Chao Che

Magnetic nanoparticle-supported Hoveyda–Grubbs catalysts for ring-closing metathesis reactions

Magnetically recyclable Hoveyda-Grubbs catalyst can be readily assembled using magnetic nanoparticles as support, and this catalyst combines convenient recyclability and excellent activity on ring-closing metathesis (RCM) reactions.

One-pot syntheses of chromeno[3,4-c]pyrrole-3,4-diones via Ugi-4CR and intramolecular Michael addition.

One-pot and diastereoselective syntheses of diverse chromeno[3,4-c]pyrrole-3,4-diones from readily available starting materials were achieved via sequential Ugi-4CR and intramolecular Michael addition.

One-Pot Syntheses of Isoquinolin-3-ones and Benzo-1,4-diazepin-2,5-diones Utilizing Ugi-4CR Post-Transformation Strategy

One-pot and efficient syntheses of structurally diverse isoquinolin-3-ones and isoquinolin-3-one-based benzo-1,4-diazepin-2,5-diones have been developed. The notable features of the process include the Ugi condensation of monomasked phthalaldehydes with amines, carboxylic acids, and isonitriles, followed by HClO4-mediated intramolecular condensation of the carbonyl with amide.

Identifying tumor cell growth inhibitors by combinatorial chemistry and zebrafish assays.

Cyclin-dependent kinases (CDKs) play important roles in regulating cell cycle progression, and altered cell cycles resulting from over-expression or abnormal activation of CDKs observed in many human cancers. As a result, CDKs have become extensive studied targets for developing chemical inhibitors for cancer therapies; however, protein kinases share a highly conserved ATP binding pocket at which most chemical inhibitors bind, therefore, a major challenge in developing kinase inhibitors is achieving target selectivity. To identify cell growth inhibitors with potential applications in cancer therapy, we used an integrated approach that combines one-pot chemical synthesis in a combinatorial manner to generate diversified small molecules with new chemical scaffolds coupled with growth inhibition assay using developing zebrafish embryos. We report the successful identification of a novel lead compound that displays selective inhibitory effects on CDK2 activity, cancer cell proliferation, and tumor progression in vivo. Our approaches should have general applications in developing cell proliferation inhibitors using an efficient combinatorial chemical genetic method and integrated biological assays. The novel cell growth inhibitor we identified should have potential as a cancer therapeutic agent.

Construction of All-Carbon Quaternary Center by R2AlCl−Mediated Ring-Opening Reaction of Oxacycles

An unexpected R(2)AlCl-mediated ring-opening reaction of oxacycles for the formation of all-carbon quaternary centers was discovered, and a possible mechanism is proposed. The developed chemistry provides a concise approach to synthesize structural diverse of dolastane-type compounds.

Syntheses of Fused Tetracyclic Quinolines via Ugi-Variant MCR and Pd-Catalyzed Bis-annulation

Diversity-oriented synthesis of fused tetracyclic 6,11-dihydroquinoxalino[2,3-b]quinolines is described via a sequential Ugi-variant multicomponent reaction and Pd-catalyzed bis-annulation in one-pot process.

A novel anti-tumor inhibitor identified by virtual screen with PLK1 structure and zebrafish assay.

Polo-like kinase 1 (PLK1), one of the key regulators of mitosis, is a target for cancer therapy due to its abnormally high activity in several tumors. Plk1 is highly conserved and shares a nearly identical 3-D structure between zebrafish and humans. The initial 10 mitoses of zebrafish embryonic cleavages occur every∼30 minutes, and therefore provide a rapid assay to evaluate mitosis inhibitors including those targeting Plk1. To increase efficiency and specificity, we first performed a computational virtual screen of∼60000 compounds against the human Plk1 3-D structure docked to both its kinase and Polo box domain. 370 candidates with the top free-energy scores were subjected to zebrafish assay and 3 were shown to inhibit cell division. Compared to general screen for compounds inhibiting zebrafish embryonic cleavage, computation increased the efficiency by 11 folds. One of the 3 compounds, named I2, was further demonstrated to effectively inhibit multiple tumor cell proliferation in vitro and PC3 prostate cancer growth in Xenograft mouse model in vivo. Furthermore, I2 inhibited Plk1 enzyme activity in a dose dependent manner. The IC50 values of I2 in these assays are compatible to those of ON-01910, a Plk1 inhibitor currently in Phase III clinic trials. Our studies demonstrate that zebrafish assays coupled with computational screening significantly improves the efficiency of identifying specific regulators of biological targets. The PLK1 inhibitor I2, and its analogs, may have potential in cancer therapeutics.

Synthesis and characterization of Sant-75 derivatives as Hedgehog-pathway inhibitors.

Summary Sant-75 is a newly identified potent inhibitor of the hedgehog pathway. We designed a diversity-oriented synthesis program, and synthesized a series of Sant-75 analogues, which lays the foundation for further investigation of the structure–activity relationship of this important class of hedgehog-pathway inhibitors.

One-pot synthesis of tetracyclic fused imidazo[1,2-a]pyridines via a three-component reaction.

Summary A novel three-component reaction has been developed to assemble biologically and pharmaceutically important tetracyclic fused imidazo[1,2-a]pyridines in a one-pot fashion utilizing readily available 2-aminopyridines, isatins and isocyanides. The three-component coupling proceeds through the Groebke–Blackburn–Bienaymé reaction followed by a retro-aza-ene reaction and subsequent nucleophilic reaction of the in-situ generated imidazo[1,2-a]pyridines bearing an isocyanate functional group.