Design, Synthesis and Evaluation of Substituted Aryl-2-Nitrovinyl Derivatives as Small Molecules Proteasome Inhibitors.

Based on the existing structure activity relationship for proteasome inhibitors, a number of substituted aryl-2-nitrovinyl derivatives have been synthesized as Michael acceptor and their cytotoxicity and proteasome inhibitory effects were evaluated on two cancer cell lines. Compound 2d exhibited IC50 values of 0.71 and 17.79 µM comparable to bortezomib against MCF-7 and PC-3, respectively. The results show that the electronic properties and steric hindrance can affect the interaction of these small molecules with their receptor at the active site of the enzyme while the presence of CH2OH group on α-carbon of Michael acceptor is favorable, and para substitution of OMe on phenyl ring of ß-carbon can increase the inhibitory potencies. Molecular docking studies confirm our experimental findings about mode of binding of our compounds with 20S proteasome.

Synthesis of N-arylmethyl Substituted Indole Derivatives as New Antiplatelet Aggregation Agents.

A number of N-arylmethyl substituted indole derivatives have been synthesized and their effectiveness against ADP and arachidonic acid induced platelet aggregation in human plasma was determined. The desired compounds were synthesized by reacting the appropriate aniline derivative with isatin (or substituted isatin) to form the corresponding imine structures. The so formed compound was then activated using sodium hydride and reacted with the proper substituted benzyl halides. Among the tested compounds, derivatives 4a, 4c, 4d, 4f-i and 4k were the most potent compounds with satisfactory IC50 values (under 38.5 µM) for inhibition of platelet aggregation induced by arachidonic acid. All indole derivatives without substitution on position 1 of the indole ring, exhibited either weaker activities or were not active at all.