scholarly journals Isolation, Structure Elucidation and Biological Evaluation of Lagunamide D: A New Cytotoxic Macrocyclic Depsipeptide from Marine Cyanobacteria

Marine Drugs ◽  
2019 ◽  
Vol 17 (2) ◽  
pp. 83 ◽  
Author(s):  
Danmeng Luo ◽  
Masteria Putra ◽  
Tao Ye ◽  
Valerie Paul ◽  
Hendrik Luesch
Keyword(s):  
Therapeutic Potential ◽  
Acyl Migration ◽  
Transformation Product ◽  
Ring Structure ◽  
Biological Evaluation ◽  
Marine Cyanobacteria ◽  
Dependent Manner ◽  
Planar Structures ◽  
Ester Exchange ◽  
Human Lung Adenocarcinoma Cells

Lagunamide D, a new cytotoxic macrocyclic depsipeptide, was discovered from a collection of marine cyanobacteria from Loggerhead Key in the Dry Tortugas, Florida. An intramolecular ester exchange was observed, where the 26-membered macrocycle could contract to a 24-membered compound via acyl migration at the 1,3-diol unit, and the transformation product was named lagunamide D’. The planar structures of both compounds were elucidated using a combination of nuclear magnetic resonance (NMR) spectroscopy and high-resolution mass spectroscopy (HRMS). The absolute configurations were determined on the basis of enantioselective analysis, modified Mosher’s analysis, Kishi NMR database, and direct comparison with lagunamide A, a structure closely resembling lagunamide D. Lagunamides A and D displayed low-nanomolar antiproliferative activity against A549 human lung adenocarcinoma cells, while the structural transformation from the 26-membered lagunamide D macrocycle to the 24-membered ring structure for lagunamide D’ led to a 9.6-fold decrease in activity. Lagunamide D also displayed potent activity in triggering apoptosis in a dose- and time-dependent manner. Further investigation on the mechanism of action of the lagunamide scaffold is needed to fully explore its therapeutic potential as an anticancer agent.

scholarly journals Design, synthesis and biological evaluation of a series of CNS penetrant HDAC inhibitors structurally derived from amyloid-β probes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Myeong A Choi ◽  
Sun You Park ◽  
Hye Yun Chae ◽  
Yoojin Song ◽  
Chiranjeev Sharma ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Hdac Inhibitors ◽  
Amyloid Β ◽  
Biological Evaluation ◽  
Pharmacokinetic Studies ◽  
Dependent Manner ◽  
Reference Drug ◽  
Novel Scaffold

Abstract To develop novel CNS penetrant HDAC inhibitors, a new series of HDAC inhibitors having benzoheterocycle were designed, synthesized, and biologically evaluated. Among the synthesized compounds, benzothiazole derivative 9b exhibited a remarkable anti-proliferative activity (GI50 = 2.01 μM) against SH-SY5Y cancer cell line in a dose and time-dependent manner, better than the reference drug SAHA (GI50 = 2.90 μM). Moreover, compound 9b effectively promoted the accumulation of acetylated Histone H3 and α-tubulin through inhibition of HDAC1 and HDAC6 enzymes, respectively. HDAC enzyme assay also confirmed that compound 9b efficiently inhibited HDAC1 and HDAC6 isoforms with IC50 values of 84.9 nM and 95.9 nM. Furthermore, compound 9b inhibited colony formation capacity of SH-SY5Y cells, which is considered a hallmark of cell carcinogenesis and metastatic potential. The theoretical prediction, in vitro PAMPA-BBB assay, and in vivo brain pharmacokinetic studies confirmed that compound 9b had much higher BBB permeability than SAHA. In silico docking study demonstrated that compound 9b fitted in the substrate binding pocket of HDAC1 and HDAC6. Taken together, compound 9b provided a novel scaffold for developing CNS penetrant HDAC inhibitors and therapeutic potential for CNS-related diseases.

