Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors

Jin, Xiaoyan; Chen, Hao; Li, Dongdong; Li, A‐Liang; Wang, Wenyan; Gu, Wen

doi:10.1080/14756366.2019.1605364

Cited by 57 publications

(33 citation statements)

References 58 publications

(59 reference statements)

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“…Also, biotransformation of ULA with the fungus Aspergillus flavus resulted in isolation of UNA [24]. Moreover, UNA can be synthesized via Jones oxidation, a technique that uses sulfuric acid, chromic trioxide, and acetone to oxidise alcohol [20,[25][26][27].…”

Section: Synthesis Of Ursonic Acidmentioning

confidence: 99%

Therapeutic Potential of Ursonic Acid: Comparison with Ursolic Acid

Son

Lee

2020

Biomolecules

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Plants have been used as drugs to treat human disease for centuries. Ursonic acid (UNA) is a naturally occurring pentacyclic triterpenoid extracted from certain medicinal herbs such as Ziziphus jujuba. Since the pharmacological effects and associated mechanisms of UNA are not well-known, in this work, we attempt to introduce the therapeutic potential of UNA with a comparison to ursolic acid (ULA), a well-known secondary metabolite, for beneficial effects. UNA has a keto group at the C-3 position, which may provide a critical difference for the varied biological activities between UNA and ULA. Several studies previously showed that UNA exerts pharmaceutical effects similar to, or stronger than, ULA, with UNA significantly decreasing the survival and proliferation of various types of cancer cells. UNA has potential to exert inhibitory effects in parasitic protozoa that cause several tropical diseases. UNA also exerts other potential effects, including antihyperglycemic, anti-inflammatory, antiviral, and antioxidant activities. Of note, a recent study highlighted the suppressive potential of UNA against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Molecular modifications of UNA may enhance bioavailability, which is crucial for in vivo and clinical studies. In conclusion, UNA has promising potential to be developed in anticancer and antiprotozoan pharmaceuticals. In-depth investigations may increase the possibility of UNA being developed as a novel reagent for chemotherapy.

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Section: Synthesis Of Ursonic Acidmentioning

confidence: 99%

Therapeutic Potential of Ursonic Acid: Comparison with Ursolic Acid

Son

Lee

2020

Biomolecules

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“…Compound 76 showed remarkable results as antiproliferative agent, capability to inhibit MEK1 kinase activity (MEK1 IC 50 = 64 nM) and activation of Ras/Raf/MEK/ERK pathway. Molecular docking analysis into the MEK1 binding site proved that the ursolic acid skeleton ensured the correct orientation of the hydrazide side chain and of the quinoline ring into the pocket, while the latter were involved in stabilizing interactions with the amino acids [ 149 ].…”

Section: Quinolines As Inhibitors Of Carcinogenic Pathwaysmentioning

confidence: 99%

“… ( a ) structure of the quinoline derivative of ursolic acid 76 ; ( b ) binding pose of 76 within MEK1 kinase domain (PDB id: 3EQF); ( c ) ligand interactions of 76 docked into MEK1 active site [ 149 ]. …”

Section: Figurementioning

confidence: 99%

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

2020

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The quinoline ring system has long been known as a versatile nucleus in the design and synthesis of biologically active compounds. Currently, more than one hundred quinoline compounds have been approved in therapy as antimicrobial, local anaesthetic, antipsychotic, and anticancer drugs. In drug discovery, indeed, over the last few years, an increase in the publication of papers and patents about quinoline derivatives possessing antiproliferative properties has been observed. This trend can be justified by the versatility and accessibility of the quinoline scaffold, from which new derivatives can be easily designed and synthesized. Within the numerous quinoline small molecules developed as antiproliferative drugs, this review is focused on compounds effective on c-Met, VEGF (vascular endothelial growth factor), and EGF (epidermal growth factor) receptors, pivotal targets for the activation of important carcinogenic pathways (Ras/Raf/MEK and PI3K/AkT/mTOR). These signalling cascades are closely connected and regulate the survival processes in the cell, such as proliferation, apoptosis, differentiation, and angiogenesis. The antiproliferative biological data of remarkable quinoline compounds have been analysed, confirming the pivotal importance of this ring system in the efficacy of several approved drugs. Furthermore, in view of an SAR (structure-activity relationship) study, the most recurrent ligand–protein interactions of the reviewed molecules are summarized.

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“…Cell cycle arrest is another important reason for growth inhibition [31]. Many anticancer agents inhibited malignant growth by arresting the cell cycle at the G1 phase [32]. Many ZNF143 target genes were related to cell cycle and DNA replication, such as CDC6, PLK1, and MCM DNA replication proteins [17].…”

Section: Disease Markersmentioning

confidence: 99%

ZNF143 Suppresses Cell Apoptosis and Promotes Proliferation in Gastric Cancer via ROS/p53 Axis

Zhang

Song

et al. 2020

Disease Markers

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Aim. This study was aimed at identifying the role of zinc finger protein 143 (ZNF143) in gastric cancer (GC) progression. Methods. The impact of ZNF143 on the proliferation ability and apoptosis of GC cells was detected. The expression of ZNF143 and related targeted genes was determined using Western blot analysis. The reactive oxygen species (ROS) level of GC cells was examined using the ROS generation assay. The role of ZNF143 in the proliferation of GC cells in vivo was examined using tumor xenograft assay. Results. The ectopic overexpression of ZNF143 promoted the proliferation of GC cells, while its knockdown reduced the effect in vitro. The downregulation of ZNF143 facilitated cell apoptosis. ZNF143 decreased the ROS level in GC cells, resulting in the reduction of cell apoptosis. Transfection with p53 reversed the antiapoptotic effect of ZNF143, while pifithrin-α, a specific inhibitor of p53, reduced the apoptosis in ZNF143-knockdown GC cells. However, p53 had no influence on the ROS level in GC cells. p53 played a key role in inhibiting ROS generation in GC cells, thereby inhibiting apoptosis. The transplanted tumor weight and volume were higher in the ZNF143-overexpressed group than in the ZNF143-knockdown group in vivo. The expression of ZNF143 in the transplanted tumor correlated positively with the proliferation index of Ki67 and negatively with the expression of p53 and cell apoptosis. Conclusion. ZNF143, as a tumor oncogene, promoted the proliferation of GC cells both in vitro and in vivo, indicating that ZNF143 might function as a novel target for GC therapy.

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Design, synthesis, and anticancer evaluation of novel quinoline derivatives of ursolic acid with hydrazide, oxadiazole, and thiadiazole moieties as potent MEK inhibitors

Cited by 57 publications

References 58 publications

Therapeutic Potential of Ursonic Acid: Comparison with Ursolic Acid

Therapeutic Potential of Ursonic Acid: Comparison with Ursolic Acid

Quinoline-Based Molecules Targeting c-Met, EGF, and VEGF Receptors and the Proteins Involved in Related Carcinogenic Pathways

ZNF143 Suppresses Cell Apoptosis and Promotes Proliferation in Gastric Cancer via ROS/p53 Axis

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