135920-28-4Relevant articles and documents
Synthesis and biological evaluation of novel quinolone derivatives dual targeting histone deacetylase and tubulin polymerization as antiproliferative agents
Wang, Xuan,Jiang, Xiaoye,Sun, Shiyou,Liu, Yongqiong
, p. 16494 - 16502 (2018)
A strategy to develop chemotherapy agents by combining two complimentary chemo-active groups into a single molecule may have higher efficacy and fewer side effects than that of single-target drugs. In this article, we describe the synthesis and evaluation of a series of novel dual-acting levofloxacin-HDACi conjugates to target both histone deacetylase (HDAC) and tubulin polymerization. These bifunctional conjugates exhibited potent inhibitory activities against HDACs and tubulin polymerization. In docking analysis provides a structural basis for HDACs inhibition activities. Moreover, these conjugates showed selective anticancer activity that is more potent against MCF-7 compared to other four cancer cells A549, HepG2, PC-3, HeLa, but they had no toxicity toward normal cells.
Reverse Anomeric Effect in Large-Amplitude Pyridinium Amide-Containing Mannosyl [2]Rotaxane Molecular Shuttles
Riss-Yaw, Benjamin,Waels, Philip,Coutrot, Frdric
, p. 1860 - 1869 (2016)
The reverse anomeric effect (RAE) was investigated in different mannosyl [2]rotaxane molecular shuttle isomers that contain dibenzo-24-crown-8 (DB24C8) as the macrocycle, and anilinium and pyridinium amide as molecular stations. The switching on or off of
Synthesis and biological evaluation of salinomycin triazole analogues as anticancer agents
Huang, Minjian,Deng, Zixin,Tian, Jian,Liu, Tiangang
, p. 900 - 908 (2017)
Salinomycin, a polyether antibiotic used for treatment of coccidial disease in animal husbandry, has demonstrated promising efficacy for treating different cancers. To enrich structure-activity relationship of salinomycin in tumours, we prepared a series of new triazole derivatives in specific site of salinomycin by click cycloaddition reactions, and assessed their antiproliferative activities on breast cancer cell lines. The screening results indicated that most derivatives modified at the C20 hydroxyl group have potent antitumour activity. Notably, salinomycin triazole dimers were 3.27–4.97 times more toxic than the natural substance in ERα-positive breast cancer cells (MCF-7), and had moderately improved toxicity in triple-negative breast cancer cells (MDA-MB-231).
A Click Chemistry Approach Reveals the Chromatin-Dependent Histone H3K36 Deacylase Nature of SIRT7
Wang, Wesley Wei,Angulo-Ibanez, Maria,Lyu, Jie,Kurra, Yadagiri,Tong, Zhen,Wu, Bo,Zhang, Ling,Sharma, Vangmayee,Zhou, Jennifer,Lin, Hening,Gao, Yi Qin,Li, Wei,Chua, Katrin F.,Liu, Wenshe Ray
, p. 2462 - 2473 (2019)
Using an engineered pyrrolysyl-tRNA synthetase mutant together with tRNACUA Pyl, we have genetically encoded N-(7-azidoheptanoyl)-l-lysine (AzHeK) by amber codon in Escherichia coli for recombinant expression of a number of AzHeK-containing histone H3 proteins. We assembled in vitro acyl-nucleosomes from these recombinant acyl-H3 histones. All these acyl-nucleosomes contained an azide functionality that allowed quick click labeling with a strained alkyne dye for in-gel fluorescence analysis. Using these acyl-nucleosomes as substrates and click labeling as a detection method, we systematically investigated chromatin deacylation activities of SIRT7, a class III NAD+-dependent histone deacylase with roles in aging and cancer biology. Besides confirming the previously reported histone H3K18 deacylation activity, our results revealed that SIRT7 has an astonishingly high activity to catalyze deacylation of H3K36 and is also catalytically active to deacylate H3K37. We further demonstrated that this H3K36 deacylation activity is nucleosome dependent and can be significantly enhanced when appending the acyl-nucleosome substrate with a short double-stranded DNA that mimics the bridging DNA between nucleosomes in native chromatin. By overexpressing SIRT7 in human cells, we verified that SIRT7 natively removes acetylation from histone H3K36. Moreover, SIRT7-deficient cells exhibited H3K36 hyperacetylation in whole cell extracts, at rDNA sequences in nucleoli, and at select SIRT7 target loci, demonstrating the physiologic importance of SIRT7 in determining endogenous H3K36 acetylation levels. H3K36 acetylation has been detected at active gene promoters, but little is understood about its regulation and functions. Our findings establish H3K36 as a physiologic substrate of SIRT7 and implicate this modification in potential SIRT7 pathways in heterochromatin silencing and genomic stability.
Design, synthesis and anticancer evaluation of acridine hydroxamic acid derivatives as dual Topo and HDAC inhibitors
Chen, Jiwei,Li, Dan,Li, Wenlu,Yin, Jingxian,Zhang, Yueying,Yuan, Zigao,Gao, Chunmei,Liu, Feng,Jiang, Yuyang
, p. 3958 - 3966 (2018)
Multitarget inhibitors design has generated great interest in cancer treatment. Based on the synergistic effects of topoisomerase and histone deacetylase inhibitors, we designed and synthesized a new series of acridine hydroxamic acid derivatives as potential novel dual Topo and HDAC inhibitors. MTT assays indicated that all the hybrid compounds displayed good antiproliferative activities with IC50 values in low micromolar range, among which compound 8c displayed potent activity against U937 (IC50 = 0.90 μM). In addition, compound 8c also displayed the best HDAC inhibitory activity, which was several times more potent than HDAC inhibitor SAHA. Subsequent studies indicated that all the compounds displayed Topo II inhibition activity at 50 μM. Moreover, compound 8c could interact with DNA and induce U937 apoptosis. This study provides a suite of compounds for further exploration of dual Topo and HDAC inhibitors, and compound 8c can be a new dual Topo and HDAC inhibitory anticancer agent.
New Dual CK2/HDAC1 Inhibitors with Nanomolar Inhibitory Activity against Both Enzymes
Coderch, Claire,De Pascual-Teresa, Beatriz,Ortín, Irene,Ramos, Ana,Rangasamy, Loganathan,Zapico, José María
supporting information, p. 713 - 719 (2020/07/14)
Four potent CK2 inhibitors derived from CX-4945 are described. They also provided nanomolar activity against HDAC1, therefore having promising utility as dual-target agents for cancer. The linker length between the hydroxamic acid and the CX-4945 scaffold plays an important role in dictating balanced activity against the targeted enzymes. The seven-carbon linker (compound 15c) was optimal for inhibition of both CK2 and HDAC1. Remarkably, 15c showed 3.0 and 3.5 times higher inhibitory activity than the reference compounds CX-4945 (against CK2) and SAHA (against HDAC1), respectively. Compound 15c exhibited micromolar activity in cell-based cytotoxic assays against multiple cell lines.
