Design, synthesis and biological activity evaluation of novel covalent S-acylation inhibitors.

In order to obtain diverse S-acylation inhibitors and address the defects of existing S-acylation inhibitors, a series of novel covalent S-acylation inhibitors are designed through synthesis. According to the results of MTT assay, most compounds produce a better anti-proliferation effect on MCF-7, MGC-803 and U937 cell lines than 2-BP. Among them, 8d, 8i, 8j and 10e exert a significant inhibitory effect on MCF-7 cell, with the IC50 values falling below 20 µM. Besides, the toxic effects of some compounds on 3T3 cell line are less significant than 2-BP. According to the results of acyl-biotin exchange (ABE) experiment, most of them could inhibit S-acylation, and 8i performs best in this respect, with the inhibitory rate reaching 89.3% at the concentration of 20 µM. The results of molecular docking show the conjugation of 8i with surrounding amino acids. Additionally, 8i could not only suppress the migration of MCF-7 cell line, but also cause it to stagnate in G0/G1 phase, thus promoting cell apoptosis.

Design, synthesis and biological evaluation of dual Topo II/HDAC inhibitors bearing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs.

Both topoisomerase II (Topo II) and histone deacetylase (HDAC) are important therapeutic targets for cancer. In this study, two series of novel compounds containing pyrimido[5,4-b]indole and pyrazolo[3,4-d]pyrimidine motifs were designed and synthesized as dual Topo II/HDAC inhibitors. MTT assay indicated that all the compounds displayed potential antiproliferative activity against three cancer cell lines (MGC-803, MCF-7 and U937) and low cytotoxicity on normal cell line (3T3). In the enzyme activity inhibition experiments, compounds 7d and 8d exhibited excellent dual inhibitory activities against Topo II and HDAC. Cleavage reaction assay showed that 7d was a Topo II poison, which was consistent with the docking results. Further experimental results revealed that compounds 7d and 8d could promote apoptosis and significantly inhibit the migration in MCF-7 cells. Molecular docking showed that compounds 7d and 8d bind Topo II and HDAC at the active sites. Molecular dynamics simulation showed that 7d can stably bind to Topo II and HDAC.