Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

Wang, Biao; Fu, Peng; Huang, Wei; Zhang, Jin; Zhang, Nan; Sheng, Jia; Haruehanroengra, Phensinee; He, Gu; Han, Bo

doi:10.1016/j.apsb.2019.12.013

Cited by 59 publications

(18 citation statements)

References 106 publications

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“…Glioblastoma is one of the most common malignant tumors in the brain and usually has poor prognosis, with a median survival time around 15 months even receiving standard treatment regimes (e.g., surgical resection, chemotherapy, and radiotherapy) [1][2][3]. Cell death plays critical roles in tissue homeostasis during development and disease progression.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-147a Targets SLC40A1 to Induce Ferroptosis in Human Glioblastoma

et al. 2022

Analytical Cellular Pathology

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Objective. Glioblastoma is one of the most common malignant tumors in the brain, and these glioblastoma patients have very poor prognosis. Ferroptosis is involved in the progression of various tumors, including the glioblastoma. This study aims to determine the involvement of microRNA (miR)-147a in regulating ferroptosis of glioblastoma in vitro. Methods. Human glioblastoma cell lines were transfected with the inhibitor, mimic and matched negative controls of miR-147a in the presence or absence of ferroptotic inducers. To knock down the endogenous solute carrier family 40 member 1 (SLC40A1), cells were transfected with the small interfering RNA against SLC40A1. In addition, cells with or without the miR-147a mimic treatment were also incubated with temozolomide (TMZ) to investigate whether miR-147a overexpression could sensitize human glioblastoma cells to TMZ chemotherapy in vitro. Results. We found that miR-147a level was decreased in human glioblastoma tissues and cell lines and that the miR-147a mimic significantly suppressed the growth of glioblastoma cells in vitro. In addition, miR-147a expression was elevated in human glioblastoma cells upon erastin or RSL3 stimulation. Treatment with the miR-147a mimic significantly induced ferroptosis of glioblastoma cells, and the ferroptotic inhibitors could block the miR-147a mimic-mediated tumor suppression in vitro. Conversely, the miR-147a inhibitor prevented erastin- or RSL3-induced ferroptosis and increased the viability of glioblastoma cells in vitro. Mechanistically, we determined that miR-147a directly bound to the 3 ′ -untranslated region of SLC40A1 and inhibited SLC40A1-mediated iron export, thereby facilitating iron overload, lipid peroxidation, and ferroptosis. Furthermore, miR-147a mimic-treated human glioblastoma cells exhibited higher sensitivity to TMZ chemotherapy than those treated with the mimic control in vitro. Conclusion. We for the first time determine that miR-147a targets SLC40A1 to induce ferroptosis in human glioblastoma in vitro.

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Section: Introductionmentioning

confidence: 99%

MicroRNA-147a Targets SLC40A1 to Induce Ferroptosis in Human Glioblastoma

et al. 2022

Analytical Cellular Pathology

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“…Flow cytometric results showed apoptotic induction and cell cycle arrest. This was confirmed in GB xenografts ( 230 ).…”

Section: Mdm2/x Inhibition and Other Combined Treatment Strategiesmentioning

confidence: 58%

MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy

et al. 2021

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Inhibition of the MDM2/X-p53 interaction is recognized as a potential anti-cancer strategy, including the treatment of glioblastoma (GB). In response to cellular stressors, such as DNA damage, the tumor suppression protein p53 is activated and responds by mediating cellular damage through DNA repair, cell cycle arrest and apoptosis. Hence, p53 activation plays a central role in cell survival and the effectiveness of cancer therapies. Alterations and reduced activity of p53 occur in 25-30% of primary GB tumors, but this number increases drastically to 60-70% in secondary GB. As a result, reactivating p53 is suggested as a treatment strategy, either by using targeted molecules to convert the mutant p53 back to its wild type form or by using MDM2 and MDMX (also known as MDM4) inhibitors. MDM2 down regulates p53 activity via ubiquitin-dependent degradation and is amplified or overexpressed in 14% of GB cases. Thus, suppression of MDM2 offers an opportunity for urgently needed new therapeutic interventions for GB. Numerous small molecule MDM2 inhibitors are currently undergoing clinical evaluation, either as monotherapy or in combination with chemotherapy and/or other targeted agents. In addition, considering the major role of both p53 and MDM2 in the downstream signaling response to radiation-induced DNA damage, the combination of MDM2 inhibitors with radiation may offer a valuable therapeutic radiosensitizing approach for GB therapy. This review covers the role of MDM2/X in cancer and more specifically in GB, followed by the rationale for the potential radiosensitizing effect of MDM2 inhibition. Finally, the current status of MDM2/X inhibition and p53 activation for the treatment of GB is given.

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“…Nitrogen‐containing heterocyclic compounds are widely present in drugs and biologically active compounds, thus incorporation of multiple structural units of this type into a candidate drug molecule can improve biological activity and pharmacological properties. [ 1 ] In particular, the spirooxindole motif is often found in medicinally relevant compounds that exhibit important biological activity such as cytotoxic, [ 2 ] anticancer, [ 3 ] antitumor, [ 4 ] antidiabetic, [ 5 ] and anti‐amyloidogenic [ 6 ] activities. Dihydropyridines are well‐known effective calcium channel blocker drugs for the treatment of hypertension and cardiovascular diseases.…”

Section: Introductionmentioning

confidence: 99%

Nickel supported on magnetic biochar as a highly efficient and recyclable heterogeneous catalyst for the one‐pot synthesis of spirooxindole‐dihydropyridines

Dong

Wang

Zhang

et al. 2022

Applied Organom Chemis

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Magnetic materials show promising applications in heterogeneous catalysis because of their ease of separation and good reusability. The present work reports the design, synthesis, and characterization of a novel magnetic biochar supported nickel catalyst. Fourier infrared spectroscopy (FT‐IR), powder X‐ray diffraction technology (XRD), scanning electron microscope (SEM), transmission electron microscope (TEM), and vibrating sample magnetometer (VSM) techniques were used for analyzing the prepared catalyst. The prepared catalyst exhibited excellent catalytic activity for synthesis of spirooxindole‐dihydropyridines derivatives by a one‐pot three‐component reaction of isatin, barbituric acid, and 6‐amino uracil or 1H‐pyrazol‐5‐amine. This new methodology demonstrated some important features, including high yields, lower loading of the catalyst, easy work‐up, and recyclability of the catalyst for a minimum of six times without an obvious decay of catalytic performance.

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Rational drug design, synthesis, and biological evaluation of novel chiral tetrahydronaphthalene-fused spirooxindole as MDM2-CDK4 dual inhibitor against glioblastoma

Cited by 59 publications

References 106 publications

MicroRNA-147a Targets SLC40A1 to Induce Ferroptosis in Human Glioblastoma

MicroRNA-147a Targets SLC40A1 to Induce Ferroptosis in Human Glioblastoma

MDM2/X Inhibitors as Radiosensitizers for Glioblastoma Targeted Therapy

Nickel supported on magnetic biochar as a highly efficient and recyclable heterogeneous catalyst for the one‐pot synthesis of spirooxindole‐dihydropyridines

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