C-H chlorination of (hetero)anilines via photo/organo co-catalysis.

Chlorinated (hetero)anilines are a class of important structural motifs that are widely present in synthetic building blocks and pharmaceuticals. Despite recent advancements, direct aniline chlorination still suffers from ortho/para and mono/poly chlorination selectivity problems. Herein, we disclose a photo-redox and organo co-catalyzed chlorination method for anilines. This method has great substrate generality and excellent mono-chlorination selectivity. Another merit of this method is the late-stage modification of drug molecules, which would be useful in medicinal chemistry.

Design and synthesis of dual inhibitors targeting snail and histone deacetylase for the treatment of solid tumour cancer.

Snail and histone deacetylases (HDACs) have an important impact on cancer treatment, especially for their synergy. Therefore, the development of inhibitors targeting both Snail and HDAC might be a promising strategy for the treatment of cancers. In this work, we synthesized a series of Snail/HDAC dual inhibitors. Compound 9n displayed the most potent inhibitory activity against HDAC1 with an IC50 of 0.405 µM, potent inhibition against Snail with a Kd of 0.180 µM, and antiproliferative activity in HCT-116 cell lines with an IC50 of 0.0751 µM. Compound 9n showed a good inhibitory effect on NCI-H522 (GI50 = 0.0488 µM), MDA-MB-435 (GI50 = 0.0361 µM), and MCF7 (GI50 = 0.0518 µM). Docking studies showed that compound 9n can be well docked into the active binding sites of Snail and HDAC. Further studies showed that compound 9n increased histone H4 acetylation in HCT-116 cells and decreased the expression of Snail protein to induce cell apoptosis. These findings highlight the potential for the development of Snail/HDAC dual inhibitors as anti-solid tumour cancer drugs.

Combining structure- and property-based optimization to identify selective FLT3-ITD inhibitors with good antitumor efficacy in AML cell inoculated mouse xenograft model.

FLT3 mutation is among the most common genetic mutations in acute myeloid leukemia (AML), which is also related with poor overall survival and refractory in AML patients. Recently, FLT3 inhibitors have been approved for AML therapy. Herein, a series of new compounds with pyrazole amine scaffold was discovered, which showed potent inhibitory activity against FLT3-ITD and significant selectivity against both FLT3-ITD and AML cells expressing FLT3-ITD. Compound 46, possessing the most promising cellular activity, blocked the autophosphorylation of FLT3 pathway in MV4-11 cell line. Furthermore, the apoptosis and downregulation of P-STAT5 were also observed in tumor cells extracted from the MV4-11 cell xenografts model upon compound 46 treatment. Compound 46 was also metabolically stable in vitro and suppressed tumor growth significantly in MV4-11 xenografts model in vivo. Compound 46 showed no toxicity to the viscera of mice and caused no decrease in body weight of mice. In conclusion, the results of this study could provide valuable insights into discovery of new FLT3 inhibitors, and compound 46 was worthy of further development as potential drug candidate to treat AML.