A new class of potent liver injury protective compounds: Structural elucidation, total synthesis and bioactivity study.

A new class of potent liver injury protective compounds, phychetins A-D (1-4) featuring an unique 6/6/5/6/5 pentacyclic framework, were isolated and structurally characterized from a Chinese medicinal plant Phyllanthus franchetianus. Compounds 2-4 are three pairs of enantiomers that were initially obtained in a racemic manner, and were further separated by chiral HPLC preparation. Compounds 1-4 were proposed to be originated biosynthetically from a coexisting lignan via an intramolecular Friedel-Crafts reaction as the key step. A bioinspired total synthesis strategy was thus designated, and allowed the effective syntheses of compounds 2-4 in high yields. Some of compounds exhibited significant anti-inflammatory activities in vitro via suppressing the production of pro-inflammatory cytokine IL-1ß. Notably, compound 4, the most active enantiomeric pair in vitro, displayed prominent potent protecting activity against liver injury at a low dose of 3 mg/kg in mice, which could serve as a promising lead for the development of acute liver injury therapeutic agent.

Synthesis of Functionalized Thiazolidin-2-imine and Oxazolidin-2-one Derivatives from p-Quinamines via [3 + 2] Annulation of Isothiocyanates and CO2.

An efficient and environmentally friendly synthetic approach to prepare thiazolidine-2-imine and oxazolidine-2-one derivatives has been developed. Thiazolidine-2-imines are synthesized in good to excellent yields by [3 + 2] annulation of p-quinamines with isothiocyanates under catalyst- and solvent-free conditions. Oxazolidine-2-ones are produced in good to excellent yields via [3 + 2] annulation of p-quinamines with CO2 using triethylenediamine (DABCO) as an organocatalyst. Furthermore, this strategy can be performed on a gram scale and tolerate a wide range of functional groups.

Chiral Phosphoric Acid Catalyzed Asymmetric Desymmetrization of para-Quinamines with Isocyanates: Access to Functionalized Imidazolidin-2-one Derivatives.

The development of enantioselective desymmetrization of para-quinamines with isocyanates catalyzed by chiral phosphoric acid is reported. The strategy provides concise access to functionalized imidazolidin-2-one derivatives in high yields and enantioselectivities under mild reaction conditions. Remarkably, this reaction could be performed on a gram scale using 5 mol % catalyst loading and the chiral imidazolidin-2-one derivatives could be easily transformed into valuable scaffolds without disturbing the enantiopurity, demonstrating the synthetic utility of this protocol.

Discovery of Evodiamine Derivatives as Highly Selective PDE5 Inhibitors Targeting a Unique Allosteric Pocket.

Clinical use of phosphodiesterase-5 (PDE5) inhibitors is limited by several side effects due to weak isoform selectivity. Herein, a unique allosteric pocket of PDE5 is identified by molecular modeling and structural biology, which enables the discovery of highly selective PDE5 inhibitors from natural product evodiamine (EVO). The crystal structure of PDE5 with bound EVO derivative (S)-7e revealed that binding of (S)-7e to the novel allosteric pocket induced dramatic conformation changes in the H-loop with a maximum 24 Å movement of their Cα atoms. This movement directly blocks the binding of substrate/inhibitors to the PDE5 active site, which is different from all traditional PDE5 inhibitors such as sildenafil, tadalafil, and vardenafil. These derivatives showed >570-fold selectivity over PDE6C and PDE11A and achieved potent efficacy for the effective treatment of pulmonary hypertension in vivo.

Discovery and Optimization of Chromone Derivatives as Novel Selective Phosphodiesterase 10 Inhibitors.

Phosphodiesterase 10 (PDE10) inhibitors have received much attention as promising therapeutic agents for central nervous system (CNS) disorders such as schizophrenia and Huntington's disease. Recently, a hit compound 1 with a novel chromone scaffold has shown moderate inhibitory activity against PDE10A (IC50 = 500 nM). Hit-to-lead optimization has resulted in compound 3e with an improved inhibitory activity (IC50 = 6.5 nM), remarkable selectivity (>95-fold over other PDEs), and good metabolic stability (RLM t1/2 = 105 min) by using an integrated strategy (molecular modeling, chemical synthesis, bioassay, and cocrystal structure). The cocrystal structural information provides insights into the binding pattern of 3e in the PDE10A catalytic domain to highlight the key role of the halogen and hydrogen bonds toward Tyr524 and Tyr693, respectively, thereby resulting in high selectivity against other PDEs. These new observations are of benefit for the rational design of the next generation PDE10 inhibitors for CNS disorders.

