Xianling Ning

Design, synthesis, and biological evaluation of (e)-3,4-dihydroxystyryl aralkyl sulfones and sulfoxides as novel multifunctional neuroprotective agents.

Novel (E)-3,4-dihydroxystyryl aralkyl sulfones and sulfoxides were designed and synthesized as new analogues of 1, which showed interesting multifunctional neuroprotective effects, including antioxidative and antineuroinflammatory properties. Specifically, target compounds display excellent potency in scavenging reactive free radicals and demonstrate potent effects against various kinds of toxicities, including H2O2, 6-hydroxydopamine, and lipopolysaccharide in different types of neuronal cells. The antioxidative properties of the target compounds are more potent than that of 1, and the antineuroinflammatory properties are less strong than that of 1. According to the parallel artificial membrane permeation assay for the blood-brain barrier, target compounds possess greater blood-brain barrier (BBB) permeability than 1. In short, due to improvement of the antioxidative effect, stability, and BBB permeability, (E)-3,4-dihydroxystyryl aralkyl sulfones and sulfoxides can thus be considered as potential multifunctional neuroprotective agents and serve as new lead candidates in the treatment of neurodegenerative diseases.

New pyridin-3-ylmethyl carbamodithioic esters activate pyruvate kinase M2 and potential anticancer lead compounds

Pyruvate kinase M2 (PKM2) is a key protein responsible for cancers Warburg effect. Activation of PKM2 may alter aberrant metabolism in cancer cells, which suggests PKM2 as a tumor selective therapeutic target. In this paper, the lead compound 8 was first discovered as a new kind of PKM2 activator from a random screening of an in-house compound library. Then, a series of lead compound 8 analogs were designed, synthesized and evaluated for their activation of PKM2 and anticancer activities. 7-Azaindole analog 32 was identified as the most potent PKM2 activator. Compounds with potent enzyme activity also exhibited selective anti-proliferation activity on cancer cell lines HCT116, Hela and H1299 compared with non-tumor cell line BEAS-2B. The structure-activity relationships of these compounds were supported by molecular docking results. Preliminary pharmacological studies also showed that compound 32 arrests the cell cycle at the G2/M phase in HCT116 cell line.

Synthesis and neuroprotective effect of E-3,4-dihydroxy styryl aralkyl ketones derivatives against oxidative stress and inflammation

E-3,4-Dihydroxy styryl aralkyl ketones as well as their 3,4-diacetylated derivatives as the analogues of neuroprotective agent CAPE were designed and synthesized for improving stability and lipid solubility. The neuroprotective activities of target compounds 10a-g and 11a-g were tested by three models in vitro, including 1,1-diphenyl-2-picrylhydrazyl radical scavenging capacity, neuronal protecting effect against damage induced by H2O2 in PC12 cells and nitric oxide suppression effect in BV2 microglial cells. The results demonstrated that compounds 10f and 11f exhibited the most potent neuroprotective effect against oxidative stress and inflammation, which is higher than that of the lead compound CAPE.

Design, synthesis and pharmacological evaluation of (E)-3,4-dihydroxy styryl sulfonamides derivatives as multifunctional neuroprotective agents against oxidative and inflammatory injury

A novel class of (E)-3,4-dihydroxy styryl sulfonamides and their 3,4-diacetylated derivatives as caffeic acid phenethyl ester (CAPE) analogs was designed and prepared for improving stability and solubility of the lead compound. Their neuroprotective properties were assessed by several models. The results showed that target compounds displayed positive free radical quenching abilities, superior to that of CAPE. Compounds 6j-k and 7j-k demonstrated remarkable protection effects against damage induced by hydrogen peroxide which were apparently stronger than that of CAPE. Most of target compounds could inhibit nitric oxide production. Additionally, target compounds showed high blood-brain barrier permeability.

Synthesis and antitumor activity of novel 2, 3-didithiocarbamate substituted naphthoquinones as inhibitors of pyruvate kinase M2 isoform

Abstract The M2 isoform of pyruvate kinase (PKM2) is a potential antitumor therapeutic target. In this study, we designed and synthesised a series of 2, 3-didithiocarbamate substituted naphthoquinones as PKM2 inhibitors based on the lead compound 3k that we previously reported. Among them, compound 3f (IC50 = 1.05 ± 0.17 µM) and 3h (IC50 = 0.96 ± 0.18 µM) exhibited potent inhibition of PKM2, and their inhibitory activities are superior to compound 3k (IC50 = 2.95 ± 0.53 µM) and the known PKM2 inhibitor shikonin (IC50 = 8.82 ± 2.62 µM). In addition, we evaluated in vitro antiproliferative effects of target compounds using MTS assay. Most target compounds exhibited dose-dependent cytotoxicity with IC50 values in nanomolar concentrations against HCT116, MCF7, Hela, H1299 and B16 cells. These small molecule PKM2 inhibitors not only provide candidate compounds for cancer therapy, but also offer a tool to probe the biological effects of PKM2 inhibition on cancer cells.

