Synthesis of Resorcinol Derivatives and their Effects on Melanin Production

Several resorcinol derivatives were synthesized and their effects on the survival rate of B16 murine melanoma cells, melanin production, and tyrosinase activity were investigated with an aim to evaluate their skin whitening effect. Twelve resorcinol derivatives were synthesized by esterification with three functional groups (L-ascorb-6-yl, ethyl, and glyceryl) linked via four alkyl chains of varying lengths (n = 2–5) at the 4-position. The structures of the 12 resorcinol derivatives were confirmed by Nuclear Magnetic Resonance (NMR). The derivatives were added to B16 murine melanoma cells and the melanin contents in the cells and culture medium were measured. To measure the tyrosinase activity, the substrate L-DOPA was added to a mushroom-derived tyrosinase solution, and the inhibition of the tyrosinase activity was determined. At 10 µM, the resorcinol derivatives did not affect the survival of the B16 murine melanoma cells, but the melanin content was reduced. At 1 µM, the derivatives significantly inhibited the tyrosinase activity in the mushroom-derived tyrosinase solution. A plot of the inhibitory effect on melanin production against the cLogP value for each resorcinol derivative indicated that the highest inhibition occurred at a cLogP value of approximately 2. Therefore, these resorcinol derivatives are expected to serve as effective skin whitening agents

PE859, a novel tau aggregation inhibitor, reduces aggregated tau and prevents onset and progression of neural dysfunction in vivo.

In tauopathies, a neural microtubule-associated protein tau (MAPT) is abnormally aggregated and forms neurofibrillary tangle. Therefore, inhibition of the tau aggregation is one of the key approaches for the treatment of these diseases. Here, we have identified a novel tau aggregation inhibitor, PE859. An oral administration of PE859 resulted in the significant reduction of sarkosyl-insoluble aggregated tau along with the prevention of onset and progression of the motor dysfunction in JNPL3 P301L-mutated human tau transgenic mice. These results suggest that PE859 is useful for the treatment of tauopathies

Chemical structure of PE859.

<p>Chemical structure of PE859.</p

The concentration of PE859 in plasma and brain after an oral administration.

<p>The concentration of PE859 in plasma and brain after an oral administration to male ICR mice at 40 mg/kg, were showed by circles with straight line and triangles with dot line, respectively. Mean ± SEM, n = 4.</p

Western blotting and immunohistochemistry.

<p>(A) The amounts of tris buffer-soluble tau (S1), sarkosyl-soluble tau (S2) and sarkosyl-insoluble tau (P2) in the spinal cord. The amount of sarkosyl-soluble tau and sarkosyl-insoluble tau of the PE859 group were significantly smaller than those of the vehicle group (p = 0.009 and 0.008, respectively; Mann-Whitney test). The data were calculated using by the standard curve, which was prepared by the 2-fold serial dilutions of the P2 samples as the pictures of WB (lanes of “Standard”). The lane “V” or “P” of the WB picture means Vehicle or PE859 treated mouse, respectively. Mean ± SEM. a.u., arbitrary unit. **p<0.01. (B) The representative photomicrographs of immunostaining against aggregated tau (AT8) and neuron (NeuN). The spinal cords of the two mice starred in the WB picture of <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0117511#pone.0117511.g009" target="_blank">Fig. 9A</a> were used. Scale bar, 0.2 mm.</p

Inhibiton of tau aggregation by PE859 was observed using by transmission electron microscopy.

<p>10 μM 3RMBD with no compound (left) and with 0.1 μM PE859 (center) or 1 μM PE859 (right) were incubated at 37°C for 24 h, and stained by 2% phosphotungstic acid. Scale bar = 1 μm.</p