Dengyou Zhang

An expedient Pd/DBU mediated cyanation of aryl/heteroaryl bromides with K4[Fe(CN)6]

A practical Pd(PPh(3))(4)/DBU catalytic system for the synthesis of pharmaceutically relevant aminopyridine nitrile intermediates, as well as a variety of other aryl nitriles using non-toxic K(4)[Fe(CN)(6)] has been developed. The key features of our new protocol for cyanation lie in that the reaction can be carried out with readily available Pd(PPh(3))(4) under mild and green conditions, even without the assistance of other ligands.

Recent Advances in Neuraminidase Inhibitor Development as Anti-influenza Drugs

The recent emergence of the highly pathogenic H5N1 subtype of avian influenza virus (AIV) and of the new type of human influenza A (H1N1) have emphasized the need for the development of effective anti‐influenza drugs. Presently, neuraminidase (NA) inhibitors are widely used in the treatment and prophylaxis of human influenza virus infection, and tremendous efforts have been made to develop more potent NA inhibitors to combat resistance and new influenza viruses. In this review, we discuss the structural characteristics of NA catalytic domains and the recent developments of new NA inhibitors using structure‐based drug design strategies. These drugs include analogues of zanamivir, analogues of oseltamivir, analogues of peramivir, and analogues of aromatic carboxylic acid and present promising options for therapeutics or leads for further development of NA inhibitors that may be useful in the event of a future influenza pandemic.

Gold(I)-Catalyzed Tandem Transformation: A Simple Approach for the Synthesis of Pyrrolo/Pyrido[2,1-a][1,3]benzoxazinones and Pyrrolo/Pyrido[2,1-a]quinazolinones

We have developed a simple method for the synthesis of pyrrolo/pyrido[2,1-a][1,3]benzoxazinones and pyrrolo/pyrido[2,1-a]quinazolinones from 2-amino benzoic acids and 2-amino benzamides via a gold(I)-catalyzed tandem coupling/cyclization process. The tricyclic or polycyclic molecular architectures were constructed in one pot with the formation of three new bonds.

Palladium-catalyzed difunctionalization of alkynes via C-N and S-N cleavages: a versatile approach to highly functional indoles.

Palladium-catalyzed intramolecular addition of C-N and S-N bond to alkynes with the migration of functional groups has been achieved. A wide range of functional groups including acyl, pyruvoyl, amide, and sulfonyl groups can migrate smoothly and be conveniently introduced at the C-3 postion of indoles in our catalytic system. The operational simplicity and broad substrate scope demonstrate the great potential of this method for the synthesis of highly functional indoles.

Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate

SIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate. To elucidate the activation mechanism, we solved the crystal structure of SIRT3/ac-RHKK(ac)-AMC complex. The structure revealed that the fluorophore blocked the H-bond formation and created a cavity between the substrate and the Rossmann fold. We built the SIRT1/ac-RHKK(ac)-AMC complex model based on the crystal structure. K(m) and K(d) determinations demonstrated that the fluorophore decreased the peptide binding affinity. The binding modes of SIRT1 activators indicated that a portion of the activators interacts with the fluorophore through π-stacking, while the other portion inserts into the cavity or interacts with the Rossmann fold, thus increasing the substrate affinity. Our study provides new insights into the mechanism of SIRT1 activation and may aid the design of novel SIRT1 activators.

Discovery of novel 2-aminopyridine-3-carboxamides as c-Met kinase inhibitors.

A series of 2-aminopyridine-3-carboxamide derivatives against c-Met were designed and synthesized by employing bioisosteric replacement of heterocyclic moieties with the amide bond. The structure-activity relationship (SAR) at various positions of the scaffold was explored. In this study, a promising compound (S)-24o with a c-Met IC(50) of 0.022 μM was identified. The compound exhibited dose-dependent inhibition of the phosphorylation of c-Met as well as downstream signaling in EBC-1 cells. Furthermore, the interactive binding model of (S)-24o with c-Met was elucidated by virtue of a molecular modeling study.

Efficient Dehydrative Sialylation of C-4-Aminated Sialyl-Hemiketal Donors with Ph2SO/Tf2O

An efficient approach to the dehydrative sialylation of various substrates with C-4-aminated sialyl-hemiketal donors by using the reagent combination of diphenyl sulfoxide and triflic anhydride is reported. By using a C-4-hindered non-nucleophilic amine auxiliary, excellent yields and high alpha-stereoselectivities were obtained for coupling with a wide range of primary and secondary acceptors.

Highly α-Selective Synthesis of Sialyl Spirohydantoins by Regiospecific Domino Condensation/O→N Acyl Migration/N-Sialylation of Carbodiimides with Peracetylated Sialic Acid

A novel and efficient process for the synthesis of alpha-sialyl spirohydantoin analogues via one-pot sequential reaction involving various carbodiimides and peracetylated Neu5Ac is reported. BF(3) x Et(2)O mediating intramolecular N-sialylation with excellent alpha-selectivity is first demonstrated.

Design, Synthesis, and Biological Evaluation of Novel Imidazo[1,2-a]pyridine Derivatives as Potent c-Met Inhibitors

A series of imidazo[1,2-a]pyridine derivatives against c-Met was designed by means of bioisosteric replacement. In this study, a selective, potent c-Met inhibitor, 22e was identified, with IC50 values of 3.9 nM against c-Met kinase and 45.0 nM against c-Met-addicted EBC-1 cell proliferation, respectively. Compound 22e inhibited c-Met phosphorylation and downstream signaling across different oncogenic forms in c-Met overactivated cancer cells and model cells. Compound 22e significantly inhibited tumor growth (TGI = 75%) with good oral bioavailability (F = 29%) and no significant hERG inhibition. On the basis of systematic metabolic study, the pathway of all possible metabolites of 22e in liver microsomes of different species has been proposed, and a major NADPH-dependent metabolite 33 was generated by liver microsomes. To block the metabolic site, 42 was designed and synthesized for further evaluation. Taken together, the imidazo[1,2-a]pyridine scaffold showed promising pharmacological inhibition of c-Met and warrants further investigation.

Synthesis and biological evaluation of 2-amino-5-aryl-3-benzylthiopyridine scaffold based potent c-Met inhibitors.

A series of 2-amino-N-benzylpyridine-3-carboxnamides, 2-amino-N-benzylpyridine-3-sulfonamides and 2-amino-3-benzylthiopyridines against c-Met were designed by means of bioisosteric replacement and docking analysis. Optimization of the 2-amino-3-benzylthiopyridine scaffold led to the identification of compound (R)-10b displaying c-Met inhibition with an IC50 up to 7.7nM. In the cytotoxic evaluation, compound (R)-10b effectively inhibited the proliferation of c-Met addictive human cancer cell lines (IC50 from 0.19 to 0.71μM) and c-Met activation-mediated cell metastasis. At a dose of 100mg/Kg, (R)-10b evidently inhibited tumor growth (45%) in NIH-3T3/TPR-Met xenograft model. Of note, (R)-10b could overcome c-Met-activation mediated gefitinib-resistance, which indicated its potential use for drug combination. Taken together, 2-amino-3-benzylthiopyridine scaffold was first disclosed and exhibited promising pharmacological profiles against c-Met, which left room for further exploration.