Recent studies indicate that tubulin can be a host factor for vector‐borne flaviviruses like dengue (DENV) and Zika (ZIKV), and inhibitors of tubulin polymerization such as colchicine have been demonstrated to decrease virus replication. However, toxicity limits the application of these compounds. Herein we report prodrugs based on combretastatin and colchicine derivatives that contain an ester cleavage site for human carboxylesterase, a highly abundant enzyme in monocytes and hepatocytes targeted by DENV. Relative to their parent compounds, the cytotoxicity of these prodrugs was reduced by several orders of magnitude. All synthesized prodrugs containing a leucine ester were hydrolyzed by the esterase in vitro. In contrast to previous reports, the phenylglycine esters were not cleaved by human carboxylesterase. The antiviral activity of combretastatin, colchicine, and selected prodrugs against DENV and ZIKV in cell culture was observed at low micromolar and sub‐micromolar concentrations. In addition, docking studies were performed to understand the binding mode of the studied compounds to tubulin.

The structure and the magnetic properties of layered Li 3 Cu 2 SbO 6 are investigated by powder X-ray diffraction, static susceptibility, and electron spin resonance studies up to 330 GHz.The XRD data experimentally verify the space group C2/m with halved unit cell volume in contrast to previously reported C2/c. In addition, the data show significant Li/Cu-intersite exchange. Static magnetic susceptibility and ESR measurements show two magnetic contributions, i.e. quasi-free spins at low-temperature and a spin-gapped magnetic subsystem, with about half of the spins being associated to each subsystem. The data suggest ferromagnetic-antiferromagnetic alternating chains with J FM = -285 K and J AFM = 160 K with a significant amount of Li-defects in the chains. The results are discussed in the scenario of fragmented 1D S = 1 AFM chains with a rather high defect concentration of about 17% and associated S = ½ edge states of the resulting finite Haldane chains.

Infections with flaviviruses such as dengue virus (DENV) are prevalent throughout tropical regions worldwide. Replication of these viruses depends on tubulin, a host cell factor that can be targeted to obtain broad-spectrum antiviral agents. Targeting of tubulin does, however, require specific measures to avoid toxic side-effects. Herein, we report the synthesis and biological evaluation of combretastatin peptide hybrids that incorporate the cleavage site of the DENV protease to allow activation of the tubulin ligand within infected cells. The prodrug candidates have no effect on tubulin polymerization in vitro and are 20−2000-fold less toxic than combretastatin A-4. Several of the prodrug candidates were cleaved by the DENV protease in vitro with similar efficiency as the natural viral substrates. Selected compounds were studied in DENV and Zika virus replication assays and had antiviral activity at subcytotoxic concentrations.

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