Synthesis and Biological Evaluation of Novel Heterocyclic Imines Linked Coumarin- Thiazole Hybrids as Anticancer Agents

2019 ◽  
Vol 19 (4) ◽  
pp. 557-566 ◽  
Author(s):  
Nerella S. Goud ◽  
Mahammad S. Ghouse ◽  
Jatoth Vishnu ◽  
Jakkula Pranay ◽  
Ravi Alvala ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Membrane Potential ◽  
Fluorescence Spectroscopy ◽  
Mitochondrial Membrane Potential ◽  
Mitochondrial Membrane ◽  
Annexin V ◽  
Biological Evaluation ◽  
Dependent Manner ◽  
Dapi Staining ◽  
Dose Dependent

Background: Human Galectin-1, a protein of lectin family showing affinity towards β-galactosides has emerged as a critical regulator of tumor progression and metastasis, by modulating diverse biological events including homotypic cell aggregation, migration, apoptosis, angiogenesis and immune escape. Therefore, galectin-1 inhibitors might represent novel therapeutic agents for cancer. Methods: A new series of heterocyclic imines linked coumarin-thiazole hybrids (6a-6r) was synthesized and evaluated for its cytotoxic potential against a panel of six human cancer cell lines namely, lung (A549), prostate (DU-145), breast (MCF-7 & MDA-MB-231), colon (HCT-15 & HT-29) using MTT assay. Characteristic apoptotic assays like DAPI staining, cell cycle, annexin V and Mitochondrial membrane potential studies were performed for the most active compound. Furthermore, Gal-1 inhibition was confirmed by ELISA and fluorescence spectroscopy. Results: Among all, compound 6g 3-(2-(2-(pyridin-2-ylmethylene) hydrazineyl) thiazol-4-yl)-2H-chromen-2- one exhibited promising growth inhibition against HCT-15 colorectal cancer cells with an IC50 value of 1.28 ± 0.14 µM. The characteristic apoptotic morphological features like chromatin condensation, membrane blebbing and apoptotic body formation were clearly observed with compound 6g on HCT-15 cells using DAPI staining studies. Further, annexin V-FITC/PI assay confirmed effective early apoptosis induction by treatment with compound 6g. Loss of mitochondrial membrane potential and enhanced ROS generation were confirmed with JC-1 and DCFDA staining method, respectively by treatment with compound 6g, suggesting a possible mechanism for inducing apoptosis. Moreover, flow cytometric analysis revealed that compound 6g blocked G0/G1 phase of the cell cycle in a dose-dependent manner. Compound 6g effectively reduced the levels of Gal-1 protein in a dose-dependent manner. The binding constant (Ka) of 6g with Gal-1 was calculated from the intercept value which was observed as 1.9 x 107 M-1 by Fluorescence spectroscopy. Molecular docking studies showed strong interactions of compound 6g with Gal-1 protein. Conclusion: Our studies demonstrate the anticancer potential and Gal-1 inhibition of heterocyclic imines linked coumarin-thiazole hybrids.

scholarly journals Repurposing cabozantinib with therapeutic potential in KIT-driven t(8;21) acute myeloid leukaemias

2021 ◽  
Author(s):  
Kuan-Wei Su ◽  
Da-Liang Ou ◽  
Yu-Hsuan Fu ◽  
Hwei-Fang Tien ◽  
Hsin-An Hou ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Ribosome Biogenesis ◽  
Kinase Inhibitor ◽  
Therapeutic Potential ◽  
Xenograft Model ◽  
Sequencing Analysis ◽  
Dependent Manner ◽  
Leukocyte Activation ◽  
Mouse Xenograft Model ◽  
Acute Myeloid

AbstractCabozantinib is an orally available, multi-target tyrosine kinase inhibitor approved for the treatment of several solid tumours and known to inhibit KIT tyrosine kinase. In acute myeloid leukaemia (AML), aberrant KIT tyrosine kinase often coexists with t(8;21) to drive leukaemogenesis. Here we evaluated the potential therapeutic effect of cabozantinib on a selected AML subtype characterised by t(8;21) coupled with KIT mutation. Cabozantinib exerted substantial cytotoxicity in Kasumi-1 cells with an IC50 of 88.06 ± 4.32 nM, which was well within clinically achievable plasma levels. The suppression of KIT phosphorylation and its downstream signals, including AKT/mTOR, STAT3, and ERK1/2, was elicited by cabozantinib treatment and associated with subsequent alterations of cell cycle- and apoptosis-related molecules. Cabozantinib also disrupted the synthesis of an AML1-ETO fusion protein in a dose- and time-dependent manner. In a mouse xenograft model, cabozantinib suppressed tumourigenesis at 10 mg/kg and significantly prolonged survival of the mice. Further RNA-sequencing analysis revealed that mTOR-mediated signalling pathways were substantially inactivated by cabozantinib treatment, causing the downregulation of ribosome biogenesis and glycolysis, along with myeloid leukocyte activation. We suggest that cabozantinib may be effective in the treatment of AML with t(8;21) and KIT mutation. Relevant clinical trials are warranted.

