Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer

Wu, Chun‐Feng; Wang, Qingchen; Chen, Rui; Zhou, Hongyuan; Wu, Tong; Du, Yao; Zhang, Nana; Zhang, Huimin; Fan, Zu-Yan; Wang, Lili; Hu, Chu-Jiao; Sang, Zhipei; Li, Hongliang; Tang, Lei; Zhang, Jiquan

doi:10.1016/j.ejmech.2021.114055

Cited by 18 publications

(7 citation statements)

References 38 publications

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“…Compound 3f was selected to investigate the stabilities by artificial gastrointestinal conditions and (human and rat) liver microsomes 33 . As displayed in Figure 13 , the remaining amount of compound 3f in blank gastric fluid, blank intestinal fluid, artificial gastric fluid and artificial intestinal fluid was 102.6%, 103.4%, 99.2% and 107.7%, respectively, after 8 h incubation, suggesting that compound 3f was stable in both artificial intestinal and gastric fluids.…”

Section: Resultsmentioning

confidence: 99%

Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Chen

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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A series of novel quinoline- O -carbamate derivatives was rationally designed for treating Alzheimer’s disease (AD) by multi-target-directed ligands (MTDLs) strategy. The target compounds were synthesised and evaluated by AChE/BuChE inhibition and anti-inflammatory property. The in vitro activities showed that compound 3f was a reversible dual ee AChE/eqBuChE inhibitor with IC 50 values of 1.3 µM and 0.81 µM, respectively. Moreover, compound 3f displayed good anti-inflammatory property by decreasing the production of IL-6, IL-1β and NO. In addition, compound 3f presented significant neuroprotective effect on A β 25-35 -induced PC12 cell injury. Furthermore, compound 3f presented good stabilities in artificial gastrointestinal fluids, liver microsomes in vitro and plasma. Furthermore, compound 3f could improve AlCl 3 -induced zebrafish AD model by increasing the level of ACh. Therefore, compound 3f was a promising multifunctional agent for the treatment of AD.

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Section: Resultsmentioning

confidence: 99%

Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Chen

et al. 2023

Journal of Enzyme Inhibition and Medicinal Chemistry

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“…4- (4-((4aR,7aR)-Hexahydro-6H- [1,4]dioxino [2,3-c]pyrrol-6-yl)-6morpholino-1,3,5-triazin-2-yl)aniline (19m). 27 Yellow solid, yield 85.1%. 1 Synthesis of Compounds 20a−m.…”

Section: Synthesis Of Compounds 15a−imentioning

confidence: 99%

“…Metabolic stability investigation of the optimal candidates is of great importance and essential before their in vivo pharmacodynamic evaluation. Considering the unstable performance of gedatolisib in artificial gastric fluid incubating conditions and blood plasma of Sprague-Dawley (SD) rats, 27 the in vitro metabolic stability profiles were assessed via incubation in standard artificial gastric and intestinal (GI) fluids, blood plasma, and liver microsomes of SD rats. As shown in Figure 13, compound PT-88 indicated good stability in all tested conditions, including artificial gastrointestinal fluids, blood plasma, and liver microsomes (Figure 13A−C).…”

Section: Journal Of Medicinal Chemistrymentioning

confidence: 99%

Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for the Treatment of Human Breast Cancer

Sun,

Chu,

Zhang

et al. 2024

J. Med. Chem.

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The aberrant activation of the PI3K/mTOR signaling pathway is implicated in various human cancers. Thus, the development of inhibitors targeting mTOR has attracted considerable attention. In this study, we used a structure-based drug design strategy to discover a highly potent and kinaseselective mTOR inhibitor 24 (PT-88), which demonstrated an mTOR inhibitory IC 50 value of 1.2 nM without obvious inhibition against another 195 kinases from the kinase profiling screening. PT-88 displayed selective inhibition against MCF-7 cells (IC 50 : 0.74 μM) with high biosafety against normal cells, in which autophagy induced by mTOR inhibition was implicated. After successful encapsulation in a lipodisc formulation, PT-88 demonstrated favorable pharmacokinetic and biosafety profiles and exerted a large antitumor effect in an MCF-7 subcutaneous bearing nude mice model. Our study shows the discovery of a highly selective mTOR inhibitor using a structure-based drug discovery strategy and provides a promising antitumor candidate for future study and development.

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“…156 Very recently, we further hybridized 25 and 3 to achieve the terminal L-prolineamide-substituted bismorpholinotriazine derivative 67. 157 Compound 67 is a PI3K/mTOR dual inhibitor (mTOR IC 50 = 3.3 nM, PI3Kα IC 50 = 0.70 nM, PI3Kβ IC 50 = 4.3 nM, PI3Kδ IC 50 = 27 nM, PI3Kγ IC 50 = 8.7 nM). In the HCT116 xenograft BALB/c nude mouse model, 67 displayed 42% TGI at 20 mg/kg via an intravenous injection, which was comparable with 25 (41%).…”

Section: Targeting the Pi3k/akt/mtor Signaling Pathway With Atp-compe...mentioning

confidence: 99%

“…Compounds 65 (mTOR IC 50 = 5.6 nM, PI3Kα IC 50 = 7.3 nM, PI3Kβ IC 50 = 21 nM, PI3Kδ IC 50 = 5.1 nM, PI3Kγ IC 50 = 440 nM) and 66 (mTOR IC 50 = 13 nM, PI3Kα IC 50 = 20 nM, PI3Kβ IC 50 = 28 nM, PI3Kδ IC 50 = 13 nM, PI3Kγ IC 50 > 1000 nM) contained a novel substituted bis(morpholino-1,3,5-triazine) bearing a benzimidazole scaffold . Very recently, we further hybridized 25 and 3 to achieve the terminal l -prolineamide-substituted bismorpholinotriazine derivative 67 . Compound 67 is a PI3K/mTOR dual inhibitor (mTOR IC 50 = 3.3 nM, PI3Kα IC 50 = 0.70 nM, PI3Kβ IC 50 = 4.3 nM, PI3Kδ IC 50 = 27 nM, PI3Kγ IC 50 = 8.7 nM).…”

Section: Targeting the Pi3k/akt/mtor Signaling Pathway With Atp-compe...mentioning

confidence: 99%

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

Huang

Chen

et al. 2022

J. Med. Chem.

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The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is one of the most important intracellular pathways involved in cell proliferation, growth, differentiation, and survival. Therefore, this route is a prospective biological target for treating various human diseases, such as tumors, neurodegenerative diseases, pulmonary fibrosis, and diabetes. An increasing number of clinical studies emphasize the necessity of developing novel molecules targeting the PI3K/AKT/mTOR pathway. This review focuses on recent advances in ATP-competitive inhibitors, allosteric inhibitors, covalent inhibitors, and proteolysis-targeting chimeras against the PI3K/AKT/mTOR pathway, and highlights possible solutions for overcoming the toxicities and acquired drug resistance of currently available drugs. We also provide recommendations for the future design and development of promising drugs targeting this pathway.

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Synthesis and bioevaluation of diaryl urea derivatives as potential antitumor agents for the treatment of human colorectal cancer

Cited by 18 publications

References 38 publications

Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Design, synthesis and evaluation of quinoline- O -carbamate derivatives as multifunctional agents for the treatment of Alzheimer’s disease

Design, Synthesis, Formulation, and Bioevaluation of Trisubstituted Triazines as Highly Selective mTOR Inhibitors for the Treatment of Human Breast Cancer

Targeting the PI3K/AKT/mTOR Signaling Pathway in the Treatment of Human Diseases: Current Status, Trends, and Solutions

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