Copper-mediated cascade radical cyclization of olefins with naphthalenyl iododifluoromethyl ketones.

Copper-mediated radical cyclization of naphthalenyl iododifluoromethyl ketones with olefins was successfully developed to generate a series of unprecedented gem-difluorodihydrophenanthrenones, especially 2,2-difluoro-3,4-dihydrophenanthren-1(2H)-one derivatives. This strategy features the use of cheap copper powder and excellent regioselectivity and diastereoselectivity, thus providing a facile approach for application in drug discovery and development. Preliminary mechanistic studies indicate the involvement of difluorinated radical intermediates. Density functional theory (DFT) calculation was performed to provide further evidence for regioselectivity.

Discovery of novel acylhydrazone neuraminidase inhibitors.

Neuraminidase (NA) plays a crucial role in the replication and transmission of influenza virus. NA inhibitors have been developed as effective treatments for influenza A and B infections. In this paper, a new lead neuraminidase inhibitor 6a (IC50 = 7.10 ±â€¯0.2 µM) was discovered by ligand-based virtual screening, receptor-based virtual screening, molecular dynamics simulation (MD), and bioassay validation. MD simulation indicates that the morpholinyl group of 6a could be embedded in 430-loop of NA. To exploit the 430-loop in the active site, a series of novel acylhydrazone NA inhibitors 6b-6g were designed and synthesized based on the lead compound 6a. Compound 6e exerts the most potency, with IC50 value of 2.37 ±â€¯0.5 µM against NA, which is lower than that of oseltamivir carboxylate (OC) (IC50 = 3.84 µM). Overall, this work provided unique insights in the discovery of potent inhibitors against NA.

Molecular modeling study, synthesis and biological evaluation of combretastatin A-4 analogues as anticancer agents and tubulin inhibitors.

As the major structural component of microtubules, tubulin is an interesting target for the development of anticancer agents. In this study, 64 tubulin polymerization inhibitors of five-membered heterocycle-based combretastatin A-4 analogues were studied by a combination of molecular modeling techniques including 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation. The CoMFA (comparative molecular field analysis) and CoMSIA (comparative molecular similarity indices analysis) models were established with desirable statistical parameters and excellent predictive ability. 20 ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. Combining the binding free energy calculations and 3D-QSAR results, some new heterocycle-based combretastatin A-4 analogues were designed. Three of them were synthesized and biologically evaluated. Compound 13a displayed potent antiproliferative activity (IC50 value of 1.31 µM against HepG2 cells, IC50 value of 1.37 µM against A549 cells) and inhibition of tubulin polymerization activity (IC50 value of 0.86 µM). Compound 13b also presented good activity against HepG2 cells (IC50 value of 4.75 µM). The experimental results demonstrated that the built models were effective for the development of novel anticancer agents and tubulin inhibitors.

Molecular modeling study of CP-690550 derivatives as JAK3 kinase inhibitors through combined 3D-QSAR, molecular docking, and dynamics simulation techniques.

To develop more potent JAK3 kinase inhibitors, a series of CP-690550 derivatives were investigated using combined molecular modeling techniques, such as 3D-QSAR, molecular docking and molecular dynamics (MD). The leave-one-out correlation (q2) and non-cross-validated correlation coefficient (r2) of the best CoMFA model are 0.715 and 0.992, respectively. The q2 and r2 values of the best CoMSIA model are 0.739 and 0.995, respectively. The steric, electrostatic, and hydrophobic fields played important roles in determining the inhibitory activity of CP-690550 derivatives. Some new JAK3 kinase inhibitors were designed. Some of them have better inhibitory activity than the most potent Tofacitinib (CP-690550). Molecular docking was used to identify some key amino acid residues at the active site of JAK3 protein. 10ns MD simulations were successfully performed to confirm the detailed binding mode and validate the rationality of docking results. The calculation of the binding free energies by MMPBSA method gives a good correlation with the predicted biological activity. To our knowledge, this is the first report on MD simulations and free energy calculations for this series of compounds. The combination results of this study will be valuable for the development of potent and novel JAK3 kinase inhibitors.

Combretastatin A-4 and Derivatives: Potential Fungicides Targeting Fungal Tubulin.

Combretastatin A-4, first isolated from the African willow tree Combretum caffrum, is a tubulin polymerization inhibitor in medicine. It was first postulated as a potential fungicide targeting fungal tubulin for plant disease control in this study. Combretastatin A-4 and its derivatives were synthesized and tested against Rhizoctonia solani and Pyricularia oryzae. Several compounds have EC50 values similar to or better than that of isoprothiolane, which is widely used for rice disease control. Structure-activity relationship study indicated the the cis configuration and hydroxyl group in combretastatin A-4 are crucial to the antifungal effect. Molecular modeling indicated the binding sites of combretastatin A-4 and carbendazim on fungal tubulin are totally different. The bioactivity of combretastatin A-4 and its derivatives against carbendazim-resistant strains was demonstrated in this study. The results provide a new approach for fungicide discovery and fungicide resistance management.