Abstract 619: Alpha Keto Acids Decompose Peroxides and Prevents Oxidation of Lipoproteins

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Chandrakala Aluganti Narasimhulu ◽  
Kathryn Young Burge ◽  
Yu Yuan ◽  
Sampath Parthasarathy
Keyword(s):  
Therapeutic Potential ◽  
Lipid Peroxides ◽  
Enzymatic Oxidation ◽  
Raw 264.7 Cells ◽  
Dependent Manner ◽  
Gene Expressions ◽  
Dual Effect ◽  
Keto Acids ◽  
Hydroperoxyoctadecadienoic Acid ◽  
Dose Dependent

Background: Alpha keto acids are unstable and decompose rapidly. In this study, we tested the ability of alpha keto acids to reduce peroxides and inhibit oxidation of lipoproteins. Methods: Keto salicylic acid (KSA) and Keto Octanoicacid (KoA) were synthesized and their ability to reduce hydrogen peroxides as well as lipid peroxides (LOOH) was measured using 13-hydroperoxyoctadecadienoic acid (13-HPODE). Lipoproteins (LDL and HDL) were isolated from human plasma and oxidation of liporproteins was performed using copper and MPO in the presence or absence of the keto compounds. RAW 264.7 cells and HUVECS were incubated with LPS and mm-LDL respectively either in the presence or absence of the keto compounds. RNA was isolated from treated cells and real time PCR was performed to analyze IL-1α, IL-6, MCP-1 and VCAM1 gene expressions. Reactive oxygen species were evaluated using DCF fluorescence in presence and absence of the keto compounds. Results: KSA reduced both H2O2 and 13-HPODE whereas KoA is able to reduce the former but not the latter. Both compounds inhibited the lipoprotein oxidation in a dose dependent manner and were able to reduce ROS production by H2O2. KSA is able to inhibit both LPS as well as mm-LDL induced inflammation. However, KoA showed a dual effect as it induced inflammatory markers in the presence of LPS, but inhibited the mm-LDL-induced inflammatory gene expressions. Conclusion: The results of our studies suggest that these keto compounds a) inhibit both enzymatic and non enzymatic oxidation of lipoproteins; b) reduce peroxides and ROS and c) have inhibitory and inducing effect on inflammatory cytokine/gene production in presence of mm-LDL and LPS respectively. Based on these results, we predict that these keto compounds could have therapeutic potential in reducing CVD/atherosclerosis-associated inflammation.

scholarly journals Enhanced antineoplastic/therapeutic efficacy using 5-fluorouracil-loaded calcium phosphate nanoparticles

2018 ◽  
Vol 9 ◽  
pp. 2499-2515 ◽  
Author(s):  
Shanid Mohiyuddin ◽  
Saba Naqvi ◽  
Gopinath Packirisamy
Keyword(s):  
Electron Microscopy ◽  
Calcium Phosphate ◽  
Cancer Cells ◽  
Therapeutic Efficacy ◽  
Therapeutic Potential ◽  
Physicochemical Characterization ◽  
A549 Cells ◽  
Dependent Manner ◽  
Calcium Phosphate Nanoparticles ◽  
Apoptotic Induction

