Discovery of Potent Selective HDAC6 Inhibitors with 5-Phenyl-1H-indole Fragment: Virtual Screening, Rational Design, and Biological Evaluation.

Among the HDACs family, histone deacetylase 6 (HDAC6) has attracted extensive attention due to its unique structure and biological functions. Numerous studies have shown that compared with broad-spectrum HDACs inhibitors, selective HDAC6 inhibitors exert ideal efficacy in tumor treatment with insignificant toxic and side effects, demonstrating promising clinical application prospect. Herein, we carried out rational drug design by integrating a deep learning model, molecular docking, and molecular dynamics simulation technology to construct a virtual screening process. The designed derivatives with 5-phenyl-1H-indole fragment as Cap showed desirable cytotoxicity to the various tumor cell lines, all of which were within 15 µM (ranging from 0.35 to 14.87 µM), among which compound 5i had the best antiproliferative activities against HL-60 (IC50 = 0.35 ± 0.07 µM) and arrested HL-60 cells in the G0/G1 phase. In addition, 5i exhibited better isotype selective inhibitory activities due to the potent potency against HDAC6 (IC50 = 5.16 ± 0.25 nM) and the reduced inhibitory activities against HDAC1 (selective index ≈ 124), which was further verified by immunoblotting results. Moreover, the representative binding conformation of 5i on HDAC6 was revealed and the key residues contributing 5i's binding were also identified via decomposition free-energy analysis. The discovery of lead compound 5i also indicates that virtual screening is still a beneficial tool in drug discovery and can provide more molecular skeletons with research potential for drug design, which is worthy of widespread application.

Mechanism and Effect of Polar Styrenes on Scandium-Catalyzed Copolymerization with Ethylene.

Copolymerization of ethylene (E) and polar vinyl monomers remains a problem because E propagation is hindered. Herein, for the first time, we report the copolymerization of E and polar styrenes (SR ) by using an oxophilic scandium catalyst that exhibits higher turnover frequencies than both E and SR homopolymerizations when R is an electron-withdrawing group. This positive comonomer effect was elucidated through computing reaction profiles of E/SF copolymerization at the DFT (B3PW91) level of theory. It reveals that the secondary interaction between Sc3+ and phenyl of the last and penultimate inserted SF units leads to a decrease of the E insertion barrier, because the electron-withdrawing substituent enhances the electrophilicity of Sc3+ by an inductive effect mediated by the secondary interaction. After three consecutive insertions of the E units, the secondary interaction is lost and the SF insertion is kinetically preferred over the E insertion. This process is in line with the NMR spectrum analyses which show that the resultant copolymers mainly contain SR (E)x SR sequences where x≤3.