Design and synthesis of novel pipernonaline derivatives as anti-austerity agents against human pancreatic cancer PANC-1 cells

Okada, Takuya; Chino, Yuri; Yokoyama, Keita; Fujihashi, Yuki; Phan, Nguyễn Duy; Maneenet, Juthamart; Prudhvi, Lanke; Awale, Suresh; Toyooka, Naoki

doi:10.1016/j.bmc.2022.116963

Cited by 6 publications

(3 citation statements)

References 25 publications

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“…For this purpose, the CytoSMART LUX2 microscope was used, which enables the visualization of the progress of the gap closing. 38 , 39 The tests were carried out in culture conditions, in an incubator with standard parameters (37°C, 5% CO 2 atmosphere). The test was carried out for 24 hours with snapshot every 5 minutes.…”

Section: Methodsmentioning

confidence: 99%

Encapsulated Oxovanadium(IV) and Dioxovanadium(V) Complexes into Solid Lipid Nanoparticles Increase Cytotoxicity Against MDA-MB-231 Cell Line

Kostrzewa¹,

Nowak²,

Feliczak-Guzik³

et al. 2023

IJN

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Introduction Solid lipid nanoparticles (SLN) have been considered lately as promising drug delivery system in treatment of many human diseases including cancers. We previously studied potential drug compounds that were effective inhibitors of PTP1B phosphatase – possible target for breast cancer treatment. Based on our studies, two complexes were selected for encapsulation into the SLNs, the compound 1 ([VO(dipic)(dmbipy)] · 2 H 2 O) and compound 2 ([VOO(dipic)](2-phepyH) · H 2 O). Here, we investigate the effect of encapsulation of those compounds on cell cytotoxicity against MDA-MB-231 breast cancer cell line. The study also included the stability evaluation of the obtained nanocarriers with incorporated active substances and characterization of their lipid matrix. Moreover, the cell cytotoxicity studies against the MDA-MB-231 breast cancer cell line in comparison and in combination with vincristine have been performed. Wound healing assay was carried out to observe cell migration rate. Methods The properties of the SLNs such as particle size, zeta potential (ZP), and polydispersity index (PDI) were investigated. The morphology of SLNs was observed by scanning electron microscopy (SEM), while the crystallinity of the lipid particles was analyzed by differential scanning calorimetry (DSC) and X-ray diffraction (XRD). The cell cytotoxicity of complexes and their encapsulated forms was carried out against MDA-MB-231 breast cancer cell line using standard MTT protocols. The wound healing assay was performed using live imaging microscopy. Results SLNs with a mean size of 160 ± 25 nm, a ZP of −34.00 ± 0.5, and a polydispersity index of 30 ± 5% were obtained. Encapsulated forms of compounds showed significantly higher cytotoxicity also in co-incubation with vincristine. Moreover, our research shows that the best compound was complex 2 encapsulated into lipid nanoparticles. Conclusion We observed that encapsulation of studied complexes into SLNs increases their cell cytotoxicity against MDA-MB-231 cell line and enhanced the effect of vincristine.

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Section: Methodsmentioning

confidence: 99%

Encapsulated Oxovanadium(IV) and Dioxovanadium(V) Complexes into Solid Lipid Nanoparticles Increase Cytotoxicity Against MDA-MB-231 Cell Line

Kostrzewa¹,

Nowak²,

Feliczak-Guzik³

et al. 2023

IJN

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“…Most of these anti-austerity agents are hydrocarbons with some oxygen functional groups. Recently, anti-austerity agents have also been identified from nitrogencontaining compounds such as naturally occurring 21,22) or synthetic amides 23,24) (Fig. 2); these preliminary findings have encouraged us to investigate further structure-activity relationships of the anti-austerity activity of nitrogen-containing compounds.…”