In the past few decades, the successful theranostic application of nanomaterials in drug delivery systems has significantly improved the antineoplastic potency of conventional anticancer therapy. Several mechanistic advantages of nanomaterials, such as enhanced permeability, retention, and low toxicity, as well as surface engineering with targeting moieties, can be used as a tool in enhancing the therapeutic efficacy of current approaches. Inorganic calcium phosphate nanoparticles have the potential to increase the therapeutic potential of antiproliferative drugs due to their excellent loading efficiency, biodegradable nature and controlled-release behaviour. Herein, we report a novel system of 5-fluorouracil (5-FU)-loaded calcium phosphate nanoparticles (CaP@5-FU NPs) synthesized via a reverse micelle method. The formation of monodispersed, spherical, crystalline nanoparticles with an approximate diameter of 160–180 nm was confirmed by different methods. The physicochemical characterization of the synthesized CaP@5-FU NPs was done with transmission electron microscopy (TEM), dynamic light scattering (DLS), field emission scanning electron microscopy (FE-SEM), Fourier-transform infrared spectroscopy (FTIR), and X-ray diffraction (XRD). The antineoplastic potential of the CaP@5-FU NPs against colorectal and lung cancer cells was reported. The CaP@5-FU NPs were found to inhibit half the population (IC50) of lung adenocarcinoma (A549) cells at 32 μg/mL and colorectal (HCT-15) cancer cells at 48.5 μg/mL treatment. The apoptotic induction of CaP@5-FU NPs was confirmed with acridine orange/ethidium bromide (AO/EB) staining and by examining the morphological changes with Hoechst and rhodamine B staining in a time-dependent manner. The apparent membrane bleb formation was observed in FE-SEM micrographs. The up-regulated proapoptotic and down-regulated antiapoptotic gene expressions were further confirmed with semiquantitative reverse transcriptase polymerase chain reaction (PCR). The increased intracellular reactive oxygen species (ROS) were quantified via flow cytometry upon CaP@5-FU NP treatment. Likewise, the cell cycle analysis was performed to confirm the enhanced apoptotic induction. Our study concludes that the calcium phosphate nanocarriers system, i.e. CaP@5-FU NPs, has higher antineoplastic potential as compared to 5-FU alone and can be used as an improved alternative to the antimitotic drug, which causes severe side effects when administrated alone.

scholarly journals Targeting the PI5P4K lipid kinase family in cancer using novel covalent inhibitors

2019 ◽  
Author(s):  
Sindhu Carmen Sivakumaren ◽  
Hyeseok Shim ◽  
Tinghu Zhang ◽  
Fleur M. Ferguson ◽  
Mark R. Lundquist ◽  
...  
Keyword(s):  
Cancer Metabolism ◽  
Target Genes ◽  
Therapeutic Potential ◽  
Dependent Manner ◽  
Cancer Cell Proliferation ◽  
Lipid Kinase ◽  
Covalent Inhibitors ◽  
Lipid Kinases ◽  
Disordered Loop

SummaryThe PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here we present the discovery and characterization of a novel pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K’s reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.

scholarly journals Meroterpenoids From Ganoderma lucidum Mushrooms and Their Biological Roles in Insulin Resistance and Triple-Negative Breast Cancer

2021 ◽  
Vol 9 ◽  
Author(s):  
Jiao-Jiao Zhang ◽  
Dai-Wei Wang ◽  
Dan Cai ◽  
Qing Lu ◽  
Yong-Xian Cheng
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Cell Line ◽  
Triple Negative Breast Cancer ◽  
Ganoderma Lucidum ◽  
Triple Negative ◽  
Raw Materials ◽  
Biological Evaluation ◽  
C2c12 Cells ◽  
Dependent Manner

Ganoderma fungi as popular raw materials of numerous functional foods have been extensively investigated. In this study, five pairs of meroterpenoid enantiomers beyond well-known triterpenoids and polysaccharides, dayaolingzhiols I−M (1–5), were characterized from Ganoderma lucidum. Their structures were identified using spectroscopic and computational methods. Structurally, compound 1 features a novel dioxabicyclo[2.2.2]octan-3-one motif in the side chain. Ethnoknowledge-derived biological evaluation found that (+)-5 could activate Akt and AMPK phosphorylation in insulin-stimulated C2C12 cells, and (+)-5 could activate glucose uptake dose dependently in C2C12 cells. Furthermore, we found that (+)-1 (+)-4, and (–)-4 could significantly inhibit cell migration of the MDA-MB-231 cell line, of which (+)-4 showed significant inhibitory effects against cell migration of the MDA-MB-231 cell line in a dose-dependent manner. These findings revealed the meroterpenoidal composition of G. lucidum and its roles in the prevention of chronic diseases such as diabetes mellitus and triple-negative breast cancer.

scholarly journals Investigation of the Iron Oxide Nanoparticle Effects on Amyloid Precursor Protein Processing in Hippocampal Cells