3-Aminooxetanes: versatile 1,3-amphoteric molecules for intermolecular annulation reactions.

Despite the versatility of amphoteric molecules, stable and easily accessible ones are still limitedly known. As a result, the discovery of new amphoteric reactivity remains highly desirable. Herein we introduce 3-aminooxetanes as a new family of stable and readily available 1,3-amphoteric molecules and systematically demonstrated their amphoteric reactivity toward polarized π-systems in a diverse range of intermolecular [3 + 2] annulations. These reactions not only enrich the reactivity of oxetanes, but also provide convergent access to valuable heterocycles.

A mild catalytic synthesis of 2-oxazolines via oxetane ring-opening: rapid access to a diverse family of natural products.

A new catalytic protocol for the expedient synthesis of oxazolines from oxetanes is disclosed. This mild process complements the conventional oxazoline synthesis based on non-catalytic cyclization of ß-hydroxy or unsaturated amides. It is also a new addition to the reactivity profile of oxetanes leading to heterocycles. In the presence of In(OTf)3, various 3-amido oxetanes underwent smooth intramolecular cyclization to form the corresponding 2-oxazolines, including some valuable oxazoline-based bidentate ligands. This protocol also provides rapid access to various natural products and antibacterial molecules.

One-Pot Synthesis of Deuterated Aldehydes from Arylmethyl Halides.

A facile, one-pot approach for synthesizing deuterated aldehydes from arylmethyl halides was developed using D2O as the deuterium source. The efficient process is realized by a sequence of formation, H/D exchange, and oxidation of pyridinium salt intermediates. The mild and air-compatible reaction conditions enable efficient synthesis of diverse deuterated aldehydes with high deuterium incorporation.

Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease.

Phosphodiesterase-9 (PDE9) is a promising target for treatment of Alzheimer's disease (AD). To discover multifunctional anti-AD agents with capability of PDE9 inhibition and antioxidant activity, a series of novel pyrazolopyrimidinone derivatives, coupling with the pharmacophore of antioxidants such as ferulic and lipolic acids have been designed with the assistance of molecular docking and dynamics simulations. Twelve out of 14 synthesised compounds inhibited PDE9A with IC50 below 200 nM, and showed good antioxidant capacities in the ORAC assay. Compound 1h, the most promising multifunctional anti-AD agent, had IC50 of 56 nM against PDE9A and good antioxidant ability (ORAC (trolox) = 3.3). The selectivity of 1h over other PDEs was acceptable. In addition, 1h showed no cytotoxicity to human neuroblastoma SH-SY5Y cells. The analysis on structure-activity relationship (SAR) and binding modes of the compounds may provide insight into further modification.

Discovery and Optimization of Chromeno[2,3-c]pyrrol-9(2H)-ones as Novel Selective and Orally Bioavailable Phosphodiesterase 5 Inhibitors for the Treatment of Pulmonary Arterial Hypertension.

Phosphodiesterase 5 (PDE5) inhibitors have been used as clinical agents to treat erectile dysfunction and pulmonary arterial hypertension (PAH). Herein, we detail the discovery of a novel series of chromeno[2,3-c]pyrrol-9(2H)-one derivatives as selective and orally bioavailable inhibitors against phosphodiesterase 5. Medicinal chemistry optimization resulted in 2, which exhibits a desirable inhibitory potency of 5.6 nM with remarkable selectivity as well as excellent pharmacokinetic properties and an oral bioavailability of 63.4%. In addition, oral administration of 2 at a dose of 5.0 mg/kg caused better pharmacodynamics effects on both mPAP (mean pulmonary artery pressure) and RVHI (index of right ventricle hypertrophy) than sildenafil citrate at a dose of 10.0 mg/kg. These activities along with its reasonable druglike properties, such as human liver microsomal stability, cytochrome inhibition, hERG inhibition, and pharmacological safety, indicate that 2 is a potential candidate for the treatment of PAH.

