Novel Chrysin-De-Allyl PAC-1 Hybrid Analogues as Anticancer Compounds: Design, Synthesis, and Biological Evaluation

Al-Oudat, Buthina A.; Ramapuram, Hariteja; Malla, Saloni; Audat, Suaad Abdallah; Hussein, Noor; Len, Jenna M.; Kumari, Shikha; Bedi, Mel F.; Ashby, Charles R.; Tiwari, Amit K.

doi:10.3390/molecules25133063

Cited by 10 publications

(7 citation statements)

References 61 publications

(85 reference statements)

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“…The MTT assay was performed to determine the cytotoxic efficacy of TPH104, as described previously [ 43 ]. Briefly, in a 96-well flat-bottom cell culture plate, cells were seeded at a density of 3 × 10 3 cells/well (in 100 µL) and incubated overnight.…”

Section: Methodsmentioning

confidence: 99%

A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells

Tukaramrao

Malla

Saraiya

et al. 2021

Cancers

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Enhancing the tumor immunogenic microenvironment has been suggested to circumvent triple-negative breast cancer (TNBC) resistance and increase the efficacy of conventional chemotherapy. Here, we report a novel chemotherapeutic compound, TPH104, which induces immunogenic cell death in the TNBC cell line MDA-MB-231, by increasing the stimulatory capacity of dendritic cells (DCs), with an IC50 value of 140 nM. TPH104 (5 µM) significantly increased ATP levels in the supernatant and mobilized intracellular calreticulin to the plasma membrane in MDA-MB-231 cells, compared to cells incubated with the vehicle. Incubating MDA-MB-231 cells for 12 h with TPH104 (1–5 µM) significantly increased TNFα mRNA levels. The supernatants of dying MDAMB-231 cells incubated with TPH104 increased mouse bone marrow-derived DC maturation, the expression of MHCII and CD86 and the mRNA expression of TNFα, IL6 and IL12. Overall, these results indicate that TPH104 induces immunogenic cell death in TNBC cells, in part, by activating DCs.

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Section: Methodsmentioning

confidence: 99%

A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells

Tukaramrao

Malla

Saraiya

et al. 2021

Cancers

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“…In the present review, we provided a mechanistic review of chrysin and its underlying mechanisms for anti-tumor activity [ 323 , 324 , 325 ]. Noteworthy, chrysin derivatives have also shown potential anti-tumor activity [ 326 , 327 , 328 , 329 ], showing that future studies can focus on chemical modification of chrysin structure in improving its bioavailability, anti-tumor activity, etc. Although chemical modification is a promising strategy in promoting the anti-tumor activity of chrysin, it seems that nanoscale delivery systems, such as polymeric nanoparticles, liposomes, solid lipid nanoparticles, etc., can also be considered in promoting cellular uptake of chrysin and enhancing its anti-tumor activity.…”

Section: Conclusion and Remarksmentioning

confidence: 99%

Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives

et al. 2020

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Pharmacological profile of phytochemicals has attracted much attention to their use in disease therapy. Since cancer is a major problem for public health with high mortality and morbidity worldwide, experiments have focused on revealing the anti-tumor activity of natural products. Flavonoids comprise a large family of natural products with different categories. Chrysin is a hydroxylated flavonoid belonging to the flavone category. Chrysin has demonstrated great potential in treating different disorders, due to possessing biological and therapeutic activities, such as antioxidant, anti-inflammatory, hepatoprotective, neuroprotective, etc. Over recent years, the anti-tumor activity of chrysin has been investigated, and in the present review, we provide a mechanistic discussion of the inhibitory effect of chrysin on proliferation and invasion of different cancer cells. Molecular pathways, such as Notch1, microRNAs, signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappaB (NF-κB), PI3K/Akt, MAPK, etc., as targets of chrysin are discussed. The efficiency of chrysin in promoting anti-tumor activity of chemotherapeutic agents and suppressing drug resistance is described. Moreover, poor bioavailability, as one of the drawbacks of chrysin, is improved using various nanocarriers, such as micelles, polymeric nanoparticles, etc. This updated review will provide a direction for further studies in evaluating the anti-tumor activity of chrysin.

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“…MitoTracker® Red and Alexa Fluor 488 annexin V kits for flow cytometry (Molecular Probes Inc., Eugene, OR, USA) were used to determine the mitochondrial membrane potential and apoptosis, respectively, in OV2008 cells, as previously described [ 68 ]. OV2008 cells were seeded in 6-well plates and incubated with the vehicle, 5 or 20 μM of DML6 for 24 h. The following day, the cells were trypsinized using 0.25% trypsin, 2.21 mM EDTA, 1×, counted and 4 μL of 10 μM MitoTracker® Red working solution was added to 1 mL of the harvested cells.…”

Section: Methodsmentioning

confidence: 99%

A Novel Dialkylamino-Functionalized Chalcone, DML6, Inhibits Cervical Cancer Cell Proliferation, In Vitro, via Induction of Oxidative Stress, Intrinsic Apoptosis and Mitotic Catastrophe

et al. 2021

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In this study, we designed, synthesized and evaluated, in vitro, novel chalcone analogs containing dialkylamino pharmacophores in the cervical cancer cell line, OV2008. The compound, DML6 was selective and significantly decreased the proliferation of OV2008 and HeLa cells in sub-micromolar concentrations, compared to prostate, lung, colon, breast or human embryonic kidney cell line (HEK293). DML6, at 5 μM, arrested the OV2008 cells in the G2 phase. Furthermore, DML6, at 5 μM, increased the levels of reactive oxygen species and induced a collapse in the mitochondrial membrane potential, compared to OV2008 cells incubated with a vehicle. DML6, at 5 μM, induced intrinsic apoptosis by significantly (1) increasing the levels of the pro-apoptotic proteins, Bak and Bax, and (2) decreasing the levels of l the anti-apoptotic protein, Bcl-2, compared to cell incubated with a vehicle. Furthermore, DML6, at 5 and 20 μM, induced the cleavage of caspase-9, followed by subsequent cleavage of the executioner caspases, caspase-3 and caspase-7, which produced OV2008 cell death. Overall, our data suggest that DML6 is an apoptosis-inducing compound that should undergo further evaluation as a potential treatment for cervical cancer.

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Novel Chrysin-De-Allyl PAC-1 Hybrid Analogues as Anticancer Compounds: Design, Synthesis, and Biological Evaluation

Cited by 10 publications

References 61 publications

A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells

A Novel Thienopyrimidine Analog, TPH104, Mediates Immunogenic Cell Death in Triple-Negative Breast Cancer Cells

Broad-Spectrum Preclinical Antitumor Activity of Chrysin: Current Trends and Future Perspectives

A Novel Dialkylamino-Functionalized Chalcone, DML6, Inhibits Cervical Cancer Cell Proliferation, In Vitro, via Induction of Oxidative Stress, Intrinsic Apoptosis and Mitotic Catastrophe

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