Section: Introductionmentioning

confidence: 98%

Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach

Tomohara,

Maneenet,

Ohashi

et al. 2023

Biological & Pharmaceutical Bulletin

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Pancreatic cancer cells have an inherent tolerance to withstand nutrition starvation, allowing them to survive in hypovascular tumor microenvironments that lack of sufficient nutrients and oxygen. Developing anti-cancer agents that target this tolerance to nutritional starvation is a promising anti-austerity strategy for eradicating pancreatic cancer cells in their microenvironment. In this study, we employed a chemical biology approach using the Ugi reaction to rapidly synthesize new anti-austerity agents and evaluate their structure-activity relationships. Out of seventeen Ugi adducts tested, Ugi adduct 11 exhibited the strongest anti-austerity activity, showing preferential cytotoxicity against PANC-1 pancreatic cancer cells with a PC 50 value of 0.5 µM. Further biological investigation of Ugi adduct 11 revealed a dramatic alteration of cellular morphology, leading to PANC-1 cell death within 24 h under nutrient-deprived conditions. Furthermore, the R absolute configuration of 11 was found to significantly contribute to the preferential anti-austerity ability toward PANC-1, with a PC 50 value of 0.2 µM. Mechanistically, Ugi adduct (R)-11 was found to inhibit the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway preferentially under nutrition starvation conditions. Consequently, Ugi-adduct (R)-11 could be a promising candidate for drug development targeting pancreatic cancer based on the anti-austerity strategy. Our study also demonstrated that the Ugi reaction-based chemical engineering of natural product extracts can be used as a rapid method for discovering novel anti-austerity agents for combating pancreatic cancer.

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“…Therefore, targeting the ability of cancer cells tolerance to nutrition starvation and hypoxia is regarded as a promising new antiausterity approach for improving treatment outcomes for patients with this aggressive disease. − In addition, combination therapy including antiausterity agents may be able to overcome chemoresistance of gemcitabine, potentially leading to better treatment outcomes in the long term. Based on this hypothesis, our research group has been actively researching the synthesis of novel derivatives that show preferential cytotoxicity under nutrient-deprived conditions without cytotoxicity under normal nutrient conditions. − …”

Section: Introductionmentioning

confidence: 99%

Targeting Pancreatic Cancer with Novel Plumbagin Derivatives: Design, Synthesis, Molecular Mechanism, In Vitro and In Vivo Evaluation

et al. 2023

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Pancreatic tumors grow in an "austerity" tumor microenvironment characterized by nutrient deprivation and hypoxia. This leads to the activation of adaptive pathways in pancreatic cancer cells, promoting tolerance to nutrition starvation and aggressive malignancy. Conventional anticancer drugs are often ineffective against tumors that grow in such austerity condition. Plumbagin, a plant-derived naphthoquinone, has shown potent preferential cytotoxicity against pancreatic cancer cells under nutrient-deprived conditions. Therefore, we synthesized a series of plumbagin derivatives and found that 2-(cyclohexylmethyl)-plumbagin (3f) was the most promising compound with a PC 50 value of 0.11 μM. Mechanistically, 3f was found to inhibit the PI3K/Akt/mTOR signaling pathways, leading to cancer cell death under nutrient-deprived conditions. In vivo studies using pancreatic cancer xenograft mouse models confirmed the efficacy of 3f, demonstrating significant inhibition of tumor growth in a dose-dependent manner. Compound 3f represents a highly promising lead for anticancer drug development based on an antiausterity strategy.

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Design and synthesis of novel pipernonaline derivatives as anti-austerity agents against human pancreatic cancer PANC-1 cells

Cited by 6 publications

References 25 publications

Encapsulated Oxovanadium(IV) and Dioxovanadium(V) Complexes into Solid Lipid Nanoparticles Increase Cytotoxicity Against MDA-MB-231 Cell Line

Encapsulated Oxovanadium(IV) and Dioxovanadium(V) Complexes into Solid Lipid Nanoparticles Increase Cytotoxicity Against MDA-MB-231 Cell Line

Ugi Adducts as Novel Anti-austerity Agents against PANC-1 Human Pancreatic Cancer Cell Line: A Rapid Synthetic Approach

Targeting Pancreatic Cancer with Novel Plumbagin Derivatives: Design, Synthesis, Molecular Mechanism, In Vitro and In Vivo Evaluation

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