299442-23-2Relevant academic research and scientific papers
Discovery of novel inhibitors of human phosphoglycerate dehydrogenase by activity-directed combinatorial chemical synthesis strategy
Gou, Kun,Luo, Youfu,Luo, Yuan,Sun, Qingxiang,Tan, Yuping,Tao, Lei,Zhao, Yinglan,Zhou, Xia,Zhou, Yue,Zuo, Zeping
, (2021/07/26)
Serine, the source of the one-carbon units essential for de novo purine and deoxythymidine synthesis plays a crucial role in the growth of cancer cells. Phosphoglycerate dehydrogenase (PHGDH) which catalyzes the first, rate-limiting step in de novo serine biosynthesis has become a promising target for the cancer treatment. Here we identified H-G6 as a potential PHGDH inhibitor from the screening of an in-house small molecule library based on the enzymatic assay. We adopted activity-directed combinatorial chemical synthesis strategy to optimize this hit compound. Compound b36 was found to be the noncompetitive and the most promising one with IC50 values of 5.96 ± 0.61 μM against PHGDH. Compound b36 inhibited the proliferation of human breast cancer and ovarian cancer cells, reduced intracellular serine synthesis, damaged DNA synthesis, and induced cell cycle arrest. Collectively, our results suggest that b36 is a novel PHGDH inhibitor, which could be a promising modulator to reprogram the serine synthesis pathway and might be a potential anticancer lead worth further exploration.
Direct C–H Arylation of Heteroarenes with Aryl Chlorides by Using an Abnormal N-Heterocyclic-Carbene–Palladium Catalyst
Ahmed, Jasimuddin,Sau, Samaresh Chandra,Sreejyothi,Hota, Pradip Kumar,Vardhanapu, Pavan K.,Vijaykumar, Gonela,Mandal, Swadhin K.
, p. 1004 - 1011 (2017/02/15)
Herein, we report a versatile catalytic system for the direct C–H arylation of heteroarenes with activated aryl chloride substrates. The catalyst works successfully for a variety of heteroarenes and aryl chloride coupling partners under very low catalyst-loading conditions. We have successfully performed the direct C–H arylations of 1-methylpyrrole, 1-methylindole, furan, thiophene, furfural, and N-benzyl-1,2,3-triazole with aryl chloride partners in good yields without the use of any additives. Furthermore, we used this catalytic process to develop a one-pot synthetic protocol for the muscle relaxant dantrolene on a gram scale. Additionally, the present catalytic system can be used to perform consecutive arylations in one pot.
Development of a novel class of B-RafV600E-selective inhibitors through virtual screening and hierarchical hit optimization
Kong, Xiangqian,Qin, Jie,Li, Zeng,Vultur, Adina,Tong, Linjiang,Feng, Enguang,Rajan, Geena,Liu, Shien,Lu, Junyan,Liang, Zhongjie,Zheng, Mingyue,Zhu, Weiliang,Jiang, Hualiang,Herlyn, Meenhard,Liu, Hong,Marmorstein, Ronen,Luo, Cheng
experimental part, p. 7402 - 7417 (2012/10/08)
Oncogenic mutations in critical nodes of cellular signaling pathways have been associated with tumorigenesis and progression. The B-Raf protein kinase, a key hub in the canonical MAPK signaling cascade, is mutated in a broad range of human cancers and especially in malignant melanoma. The most prevalent B-RafV600E mutant exhibits elevated kinase activity and results in constitutive activation of the MAPK pathway, thus making it a promising drug target for cancer therapy. Herein, we describe the development of novel B-RafV600E selective inhibitors via multi-step virtual screening and hierarchical hit optimization. Nine hit compounds with low micromolar IC 50 values were identified as B-RafV600E inhibitors through virtual screening. Subsequent scaffold-based analogue searching and medicinal chemistry efforts significantly improved both the inhibitor potency and oncogene selectivity. In particular, compounds 22f and 22q possess nanomolar IC 50 values with selectivity for B-RafV600Ein vitro and exclusive cytotoxicity against B-RafV600E harboring cancer cells.
