scholarly journals Heterogeneity of Response to Iron-Based Metallodrugs in Glioblastoma Is Associated with Differences in Chemical Structures and Driven by FAS Expression Dynamics and Transcriptomic Subtypes

2021 ◽  
Vol 22 (19) ◽  
pp. 10404
Author(s):  
Anne Vessières ◽  
Emie Quissac ◽  
Nolwenn Lemaire ◽  
Agusti Alentorn ◽  
Patrycja Domeracka ◽  
...  
Keyword(s):  
Cell Lines ◽  
Death Receptor ◽  
Mechanisms Of Action ◽  
Differential Analysis ◽  
Phenol Group ◽  
Chemical Structures ◽  
Ic50 Values ◽  
Iron Based ◽  
Personalized Approach ◽  
New Treatments

Glioblastoma (GBM) is the most frequent and deadliest primary brain cancer in adults, justifying the search for new treatments. Some members of the iron-based ferrocifen family have demonstrated a high cytotoxic effect on various cancer cell lines via innovative mechanisms of action. Here, we evaluated the antiproliferative activity by wst-1 assay of six ferrocifens in 15 molecularly diverse GBM patient-derived cell lines (PDCLs). In five out of six compounds, the half maximal inhibitory concentration (IC50) values varied significantly (10 nM < IC50 < 29.8 µM) while the remaining one (the tamoxifen-like complex) was highly cytotoxic against all PDCLs (mean IC50 = 1.28 µM). The pattern of response was comparable for the four ferrocifens bearing at least one phenol group and differed widely from those of the tamoxifen-like complex and the complex with no phenol group. An RNA sequencing differential analysis showed that response to the diphenol ferrocifen relied on the activation of the Death Receptor signaling pathway and the modulation of FAS expression. Response to this complex was greater in PDCLs from the Mesenchymal or Proneural transcriptomic subtypes compared to the ones from the Classical subtype. These results provide new information on the mechanisms of action of ferrocifens and highlight a broader diversity of behavior than previously suspected among members of this family. They also support the case for a molecular-based personalized approach to future use of ferrocifens in the treatment of GBM.

scholarly journals A novel ferronucleoside that targets DNA replication in pancreatic cancer cells

2021 ◽  
Author(s):  
Marium Rana ◽  
Alessio Perotti ◽  
Lucy Bisset ◽  
James Smith ◽  
Emma Lamben ◽  
...  
Keyword(s):  
Dna Replication ◽  
Cell Lines ◽  
Single Molecule ◽  
Ductal Adenocarcinoma ◽  
Phase Cell ◽  
Mrn Complex ◽  
Stress Studies ◽  
Pancreatic Cancer Cells ◽  
Ic50 Values ◽  
New Treatments

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a disease that remains largely refractory to existing treatments including the nucleoside analogue gemcitabine. In the current study we demonstrate that the ferronucleoside 1-(S,Rp) is cytotoxic in a panel of PDAC cell lines including gemcitabine resistant MIAPaCa2, with IC50 values comparable to cisplatin. Biochemical studies show that the mechanism of action is inhibition of DNA-replication, S-phase cell cycle arrest and stalling of DNA-replication forks which were directly observed at single molecule resolution by DNA-fibre fluorography. In agreement with this, transcriptional changes following treatment with 1-(S,Rp) include activation of three of the four genes (HUS1, RAD1, RAD17) of the 9-1-1 check point complex clamp and two of the three genes (MRE11, NBN) that form the MRN complex as well as activation of multiple downstream targets. Furthermore, there was evidence of phosphorylation of checkpoint kinases 1 and 2 as well as RPA1 and gamma H2AX, all of which are considered biochemical markers of replication stress. Studies in p53 deficient cell lines showed activation of CDKN1A (p21) and GADD45A by 1-(S,Rp) was at least partially independent of p53. In conclusion, because of its potency and activity in gemcitabine resistant cells, 1-(S,Rp) is a promising candidate molecule for development of new treatments for PDAC.

scholarly journals Nano-chemistry and Bio-conjugation with perspectives on the design of Nano-Immune platforms, vaccines and new combinatorial treatments

2021 ◽  
pp. 049-056
Author(s):  
Gomez Palacios Luna R ◽  
Martinez Sofia ◽  
Tettamanti Cecilia ◽  
Quinteros Daniela ◽  
Bracamonte A Guillermo
Keyword(s):  
Small Molecules ◽  
Mechanisms Of Action ◽  
Chemical Structures ◽  
Functional Nanoparticles ◽  
Corona Virus ◽  
New Treatments

