Junhai Xiao

Beclin 1-independent autophagy induced by a Bcl-XL/Bcl-2 targeting compound, Z18.

Inhibitors of Bcl-XL/Bcl-2 can induce autophagy by releasing the autophagic protein Beclin 1 from its complexes with these proteins. Here we report a novel compound targeting the BH3 binding groove of Bcl-XL/Bcl-2, Z18, which efficiently induces autophagy-associated cell death in HeLa cells, without apparent apoptosis. Unexpectedly, the inhibition of Beclin 1 and phosphatidylinositol 3-kinase have no obvious effect on Z18-induced autophagy in HeLa cells, implying that it is a non-canonical Beclin 1-independent autophagy. Meanwhile, the accumulation of autophagosomes is positively correlated with Z18-induced cell death and the full flux of autophagy is not necessary.

Super adsorption capability from amorphousization of metal oxide nanoparticles for dye removal

Transitional metal oxide nanoparticles as advanced environment and energy materials require very well absorption performance to apply in practice. Although most metal oxides are based on crystalline, high activities can also be achieved with amorphous phases. Here, we reported the adsorption behavior and mechanism of methyl blue (MB) on the amorphous transitional metal oxide (Fe, Co and Ni oxides) nanoparticles, and we demonstrated that the amorphousization of transitional metal oxide (Fe, Co and Ni oxides) nanoparticles driven by a novel process involving laser irradiation in liquid can create a super adsorption capability for MB, and the maximum adsorption capacity of the fabricated NiO amorphous nanostructure reaches up to 10584.6 mgg−1, the largest value reported to date for all MB adsorbents. The proof-of-principle investigation of NiO amorphous nanophase demonstrated the broad applicability of this methodology for obtaining new super dyes adsorbents.

A novel Bcl-XL inhibitor Z36 that induces autophagic cell death in Hela cells

Inhibition of Bcl2 family proteins Bcl-XL and Bcl-2 represents a promising drug development strategy for cancer treatment by triggering apoptosis in cancer cells. Here we report a novel Bcl-XL inhibitor, Z36, which unexpectedly induces only autophagic cell death, but not apoptosis. This special property distinguishes Z36 from other previously reported Bcl-XL and Bcl-2 inhibitors that induce cancer cell death mainly through apoptosis, and makes Z36 an attractive molecular tool for studying the cellular regulation of autophagic cell death and apoptosis.

Synthesis and biological evaluation of 1,2,4-trisubstituted imidazoles and 1,3,5-trisubstituted pyrazoles as inhibitors of transforming growth factor β type 1 receptor (ALK5)

Two series of nitrogenous heterocycle compounds--1,2,4-trisubstituted imidazoles and 1,3,5-trisubstituted pyrazoles have been synthesized and evaluated for their ALK5 inhibitory activity and cytotoxicity in TGFbeta-Smad2 assay and MTT assay, respectively. The ALK4/5/7 inhibitory activity of some compound was also evaluated in ALK4/5/7 autophosphorylation assays. Compounds 6c and 14c showed relatively potent ALK5 inhibition while weak cytotoxicity. At the same time, compounds 6c and 14c display relatively better ALK5 selectivity versus ALK4/ALK7 (nearly 10-fold) compared with SB431542, a well known ALK5 inhibitor. Compound 6g2 proved to be a moderately selective ALK4 inhibitor versus ALK5 and ALK7 (>10-fold). The binding mode of 14c generated by flexible docking study shows that 14c fits well into the site cavity of ALK5 by forming several tight interactions.

Design and Synthesis of a Series of Pyrido[2,3-d]pyrimidine Derivatives as CCR4 Antagonists

A series of pyrido[2,3-d]pyrimidine derivatives were designed and synthesized based on known CC chemokine receptor 4 (CCR4) antagonists. The activities of all the newly synthesized compounds were evaluated using a chemotaxis inhibition assay. Compound 6b was proven to be a potent CCR4 antagonist that can block cell chemotaxis induced by macrophage-derived chemokine (MDC), thymus and activation regulated chemokine (TARC), and CKLF1, the natural ligands of CCR4. In addition, compound 6b is more effective than budesonide in the murine rhinitis model. The intravenous injection LD50 of compound 6b is 175 mg/kg and the oral LD50 is greater than 2,000 mg/kg.

