Wenjin Yan

Synthesis of N-alkoxycarbonyl ketimines derived from isatins and their application in enantioselective synthesis of 3-aminooxindoles.

A simple and general method in the synthesis of N-alkoxycarbonyl ketimines derived from isatins has been described first. Generally, the enantioselective addition of 1,3-dicarbonyl compounds to this kind of ketimine affords chiral 3-amino oxindoles in high yield and excellent ee.

Asymmetric aza-Mannich addition of oxazolones to N-tosyl aldimines: synthesis of chiral alpha-disubstituted alpha,beta-diamino acids.

An organocatalytic enantioselective addition of oxazolones to N-tosyl aldimines has been developed. The process is promoted by a readily prepared cinchona alkaloid ligand and affords a series of valuable alpha-disubstituted alpha,beta-diamino acid derivatives with excellent enantioselectivities (up to 97% ee) and diastereoselectivities (up to >30:1 dr). The adducts can be transformed into the corresponding protected chiral alpha-disubstituted alpha,beta-diamino acids by a one-pot hydrolyzed reaction smoothly.

Construction of Vicinal Tetrasubstituted Stereocenters with a C-F Bond through a Catalytic Enantioselective Detrifluoroacetylative Mannich Reaction

An efficient asymmetric detrifluoroacetylative Mannich reaction of 2-fluoro-1,3-diketones/hydrates with isatin-derived ketimines catalyzed by a chiral copper(II)-diamine complex has been realized. The reaction afforded a series of 3-substituted 3-amino-2-oxindoles bearing fluorine-containing vicinal tetrasubstituted stereocenters in high yields (up to 99%) with excellent diastereoselectivities (up to >20:1 dr) and enantioselectivities (up to 94% ee).

Highly Enantioslective Synthesis of Multisubstituted Polyfunctional Dihydropyrrole via an Organocatalytic Tandem Michael/Cyclization Sequence

A unique approach to asymmetric synthesis of various optically pure multisubstituted 2,3-dihydropyrroles catalyzed by a novel rosin-derived tertiary amine-thiourea via a tandem Michael/cyclization sequence with high yield (up to 97%) and good to excellent enantioselectivities (up to 97% ee) is present. This strategy provides an efficient and convenient method to access enantioenrich nitrogen heterocycles.

Highly Enantioselective Cascade Reaction Catalyzed by Squaramides: the Synthesis of CF3-Containing Chromanes.

A catalytic asymmetric method for the synthesis of 2-CF3 chromanes has been described. Generally, the squaramide-catalyzed cascade reaction of 2-hydroxychalcones with β-CF3-nitroalkenes gave the CF3-containing heterocyclic compounds bearing three contiguous stereogenic centers in excellent yields, diastereoselectivities, and enantioselectivities.

Dual antifungal properties of cationic antimicrobial peptides polybia-MPI: Membrane integrity disruption and inhibition of biofilm formation

With the increasing emergence of resistant fungi, the discovery and development of novel antifungal therapeutics were urgently needed. Compared with conventional antibiotics, the limited propensity of AMPs to induce resistance in pathogens has attracted great interest. In the present study, the antifungal activity and its mechanism-of-action of polybia-MPI, a cationic peptide from the venom of Social wasp Polybia Paulista was investigated. We demonstrated that polybia-MPI could potently inhibit the growth of Candida albicans (C. albicans) and Candida glabrata (C. glabrata). The 50% inhibitory concentrations (IC50) of Polybia-MPI against cancer cells were much higher than the MICs against the tested C. albicans and C. glabrata cells, indicating that polybia-MPI had high selectivity between the fungal and mammalian cells. Our results also indicated that membrane disturbance mechanism was involved in the antifungal activity. Furthermore, polybia-MPI could inhibit the bio film forming of C. glabrata, which was frequently associated with clinically significant biofilm. These results suggest that polybia-MPI has great advantages in the development of antifungal agents.