The discovery, complex crystal structure, and recognition mechanism of a novel natural PDE4 inhibitor from Selaginella pulvinata.

Phosphodiesterase-4 (PDE4) is an important drug target for treatment of inflammation-related diseases. Till now, natural PDE4 inhibitors are rare and their co-crystal structures with PDE4 are hardly available. In the present study, selaginpulvilins K and L (1 and 2), two novel fluorene derivatives, were isolated from a traditional Chinese medicine Selaginella pulvinata and exhibited remarkable inhibition against phosphodiesterase-4D (PDE4D) at IC50 11nM and 90nM, respectively. Compound 1 also showed a good selectivity across PDE families with the selective fold ranging from 30 to 909. To understand the recognition mechanism of selaginpulvilins towards PDE4, the crystal structure of PDE4D bound with 1 was successfully determined by the X-ray diffraction method and presented an unusual binding mode in which the stretched skeleton of the inhibitor bound shallowly to the active site but had interactions with multi sub-pockets, such as Q, HC, M, and S, especially strong interaction with the metal region. Assisted with molecular modeling, the structure-activity relationship and the selectivity of selaginpulvilins were also well explored, which would facilitate the future rational inhibitor design or structural optimizations.

Organocatalytic Asymmetric Nucleophilic Addition to o-Quinone Methides by Alcohols.

The first catalytic asymmetric intermolecular alcohol conjugate addition to o-quinone methides (o-QMs) is disclosed. Due to reversible C-O bond formation and low nucleophilicity of alcohols, catalytic asymmetric oxa-Michael additions with simple alcohol nucleophiles to establish acyclic oxygenated carbon stereocenters remain scarce. The present reaction represents a rare example of this type. With a suitable chiral acid catalyst, the in situ formation of o-QMs and subsequent conjugate addition proceeded with high efficiency and enantioselectivity. The chiral ether products are versatile precursors to other chiral molecules.

Synthesis of 1-[bis(trifluoromethyl)phosphine]-1'-oxazolinylferrocene ligands and their application in regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates.

A class of novel, easily accessible and air-stable 1-[bis(trifluoromethyl)phosphine]-1'-oxazolinylferrocene ligands has been synthesized from ferrocene. It became apparent that these ligands can be used in the regio- and enantioselective Pd-catalyzed allylic alkylation of monosubstituted allyl substrates in a highly efficient manner. Excellent regio- and enantioselectivity could be obtained for a wide range of substrates.

Discovery of highly potent DPP-4 inhibitors by hybrid compound design based on linagliptin and alogliptin.

Highly potent DPP-4 inhibitors have been identified by hybrid compound design based on linagliptin and alogliptin. The most promising compound 2h (IC50 = 0.31 nM) exhibited 8.5-fold and 2.5-fold more potent activity than that of alogliptin (IC50 = 2.63 nM) and linagliptin (IC50 = 0.77 nM), respectively. Compound 2h had a good inhibition selectivity for DPP-4 over DPP-8/9 and thus was selected for further biological evaluation, including oral glucose tolerance, plasma DPP-4 inhibitory activity, pharmacokinetic profile, acute toxicity and hERG inhibition. The assay results showed that 2h displayed significant in vivo glucose-lowering effect and low risk of toxicity. Further studies are expected to confirm 2h as a potential drug candidate for the treatment of type 2 diabetes.

Total synthesis of (-)-8-deoxyserratinine via an efficient Helquist annulation and double N-alkylation reaction.

The first enantioselective total synthesis of (-)-8-deoxyserratinine has been achieved in 15 steps from enone 4 with 7% overall yield. The key features include a highly efficient Helquist annulation to furnish the cis-fused 6/5 bicycle, facile construction of the aza nine-membered ring system employing double N-alkylation strategy, as well as asymmetric Shi epoxidation, delivering the desired beta-epoxide stereospecifically.