This Mini-Review and Opinion letter, it was addressed different themes and topics implicated in the development of new treatments and vaccines applied to pathologies developed in humans such as by Virus and related pathogens. In this context, it was presented and discussed different strategies used, which were contemplated from the design of small molecules, towards higher sized chemical structures and new Nanoarchitectures. In particular, it was discussed varied studies developed for the Corona Virus treatment; which afforded to the main mechanisms of action of pharmacophores and targeted functional Nanoparticles. In this direction, it was highlighted the importance of Bioconjugation of molecules and variable Nanoarchitectures for their incorporation within cells as well as for the development of Nano-vaccines. Moreover, it was discussed about the development of combinatory treatments based on different strategies recently reported. Similarly, it was presented different studies and developments actually in progress related to the design of functional and Multifunctional Nano-platforms with potential perspectives on Lab-On particles and Nano-vaccines for precision Nanomedicine and new treatments.

scholarly journals Development of Nimesulide Analogues as Dual Tubulin and HSP27 Inhibitor for Treating Female Cancers

2020 ◽  
Author(s):  
Laila Jarragh Alhadad ◽  
Fars Alanazi ◽  
Gamaleldin Harisa
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Cell Lines ◽  
Biological Activities ◽  
Critical Role ◽  
Biological Evaluation ◽  
Crystallographic Analysis ◽  
Skbr3 Cell ◽  
Chemical Structures ◽  
Ic50 Values

Tubulin and heat shock protein 27 (HSP27) are up-regulated in cancer cells, and play a critical role in cell division, and proliferation. Therefore, they are targets for discovery of anticancer therapy. The objective of this study is to design, characterize, and biologically evaluate the nimesulide analogues to combat female cancer such as ovarian cancer, and breast cancer. Herein, the nimesulide analogues are designed to target both tubulin and HSP27 functions. Ovarian cancer (SKOV3) and breast cancer (SKBR3) cell lines were used as surrogate models to test the nimesulide analogs biological activities using MTT assay. In the present study, four nimesulide analogues were designed, synthesized and the chemical structures were with the biological evaluation were studied. The synthesized agents were characterized by 1H-NMR, 13C-NMR, the molecular weight was confirmed using GC-MS technique, and melting point. Besides, the agent L4 structure was confirmed using X-ray crystallographic analysis. The present data revealed that nimesulide analogs have potent anticancer activity against SKOV3and SKBR3 cell lines. The IC50 values for both SKOV3 and SKBR3 cell lines treated with the agents showed a potent cell growth inhibition range of 0.23-2.02 &micro;M and 0.50-3.73 &micro;M respectively. In conclusion, the designed nimesulide analogues can target both tubulins, and HSP27 concurrently, and they are promising agents as future chemotherapy female cancers.

scholarly journals New Cytotoxic Cycloartane Triterpenes from the Aerial Parts of Actaea heracleifolia (syn. Cimicifuga heracleifolia)

Planta Medica ◽  
2018 ◽  
Vol 85 (02) ◽  
pp. 154-159
Author(s):  
Qiang-Qiang Shi ◽  
Wei-Hua Wang ◽  
Jing Lu ◽  
Da-Shan Li ◽  
Lin Zhou ◽  
...  
Keyword(s):  
Cell Lines ◽  
Human Tumor ◽  
Human Tumor Cell ◽  
Human Tumor Cell Lines ◽  
Chemical Structures ◽  
Aerial Parts ◽  
Ic50 Values ◽  
Weak Activity ◽  
Mcf 7

AbstractOne new 15,16-seco-cycloartane triterpene (1), three new cycloartane triterpene glycosides (2–4), and five known compounds (5–9) were isolated from the aerial parts of Actaea heracleifolia. The chemical structures of these compounds were determined on the basis of NMR analysis, HRTOF-ESIMS data, and other spectroscopic methods. Selected compounds were evaluated for their cytotoxicity against human tumor cell lines (HL-60, SMMC-7721, A549, MCF-7, and SW480) in vitro. Compounds 3 and 4 showed weak activity against the HL-60, A-549, and MCF-7 cell lines with IC50 values ranging from 21.34 to 36.98 µM.