Design, synthesis and biological evaluation of (E)-3,4-dihydroxystyryl 4-acylaminophenethyl sulfone, sulfoxide derivatives as dual inhibitors of HIV-1 CCR5 and integrase

Aiming at the limited effectiveness of current clinical therapeutic effect of AIDS, novel series of compounds bearing (E)-3,4-dihydroxystyryl sulfone (or sulfoxide) and anilide fragments were designed and synthesized as dual inhibitors of HIV-1 CCR5/IN. The biological results indicated that several target compounds showed inhibitory activity against HIV-1 Bal (R5) infection in TZM-bl cells. Besides targeting the chemokine receptor on the host cell surface, they also displayed binding affinities with HIV-1 integrase using the surface plasmon resonance (SPR) binding assays. Molecular docking studies have inferred the possible binding mode of target compounds against integrase. These data demonstrate that the structure of (E)-3,4-dihydroxystyryl sulfone and sulfoxide derivatives have the potential to derive potent dual inhibitors of HIV-1 Integrase and CCR5.

Neuroprotective effects of (E)-3,4-diacetoxystyryl sulfone and sulfoxide derivatives in vitro models of Parkinson's disease

Abstract (E)-3,4-dihydroxystyryl aralkyl sulfones and sulfoxides have been reported as novel multifunctional neuroprotective agents in previous studies, which as phenolic compounds display antioxidative and antineuroinflammatory properties. To further enhance the neuroprotective effects and study structure-activity relationship of the derivatives, we synthesized their acetylated derivatives, (E)-3,4-diacetoxystyryl sulfones and sulfoxides, and examined their neuroprotective effects in vitro models of Parkinson’s disease. The results indicate that (E)-3,4-diacetoxystyryl sulfones and sulfoxides can significantly inhibit kinds of neuron cell injury induced by toxicities, including 6-OHDA, NO, and H2O2. More important, they show higher antineuroinflammatory properties and similar antioxidative properties to corresponding un-acetylated compounds. Thus, we suggest that (E)-3,4-diacetoxystyryl sulfones and sulfoxides may have potential for the treatment of neurodegenerative disorders, especially Parkinson’s disease.

Eg5 inhibitor YL001 induces mitotic arrest and inhibits tumor proliferation

Eg5 is a kinesin spindle protein that controls chromosomal segregation in mitosis and is thus a critical drug target for cancer therapy. We report the discovery of a potent, selective inhibitor of Eg5 designated YL001. YL001 was obtained through shape similarity based virtual screening, and it bears a 1,5-disubstituted tetrazole scaffold. YL001 exhibits favorable bioactivity in a variety of cancer cell lines, including taxol-resistant ovarian cancer and 6TG-resistant breast cancer cell lines. This compound inhibits tumor growth by 60% and significantly prolongs median survival time by more than 50% in a xenograft mouse model. YL001 blocks the ATPase activity of Eg5 and causes mitotic failure, ultimately resulting in apoptosis of cancer cells through activation of the caspase-3 pathway. Our findings demonstrate that YL001 is a potent antitumor agent that may be developed for cancer therapeutics.

Synthesis and neuroprotective evaluation of ( E )-3,4-dihydroxystyryl p -substituted-phenethyl ketone derivatives against inflammatory and oxidative injury

Abstract(E)-3,4-dihydroxystyryl p-substituted-phenethyl ketones and their 3,4-diacetylated derivatives were synthesized and examined their neuroprotective activities to further study the effect of p-substituents on the aromatic ring. The results revealed that steric hindrance effect of p-substituents has impact on neuroprotective activities against inflammatory and oxidative injury. Introduction of the bulkier groups are more beneficial to improve the neuroprotective activities than smaller groups. Compounds (4–5h, 4–5i and 4–5e) with p-substituted trifluoromethyl, isopropyl and t-butyl groups exhibited the best effects among all the target compounds.