2021 ◽  
Author(s):  
Leila Sadeghi ◽  
◽  
Arezu Marefat ◽  
Keyword(s):  
Iron Oxide ◽  
Alzheimer Disease ◽  
Amyloid Precursor Protein ◽  
Magnetic Particles ◽  
Therapeutic Potential ◽  
Precursor Protein ◽  
Neonatal Rat ◽  
Amyloid Precursor Protein Processing ◽  
Iron Oxide Nanoparticle ◽  
Dependent Manner

Introduction: Iron oxide nanoparticles (Fe2O3-NPs) are small magnetic particles that widely used in different aspects of biology and medicine in modern life. Fe2O3-NP accumulated in the living cells due to absence of active system to excrete the iron ions so damages cellular organelles by highly reactivity. Method: Herein cytotoxic effects of Fe2O3-NP with 50 nm size were investigated on primary culture of neonatal rat hippocampus by MTT assay. Pathophysiological signs of Alzheimer disease such as amyloid precursor protein (APP) expression, Aβ aggregation, soluble APPα and APPβ secretion also were investigated in hippocampal cells treated by various concentration of NP for different exposure time. Results: Our results revealed, Fe2O3-NP treatment causes oxidative stress in cells that accompanied by upregulation of the APP and Aβ in a concentration dependent manner. NP exposing also leads to more secretion of sAPPβ rather than sAPPα that concluded to increased activation of β-secretase in NP received cells. All of the harmful effects accumulate in neurons that could not be renovated so lead to neurodegeneration in Alzheimer disease. Conclusion: This study approved iron-based NPs could help to develop the Alzheimer and related neurological disorders and explained why some of the iron chelators have therapeutic potential in Alzheimer disease.

scholarly journals Evaluation of pro-apoptotic potential of taxifolin against liver cancer

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e11276
Author(s):  
Sania Safdar Butt ◽  
Khushbukhat Khan ◽  
Yasmin Badshah ◽  
Mehak Rafiq ◽  
Maria Shabbir
Keyword(s):  
Liver Cancer ◽  
Cell Lines ◽  
Anticancer Agents ◽  
Therapeutic Potential ◽  
Huh7 Cell ◽  
Dependent Manner ◽  
Dna Ladder ◽  
Cell Viability Assay ◽  
Migration Assay ◽  
In Silico Docking

Liver cancer is the second most common cause of cancer-induced deaths worldwide. Liver cirrhosis and cancer are a consequence of the abnormal angio-architecture formation of liver and formation of new blood vessels. This angiogenesis is driven by overexpression of hypoxia-inducible factor 1-alpha (Hif1-α) and vascular endothelial growth factor (VEGF). Apart from this, protein kinase B (Akt) is also impaired in liver cancer. Despite the advancement in conventional treatments, liver cancer remains largely incurable. Nowadays, the use of naturally occurring anticancer agents particularly flavonoids is subject to more attention due to their enhanced physicochemical properties. Therefore, this study underlines the use of a natural anticancer agent taxifolin in the treatment of liver cancer using hepatocellular carcinoma cell line HepG2 and Huh7. The aim of our study is to devise a natural and efficient solution for the disease prevalent in Pakistan. The study involved the assessment of binding of ligand taxifolin using molecular docking. The binding of taxifolin with the proteins (Hif1-α, VEGF and Akt) was calculated by docking using Vina and Chimera. Further evaluation was performed by cell viability assay (MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) Assay), colony formation assay, cell migration assay, DNA ladder assay and flow cytometry. To see whether taxifolin directly affected expression levels, analysis of gene expression of Hif1-α, VEGF and Akt was performed using real-time polymerase chain reaction (qPCR) and western blotting. In silico docking experiments revealed that these proteins showed favorable docking scores with taxifolin. Treatment with taxifolin resulted in the inhibition of the liver cancer growth and migration, and induced apoptosis in HepG2 and Huh7 cell lines at an inhibitory concentration (IC50) value of 0.15 µM and 0.22 µM, respectively. The expression of HIF1-α, VEGF and Akt was significantly reduced in a dose- dependent manner. The inhibitory effect of taxifolin on hepatic cells suggested its chemopreventive and therapeutic potential. The studied compound taxifolin exhibited pronounced pro-apoptotic and hepatoprotective potential. Our study has confirmed the pro-apoptotic potential of taxifolin in liver cancer cell lines and will pave a way to the use of taxifolin as a chemotherapeutic agent after its further validation on the animal models and humans based epidemiological studies.

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