Fungal Phytotoxins in Sustainable Weed Management

2018 ◽  
Vol 25 (2) ◽  
pp. 268-286 ◽  
Author(s):  
Maurizio Vurro ◽  
Angela Boari ◽  
Francesca Casella ◽  
Maria Chiara Zonno
Keyword(s):  
Weed Management ◽  
Pathogenic Fungi ◽  
Mechanisms Of Action ◽  
Limiting Factors ◽  
Integrated Weed Management ◽  
Plant Pathogenic Fungi ◽  
Design Strategies ◽  
Disease Etiology ◽  
Chemical Structures ◽  
Toxic Metabolites

Fungal phytotoxins are natural secondary metabolites produced by plant pathogenic fungi during host–pathogen interactions. They have received considerable particular attention for elucidating disease etiology, and consequently to design strategies for disease control. Due to wide differences in their chemical structures, these toxic metabolites have different ecological and environmental roles and mechanisms of action. This review aims at summarizing the studies on the possible use of these metabolites as tools in biological and integrated weed management, e.g. as: novel and environmentally friendly herbicides; lead for novel compounds; sources of novel mechanisms of action. Moreover, the limiting factors for utilizing those metabolites in practice will also be briefly discussed.

Phytochemical Constituents of Annona reticulata and their Cytotoxic Activity

2020 ◽  
Vol 17 (3) ◽  
pp. 206-210
Author(s):  
Ty Viet Pham ◽  
Thang Quoc Le ◽  
Anh Tuan Le ◽  
Hung Quoc Vo ◽  
Duc Viet Ho
Keyword(s):  
Cytotoxic Activity ◽  
Cell Lines ◽  
Structural Determination ◽  
Phytochemical Investigation ◽  
Ic50 Values ◽  
Phytochemical Constituents ◽  
First Time ◽  
Annona Reticulata

A phytochemical investigation of the leaves of Annona reticulata led to the isolation and structural determination of β-sitosterol (1), ent-pimara-8(14),15-dien-19-oic acid (2), ent-pimara- 8(14),15-dien-19-ol (3), quercetin (4), quercetin 3-O-α-L-arabinopyranoside (5), and a mixture of quercetin 3-O-β-D-galactopyranoside (6a) and quercetin 3-O-β-D-glucopyranoside (6b). Of these, compounds 2 and 3 were isolated from the genus Annona for the first time. Compound 3 showed strong cytotoxicity against SK-LU-1 and SW626 cell lines with IC50 values of 17.64 ± 1.07 and 19.79 ± 1.41 μg mL-1, respectively.

Isolation of New Glycosides from Anemarrhena Asphodeloides Rhizome and Screening of their Anticancer Activity

2019 ◽  
Vol 16 (6) ◽  
pp. 474-477 ◽  
Author(s):  
Pham Van Khang ◽  
Nguyen Thi Hien Lan ◽  
Le Quang Truong ◽  
Mai Thi Minh Chau ◽  
Mai Xuan Truong ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Spectral Data ◽  
Cell Lines ◽  
Cancer Cell ◽  
Spectroscopic Analysis ◽  
2D Nmr ◽  
Ic50 Values ◽  
Nmr Techniques ◽  
Inhibitory Activities ◽  
Anemarrhena Asphodeloides

In this report, two new steroidal glycosides were isolated and determined from n-butanol fraction of A.asphodeloides. The structures were confirmed in comparison with the spectral data of known compounds by using different spectroscopic analysis approaches including 1D & 2D-NMR techniques and HRMS. The anti-proliferation screening against cancer cell lines A549 and HeLa indicated that compound 1 exhibited good inhibitory activities with IC50 values of 0.79 and 0.55 &#181;g/mL, respectively.

Synthesis and Antitumor Activity Evaluation of New Phenanthrene-Based Tylophorine Derivatives

2019 ◽  
Vol 16 (6) ◽  
pp. 462-467
Author(s):  
Songtao Li ◽  
Hongling Zhao ◽  
Zhifeng Yin ◽  
Shuhua Deng ◽  
Yang Gao ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Cell Lines ◽  
Antitumor Activities ◽  
Human Carcinoma ◽  
Carcinoma Cell Lines ◽  
Structure Activity ◽  
Human Carcinoma Cell ◽  
Ic50 Values ◽  
Relationship Of

A series of new phenanthrene-based tylophorine derivatives (PBTs) were synthesized in good yield and their structures were characterized by 1H-NMR spectroscopy and ESI MS. In vitro antitumor activity of these compounds against five human carcinoma cell lines, including HCT116 (colorectal), BGC-823 (gastric), HepG-2 (hepatic), Hela (cervical) and H460 (lung) cells, was evaluated by MTT assay. Among these PBTs, compound 6b showed the highest antitumor activities against HCT116 and HepG-2 cell lines with IC50 values of 6.1 and 6.4 μM, respectively, which were comparable to that of adriamycin hydrochloride. The structure-activity relationship of these compounds was also discussed based on the results of their antitumor activity.