Design, Synthesis and Biological Evaluation of N-Sulfonyl Homoserine Lactone Derivatives as Inhibitors of Quorum Sensing in Chromobacterium violaceum

A novel series of N-sulfonyl homoserine lactone derivatives 5a–l has been designed, synthesized and evaluated for quorum sensing inhibitory activities towards violacein production. Of the compounds synthesized, compound 5h was found to possess an excellent level of enantiopurity (99.2% e.e.). The results indicated that compounds bearing an ortho substituent on their phenyl ring exhibited excellent levels of inhibitory activity against violacein production. Compounds 5h and 5k in particular, with IC50 values of 1.64 and 1.66 µM, respectively, were identified as promising lead compounds for further structural modification.

Pharmacophore-based design, synthesis, and biological evaluation of novel chloro-pyridazine piperazines as human rhinovirus (HRV-3) inhibitors.

A series of chloro-pyridazine piperazines were developed based on the structure of human rhinovirus (HRV) capsid-binding inhibitors with proven activity using a pharmacophore model. A preliminary evaluation demonstrated potent activity against HRV-3 with low cytotoxicity. A docking analysis indicated that 8a could fit into, and form tight interactions (e.g., H-bonds, σ-π effect) with the active site in VP1.

Development of amino- and dimethylcarbamate-substituted resorcinol as programmed cell death-1 (PD-1) inhibitor.

Blockading the interaction of programmed death-1 (PD-1) protein with its ligands (PD-Ls, such as PD-L1) was proved to be a pathway for suppressing the development of tumors and other degradations of biological species. Thus, finding PD-1 inhibitors situated at the convergence point of drug discovery. In addition to some monoclonal antibodies applied to treat cancers clinically, the screening of organic molecules for hindering the interaction of PD-1 with PD-L1 became an efficient strategy in the development of PD-1 inhibitors. We herein applied resorcinol and 3-hydroxythiophenol as the core to link with N,N-dimethylcarbamate and other alkyl-substituted amines to afford 13 amine-appended phenyl dimethylcarbamates (AAPDs). The test for blockading the combination of PD-1 with PD-L1 revealed that abilities of 13 AAPDs were higher than that of sulfamethizole, a successful PD-1 inhibitor. In particular, large hydrophobic substituents at amine moiety or a nitro at resorcinol skeleton enhanced the inhibitory effect of AAPD even higher than that of sulfamethoxypyridazine, another successful PD-1 inhibitor. The present results may provide valuable information for further investigation on synthetic PD-1 inhibitors.

Novel Substituted Heteroaromatic Piperazine and Piperidine Derivatives as Inhibitors of Human Enterovirus 71 and Coxsackievirus A16

A series of substituted heteroaromatic piperazine and piperidine derivatives were found through virtual screening based on the structure of human enterovirus 71 capsid protein VP1. The preliminary biological evaluation revealed that compounds 8e and 9e have potent activity against EV71 and Coxsackievirus A16 with low cytotoxicity.

An Antagonist for CCR4 Alleviates Murine Allergic Rhinitis by Intranasal Administration

Background: CCR4 is highly expressed on Th2 cells. These cells play an important role in acute inflammatory responses, including those involved in allergic rhinitis. We determined whether disrupting the CCR4 ligand interaction with CCR4 antagonist could alleviate allergic rhinitis in a mouse model. Methods: BALB/c mice were sensitized with ovalbumin and alum by intraperitoneal injection and challenged with intranasally administered ovalbumin. Compound 22, which has been reported as a novel small-molecule antagonist of CCR4, was also administered intranasally. In addition, budesonide, an efficient glucocorticoid, was used as a positive control. The effects of compound 22 were quantified by multiple parameters of allergic responses in both nasal and pulmonary tissues. Results: Compound 22 significantly improved symptoms of allergic rhinitis and suppressed levels of total IgE of serum. It dramatically reduced the levels of IL-4 in bronchoalveolar lavage fluid and also decreased the number of inflammatory cells in the fluid. The infiltration of inflammatory cells, especially eosinophils, was markedly reduced in the nasal and pulmonary tissues. The number of IL-4+ cells was also significantly reduced in these tissues. Moreover, the numbers of Foxp3+ cells and IL-17+ cells were reduced, though not to a statistically significant degree. Conclusions: In our research, CCR4 antagonists such as compound 22 were proven for the first time to alleviate murine allergic rhinitis when administered nasally. CCR4 antagonists may have therapeutic potential for the treatment of allergic rhinitis.