phosphate (S1P), and control the critical balance. SK1 overexpression was reported to increase cell survival and proliferation. Although several SK1 selective inhibitors have been reported, detailed analysis toward their selectivity to understand the molecular mechanism has not been performed to our knowledge. Herein, the crystal structure of SK1 and a homology model of SK2 were used to dock five inhibitors (1, 2, 3, 4 and 5). Protein–ligand complexes were then subjected to a molecular dynamics study and MM-PBSA binding free energy calculations. By analyzing the binding model of these inhibitors, we found that residues ILE170, PHE188 and THR192 in SK1 significantly contribute a favorable binding energy to the selectivity.

The discovery and development of a general method for the one-pot synthesis of substituted phenanthridines is presented. In the presence of Pd(PPh3)4, accessible precursors undergo a Suzuki cross-coupling reaction with 2-(Boc-amino)benzeneboronic acid pinacol ester and then spontaneously undergo deprotection and intramolecular condensation to form the corresponding phenanthridines in one step. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.

•We discovered the trihydroxybenzohydrazide scaffold as an SphK inhibitor.•51 derivatives were synthesized and evaluated for SAR study.•The most potent compound 33 decreased SphK expression in HCT116.•33 significantly inhibited DSS induced colitis in mice.•33 inhibited IL-6 and COX-2 overexpression induced by DSS.Sphingosine kinase (SphK)-catalyzed production of sphingosine-1-phosphate (S1P) regulates cell growth, survival and proliferation as well as inflammatory status in animals. In recent study we reported the N′-(3-(benzyloxy)benzylidene)-3,4,5-trihydroxybenzohydrazide scaffold as a potent SphK inhibitor. As a continuation of these efforts, 51 derivatives were synthesized and evaluated by SphK1/2 inhibitory activities for structure–activity relationship (SAR) study. Among them, 33 was identified as the most potent SphK inhibitor. Potency of 33 was also observed to efficiently decrease SphK1/2 expression in human colorectal cancer cells (HCT116) and significantly inhibit dextran sodium sulfate (DSS)-induced colitis as well as the decreased expression of interleukin (IL)-6 and cyclooxygenase-2 (COX-2) in mouse models. Collectively, 33 was validated as an effective SphK inhibitor, which can be served as anti-inflammatory agent to probably treat inflammatory bowel diseases in human.

Development of the methodology for hydrogenation is of great significance in organic chemistry. Ionic hydrogenation is attractive for its chemoselectivity and unique feature of product structures which is a result of the combination of reduction, cyclization and intermolecular addition. It is mostly suitable for the reduction of carbonyl groups, unsaturated hydrocarbons, imines and reductive amination of carbonyl compounds. Recent advances in ionic hydrogenation as well as its fundamental mechanism are summarized and discussed.

Sphingosine kinase 1 (SphK1) is an oncogenic lipid kinase, emerging as a novel and promising target for cancer and other diseases. Herein, hierarchical structure-based virtual screening against the sphingosine kinase 1(SphK1) binding pocket was performed. Consequently, three compounds have been identified as dual inhibitors of SphK1 and SphK2. Among them, compound 25 exhibited comparable SphK1 and SphK2 inhibitory activities to the positive control N,N-dimethylsphingosine (DMS) 1, and exerted anti-proliferative effects on U937 cells. Furthermore, molecule dynamic (MD) simulations have been conducted to provide a more detailed insight into the binding model between SphK1 and 25 in a state close to physiological conditions. 25 may serve as a potential novel scaffold for further development of SphK1 inhibitors.

The discovery and development of an efficient and versatile method for the synthesis of N-substituted lactams is described. Pyrrolindinones, piperidones, and structurally related heterocycles were formed by Al(OTf)3-catalyzed cascade cyclization and ionic hydrogenation reactions of corresponding nitrogen substituted ketoamides in good yields.

•A highly predictive 3D QSAR pharmacophore model of S1P1 agonists was developed.•35 target compounds were designed and synthesized based on the pharmacophore model.•Click chemistry reaction was used for rapidly assembly of molecules.•Most compounds were identified as potent and selective S1P1 agonists.•Three compounds showed good in vivo activities and favorable PK profiles.We have discovered a series of triazole/oxazole-containing 2-substituted 2-aminopropane-1,3-diol derivatives as potent and selective S1P1 agonists (prodrugs) based on pharmacophore-guided rational design. Most compounds showed high affinity and selectivity for S1P1 receptor. Compounds 19b, 19d and 19p displayed clear dose responsiveness in the lymphocyte reduction model when administered orally at doses of 0.3, 1.0, 3.0 mg/kg with reduced effect on heart rate. These three compounds were also identified to have favorable pharmacokinetic properties.A series of triazole/oxazole-containing 2-substituted 2-aminopropane-1,3-diol derivatives were discovered as potent and selective S1P1 agonists based on pharmacophore-guided rational design.

A facile and versatile synthesis of dihydrobenzoheterocycles via Al(OTf)3-mediated cascade cyclization and ionic hydrogenation has been developed. The reaction is applicable to a wide range of substrates with various functional groups to afford the corresponding products in good yields.

An efficient, one-pot synthesis of 4-methylisoquinolines via a cascade Pd-catalyzed Heck reaction, intramolecular cyclization and isomerization has been developed. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.

A facile method for the synthesis of tetralins has been described which uses various substituted phenylpentane-1,4-diones as starting material with a combination of TiCl4/Et3SiH. The synthesis involves three reactions under mild conditions. A mechanism has been proposed for the reductive cyclization through ionic hydrogenation, and titanium(IV) chloride catalyzed cyclization.We herein report a new efficient method for the synthesis of tetralin. The synthesis involves three reactions under mild conditions in good yields.

An efficient, one-pot synthesis of 4-methylisoquinolines via a cascade Pd-catalyzed Heck reaction, intramolecular cyclization and isomerization has been developed. This reaction has a wide range of substrates with various functional groups, and the corresponding products have been obtained in good yields.