Microwave-assisted Synthesis of Polymethoxychalcone Mannich Bases and Their Antiproliferative Activity

2019 ◽  
Vol 16 (2) ◽  
pp. 117-121 ◽  
Author(s):  
Peipei Han ◽  
Wenhua Zhou ◽  
Mingxia Chen ◽  
Qiuan Wang
Keyword(s):  
Cell Lines ◽  
Cancer Cell ◽  
Antiproliferative Activity ◽  
Mannich Base ◽  
Cancer Cell Lines ◽  
Secondary Amines ◽  
Conventional Heating ◽  
Microwave Assisted ◽  
Ic50 Values ◽  
Antiproliferative Activities

A series of eight polymethoxychalcone Mannich base derivatives 2a-2h was synthesized via the microwave-assisted Mannich reaction of natural product 2&#039;-hydroxy-3,4,4&#039;,5,6&#039;-pentamethoxychalcone (1) with various secondary amines and formaldehyde. Compared to conventional heating method (80&#176;C), the microwave-assisted method (700W, 65&#176;C) is efficient with short reaction time (0.5-1 h) and good yields (74-88%). The antiproliferative activities of eight Mannich base derivatives were evaluated in vitro on a panel of three human cancer cell lines (Hela, HCC1954 and SK-OV-3) by CCK-8 assay. The results showed that all of the Mannich base derivatives exhibited potential antiproliferative activities on tested cancer cell lines with the IC50 values of 9.13-48.51 &#181;M. Some active compounds exhibited more activity as compared to positive control cis-Platin. Among them, compound 2b revealed to have the strongest antiproliferative activity against all the three cancer cell lines with IC50 values ranging from 9.13 to 11.24 &#181;M.

Design, Synthesis and Biological Evaluation: 5-amino-1H-pyrazole-1- carbonyl derivatives as FGFR Inhibitors

2020 ◽  
Vol 17 (11) ◽  
pp. 1330-1341
Author(s):  
Yan Zhang ◽  
Niefang Yu
Keyword(s):  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Biological Evaluation ◽  
Human Gastric Cancer ◽  
Design Synthesis ◽  
Carbonyl Derivatives ◽  
Ic50 Values ◽  
Inhibitory Activities

Background: Fibroblast growth factors (FGFs) and their high affinity receptors (FGFRs) play a major role in cell proliferation, differentiation, migration, and apoptosis. Aberrant FGFR signaling pathway might accelerate development in a broad panel of malignant solid tumors. However, the full application of most existing small molecule FGFR inhibitors has become a challenge due to the potential target mutation. Hence, it has attracted a great deal of attention from both academic and industrial fields for hunting for novel FGFR inhibitors with potent inhibitory activities and high selectivity. Objective: Novel 5-amino-1H-pyrazole-1-carbonyl derivatives were designed, synthesized, and evaluated as FGFR inhibitors. Methods: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives were established by a condensation of the suitable formyl acetonitrile derivatives with either hydrazine or hydrazide derivatives in the presence of anhydrous ethanol or toluene. The inhibitory activities of the target compounds were screened against the FGFRs and two representative cancer cell lines. Tests were carried out to observe the inhibition of 8e against FGFR phosphorylation and downstream signal phosphorylation in human gastric cancer cell lines (SNU-16). The molecular docking of all the compounds were performed using Molecular Operating Environment in order to evaluate their binding abilities with the corresponding protein kinase. Results: A series of 5-amino-1H-pyrazole-1-carbonyl derivatives have been designed and synthesized, screened for their inhibitory activities against FGFRs and cancer cell lines. Most of the target compounds showed moderate to good anti-proliferate activities against the tested enzymes and cell lines. The most promising compounds 8e suppressed FGFR1-3 with IC50 values of 56.4, 35.2, 95.5 nM, and potently inhibited the SNU-16 and MCF-7 cancer cells with IC50 values of 0.71 1.26 μM, respectively. And 8e inhibited the growth of cancer cells containing FGFR activated by multiple mechanisms. In addition, the binding interactions were quite similar in the molecular models between generated compounds and Debio-1347 with the FGFR1. Conclusion: According to the experimental findings, 5-amino-1H-pyrazole-1-carbonyl might serve as a promising template of an FGFR inhibitor.

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