Bo Han

Asymmetric synthesis of a structurally and stereochemically complex spirooxindole pyran scaffold through an organocatalytic multicomponent cascade reaction.

A novel and convenient organocatalytic tandem reaction has been developed for the asymmetric assembly of saturated aldehydes (or enals), nitroolefins and isatins to produce six-membered oxa-spirooxindole backbones bearing four contiguous stereogenic centers and multiple functional groups with high stereoselectivity.

Synthesis of novel spirooxindolo-pyrrolidines, pyrrolizidines, and pyrrolothiazoles via a regioselective three-component [3+2] cycloaddition and their preliminary antimicrobial evaluation

A series of spirooxindolo-pyrrolidines, pyrrolizidines, and pyrrolothiazoles hybrid compounds were prepared in good yields by regioselective, three-component, 1,3-dipolar cycloaddition reactions between

Synthesis of functionalized γ-lactones via a three-component cascade reaction catalyzed by consecutive N-heterocyclic carbene systems

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Organocatalytic Asymmetric Synthesis of Spiro-oxindole Piperidine Derivatives That Reduce Cancer Cell Proliferation by Inhibiting MDM2–p53 Interaction

-unsaturated ketones with furanyl substituents and unstable azomethine ylides, which were generated in situ from isatin and various types of amino acids. The synthesized compounds were screened for their antibacterial activities against a spectrum of pathogens. Preliminary studies identified compound 5c as a potent antimicrobial agent against drug-resistant bacteria. In addition, molecular docking studies indicated that compound 5c showed strong interactions with the active sites of lanosterol demethylase, dihydrofolate reductase, and topoisomerase II. This study provides an effective entry to the rapidly construction of a chemical library of heterocycles and compound 5c is one potent antibacterial lead for subsequent optimization.Graphic Abstract

Control of Activation Mode To Achieve Diastereodivergence in Asymmetric Syntheses of Chiral Spiropiperidinone Derivatives

Since MDM2 is an inhibitor of the p53 tumor suppressor, disrupting the MDM2-p53 interaction is a promising approach for cancer therapy. Here, we used molecular dynamics simulations followed by free energy decomposition analysis to study conformational changes in MDM2 induced by three known spiro-oxindole inhibitors. Analysis of individual energy terms suggests that van der Waals and electrostatic interactions explain much of the binding affinities of these inhibitors. Binding free energies calculated for the three inhibitors using the molecular mechanics-generalized Born surface area model were consistent with experimental data, suggesting the validity of this approach. Based on this structure-function analysis, several novel spiro-oxindole derivatives were selected and evaluated for their ability to block the MDM2-p53 interaction in vitro. These results suggest that combining in silico and experimental techniques can provide insights into the structure-function relationships of MDM2 inhibitors and guide the rational design of anticancer drugs targeting the MDM2-p53 interaction.

Core-Scaffold-Inspired Asymmetric Synthesis of Polysubstituted Chiral Hexahydropyridazines that Potently Inhibit Breast Cancer Cell Proliferation by Inducing Apoptosis

Two consecutive N-heterocyclic carbene (NHC) catalytic systems were combined in a one-pot cascade reaction for the assembly of aromatic aldehydes and 2-haloenals into a structurally complex γ-lactone backbone. To our knowledge, this is the first report of NHC-catalyzed [3 + 2] annulation of α,β-unsaturated acylazoliums with 1,2-bisnucleophiles.

Catalyst-free [3 + 2] cyclization of imines and Morita–Baylis–Hillman carbonates: a general route to tetrahydropyrrolo[2,1-a]isoquinolines and dihydropyrrolo[2,1-a]isoquinolines

The flexible and simple cascade reaction involving a Michael–aldol or vinylogous Henry-acetalization relay is described. We have used the cascade reaction to assemble functionalized tetrahydronaphthalene- or isochroman-fused spirooxindoles and other drug-like spirocyclic scaffolds. The mild reaction conditions, short reaction times, and high tolerance for various functional groups make this method attractive for constructing pharmacologically interesting architectures.

A practical green chemistry approach to synthesize fused bicyclic 4H-pyranes via an amine catalysed 1,4-addition and cyclization cascade

Asymmetric synthesis of pharmacologically interesting piperidine-fused spiro-oxindole derivatives has been achieved via an organocatalytic Michael/aza-Henry/hemiaminalization cascade reaction. Chiral compounds synthesized by this strategy potently inhibited the proliferation of several breast cancer cell lines. Mechanistic studies suggest that the most potent compound 9e can directly interfere with MDM2-p53 interactions and elevate protein levels of p53 and p21, thereby inducing cell cycle arrest and mitochondrial apoptosis.