1374414-07-9Relevant academic research and scientific papers
Hydroxamic Acid Derivatives of β-Carboline/Hydroxycinnamic Acid Hybrids Inducing Apoptosis and Autophagy through the PI3K/Akt/mTOR Pathways
Ling, Yong,Li, Yangyang,Zhu, Rui,Qian, Jianqiang,Liu, Ji,Gao, Weijie,Meng, Chi,Miao, Jiefei,Xiong, Biao,Qiu, Xiaodong,Ling, Changchun,Dai, Hong,Zhang, Yanan
, p. 1442 - 1450 (2019)
Naturally occurring β-carbolines are known to have antitumor activities but with limited effectiveness. In order to improve their efficacy, a series of new hydroxamic-acid-containing β-carbolines connected via a hydroxycinnamic acid moitey (12a-f) were developed to incorporate histone deacetylase (HDAC) inhibition for possible synergistic effects. When evaluated in in vitro assays, most of the analogues showed significant antitumor activities against four human cancer cells. In particular, 12b showed the highest cytotoxic potency of the series, including drug-resistant Bel7402 cells, but had minimal effect on normal hepatic LO2 cells. These compounds also showed excellent inhibitory effects against HDAC1/6, which appear to contribute greatly to their antiproliferative properties. Compound 12b enhanced the acetylation levels of histone H3 and α-tubulin and induced greater cancer cell apoptosis than the FDA-approved HDAC inhibitor SAHA by regulating expression of apoptotic proteins Bax, Bcl-2, and caspase 3. Importantly, 12b also induced a significant amount of autophagic flux activity in Bel7402 cells by increasing the expression of Beclin-1 and LC3-II proteins and decreasing that of LC3-I and p62. Finally, 12b significantly inhibited PI3K/Akt/mTOR signaling, an important cell-growth-promoting pathway aberrantly activated in many cancers. Together, the results suggest that these hydroxamic-acid-containing β-carboline derivatives may be new leads for the discovery of agents for the treatment of human carcinoma cancers.
Design and synthesis of rosiglitazone-ferulic acid-nitric oxide donor trihybrids for improving glucose tolerance
Liu, Jingchao,Huang, Zhangjian,Ma, Wenhuan,Peng, Sixun,Li, Yunman,Miranda, Katrina M.,Tian, Jide,Zhang, Yihua
, p. 650 - 665 (2018/11/27)
Glucose intolerance is associated with metabolic syndrome and type 2 diabetes mellitus (T2DM) while some new therapeutic drugs, such as rosiglitazone (Rosi), for T2DM can cause severe cardiovascular side effects. Herein we report the synthesis of Rosi-ferulic acid (FA)-nitric oxide (NO) donor trihybrids to improve glucose tolerance and minimize the side effects. In comparison with Rosi, the most active compound 21 exhibited better effects on improving glucose tolerance, which was associated with its NO production, antioxidant and anti-inflammatory activities. Furthermore, 21 displayed relatively high stability in the simulated gastrointestinal environments and human liver microsomes, and released Rosi in plasma. More importantly, 21, unlike Rosi, had little stimulatory effect on the membrane translocation of aquaporin-2 (AQP2) in kidney collecting duct epithelial cells. These, together with a better safety profile, suggest that the trihybrids, like 21, may be promising candidates for intervention of glucose intolerance-related metabolic syndrome and T2DM.
Design, synthesis and evaluation of novel tacrine-ferulic acid hybrids as multifunctional drug candidates against Alzheimer's disease
Fu, Yingbo,Mu, Yu,Lei, Hui,Wang, Pu,Li, Xin,Leng, Qiao,Han, Li,Qu, Xiaodan,Wang, Zhanyou,Huang, Xueshi
, (2016/11/06)
Five novel tacrine-ferulic acid hybrid compounds (8a-e) were synthesized and their structures were identified on the basis of a detailed spectroscopic analysis. The activities of inhibiting acetyl cholinesterase (AChE) and butyryl cholinesterase (BuChE), reducing self-induced β-Amyloid (Aβ) aggregation and chelating Cu2+ were evaluated in vitro. Among them, 8c and 8d displayed the higher selectivity in inhibiting AChE over BuChE. Moreover, 8d also showed dramatic inhibition of self-Aβ aggregation, activity of chelating Cu2+ and activity against Aβ-induced neurotoxicity in Neuro-2A cells.
Tacrine-ferulic acid-nitric oxide (no) donor trihybrids as potent, multifunctional acetyl- and butyrylcholinesterase inhibitors
Chen, Yao,Sun, Jianfei,Fang, Lei,Liu, Mei,Peng, Sixun,Liao, Hong,Lehmann, Jochen,Zhang, Yihua
, p. 4309 - 4321 (2012/07/27)
In search of multifunctional cholinesterase inhibitors as potential anti-Alzheimer drug candidates, tacrine-ferulic acid-NO donor trihybrids were synthesized and tested for their cholinesterase inhibitory activities, release of nitric oxide, vasodilator properties, cognition improving potency, and hepatotoxicity. All of the novel target compounds show higher in vitro cholinesterase inhibitory activity than tacrine. Three selected compounds (3a, 3f, and 3k) produce moderate vasorelaxation in vitro, which correlates with the release of nitric oxide. Compared to its non-nitrate dihybrid analogue (3u), the trihybrid 3f exhibits better performance in improving the scopolamine-induced cognition impairment (mice) and, furthermore, less hepatotoxicity than tacrine.