Membrane active antimicrobial activity and molecular dynamics study of a novel cationic antimicrobial peptide polybia-MPI, from the venom of Polybia paulista

As the frequent emergence of the resistant bacteria, the development of new agents with a new action mode attracts a great deal of interest. It is now widely accepted that antimicrobial peptides (AMPs) are promising alternatives to conventional antibiotics. In this study, antimicrobial peptide polybia-MPI and its analogs were synthesized and their antibacterial activity was studied. Our results revealed that polybia-MPI has potent antibacterial activity against both Gram-positive and Gram-negative bacteria. Its ability to make PI permeate into bacteria and lead to the leakage of calcein from model membrane LUVs, suggests a killing mechanism involving membrane perturbation. SEM and TEM microscopy experiments verified that the morphology of bacteria was changed greatly under the treatment of polybia-MPI. Compared with the conventional chemotherapy, polybia-MPI targets the cell membrane rather than entering into the cell to exert its antibacterial activity. Furthermore, molecular dynamics (MD) simulations were employed to investigate the mechanism of membrane perturbation. The results indicated that the α-helical conformation in the membrane is required for the exhibition of antibacterial activity and the membrane disturbance by polybia-MPI is a cooperative process. In conclusion, with the increasing resistance to conventional antibiotics, there is no doubt that polybia-MPI could offer a new strategy to defend the resistant bacteria.

Asymmetric Synthesis of CF3- and Indole-Containing Thiochromanes via a Squaramide-Catalyzed Michael–Aldol Reaction

A Michael-aldol reaction of 2-mercaptobenzaldehyde with β-indole-β-CF3 enones catalyzed by a squaramide has been realized. The method affords a series of 2-CF3-2-indole-substituted thiochromanes featuring a CF3-containing quaternary stereocenter in excellent yields, diastereoselectivities, and enantioselectivities.

Membrane Perturbation Action Mode and Structure-Activity Relationships of Protonectin, a Novel Antimicrobial Peptide from the Venom of the Neotropical Social Wasp Agelaia pallipes pallipes

ABSTRACT With the extensive use of antibiotics, multidrug-resistant bacteria emerge frequently. New antimicrobial agents with novel modes of action are urgently needed. It is now widely accepted that antimicrobial peptides (AMPs) could be promising alternatives to conventional antibiotics. In this study, we aimed to study the antimicrobial activity and mechanism of action of protonectin, a cationic peptide from the venom of the neotropical social wasp Agelaia pallipes pallipes. We demonstrated that protonectin exhibits potent antimicrobial activity against a spectrum of bacteria, including multidrug-resistant strains. To further understand this mechanism, the structural features of protonectin and its analogs were studied by circular dichroism (CD). The CD spectra demonstrated that protonectin and its natural analog polybia-CP formed a typical α-helical conformation in the membrane-mimicking environment, while its proline-substituted analog had much lower or even no α-helix conformation. Molecular dynamics simulations indicated that the α-helical conformation in the membrane is required for the exhibition of antibacterial activity. In conclusion, protonectin exhibits potent antimicrobial activity by disruption of the integrity of the bacterial membrane, and its α-helical confirmation in the membrane is essential for this action.

Antimicrobial peptide protonectin disturbs the membrane integrity and induces ROS production in yeast cells

Candidiasis is often observed in immunocompromised patients and is the 4th most common cause of bloodstream infections. However, antifungals are limited, so novel antifungal agents are urgently needed. Antimicrobial peptides (AMPs) are considered as potential alternatives of conventional antibiotics. In the present study, antimicrobial peptide protonectin was chemically synthesized and its antifungal activity and mode of action were studied. Our results showed that protonectin has potent antifungal activity and fungicidal activity against the tested fungi cells. Its action mode involved the disruption of the membrane integrity and the inducing of the production of cellular ROS. Furthermore, protonectin could inhibit the formation of biofilm and kill the adherent fungi cells. In conclusion, with the increase of fungal infection, protonectin may offer a new strategy and be considered as a potential therapeutic agent against fungal disease.