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

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.

SKRINING FITOKIMIA DAN PENETAPAN KADAR FENOL TOTAL PADA EKSTRAK DAUN NANGKA (Artocarpus heterophyllus), CEMPEDAK (Artocarpus integer), dan TARAP (Artocarpus odoratissimus) ASAL DESA PENGARON KABUPATEN BANJAR

The leaves of jackfruit (Artocarpus heterophyllus), cempedak (Artocarpus integer), and tarap (Artocarpus odoratissimus) are used empirically by the people of Desa Pengaron, Banjar Regency for treat antimalarials, antidiabetic, abdominal pain, and cancer. The secondary metabolites of the phenol group are responsible for various plant activities. This study aims to determine of compounds and total phenol content in leaves of jackfruit (A. heterophyllus), cempedak (A. integer), and tarap (A. odoratissimus). The leaf samples were oven-dried, then the leaf powder was extracted using ethanol. Phytochemical screening was carried out on the extract using reagents, and phenol content was determined using a spectrophotometer UV-Vis. The results showed that the extracts of leaves jackfruit (A. heterophyllus), cempedak (A. integer), and tarap (A. odoratissimus) contained phenol, flavonoids, and tannins. Total phenol content of leaves A. heterophyllus, A. integer and A. odoratissimus were 13,174 ± 1,378 mgGAE / gram extract, 37,204 ± 2,202 mgGAE / gram extract, and 35,886 ± 0.890 mgGAE / gram extract.

Second sphere effects on H2O2 activation by non-heme FeII complexes: Role of a phenol group in the [H2O2]-dependent accumulation of FeIVO vs FeIIIOOH

Redox metalloenzymes achieve very selective oxidation reactions under mild conditions using O2 or H2O2 as oxidants and release harmless side-products like water. Their oxidation selectivity is intrinsically linked to the...

Effects of side chain length of 10-methyl-aplog-1, a simplified analog of debromoaplysiatoxin, on PKC binding, anti-proliferative, and pro-inflammatory activities

10-Methyl-aplog-1 (1), a simplified analog of debromoaplysiatoxin, exhibits a high binding affinity for protein kinase C (PKC) isozymes and potent antiproliferative activity against several cancer cells with few adverse effects. A recent study has suggested that its phenol group in the side chain is involved in hydrogen bonding and CH/π interactions with the binding cleft-forming loops in the PKCδ-C1B domain. To clarify the effects of the side chain length on these interactions, four analogs of 1 with various lengths of side chains (2-5) were prepared. The maximal PKC binding affinity and antiproliferative activity were observed in 1. Remarkably, the introduction of a bromine atom into the phenol group of 2 increased not only these activities but also proinflammatory activity. These results indicated that 1 has the optimal side chain length as an anticancer seed. This conclusion was supported by docking simulations of 1-5 to the PKCδ-C1B domain.

5-Aryl-2-(3,5-dialkyl-4-hydroxyphenyl)-4,4-dimethyl-4H-imidazole 3-Oxides and Their Redox Species: How Antioxidant Activity of 1-Hydroxy-2,5-dihydro-1H-imidazoles Correlates with the Stability of Hybrid Phenoxyl–Nitroxides

Cyclic nitrones of the imidazole series, containing a sterically hindered phenol group, are promising objects for studying antioxidant activity; on the other hand, they can form persistent hybrid phenoxyl–nitroxyl radicals (HPNs) upon oxidation. Here, a series of 5-aryl-4,4-dimethyl-4H-imidazole 3-oxides was obtained by condensation of aromatic 2-hydroxylaminoketones with 4-formyl-2,6-dialkylphenols followed by oxidation of the initially formed N-hydroxy derivatives. It was shown that the antioxidant activity of both 1-hydroxy-2,5-dihydroimidazoles and 4H-imidazole 3-oxides increases with a decrease in steric volume of the alkyl substituent in the phenol group, while the stability of the corresponding HPNs generated from 4H-imidazole 3-oxides reveals the opposite tendency.

Effect of photoinitiator on chain degradation of hyaluronic acid

Objectives Photocrosslinking systems of polymers have been widely studied using UV or visible light irradiation. However, the photodegradation behavior derived from light irradiation was rarely reported, comparing with the photocrosslinking. In this study, the tyramine-modified hyaluronic acid (HA/Tyr) hydrogel was prepared using riboflavin (RF) as a photoinitiator, and the degradation behavior of HA by the reactive oxygen species (ROS) generated in photochemical process was investigated. Materials and methods The HA/Tyr conjugate was synthesized by EDC/NHS chemistry to introduce phenol group. Degree of substitution (DS, %) of phenol group to HA molecule was about 25%. The structural change of HA/Tyr was measured by proton nuclear magnetic resonance (1H-NMR) and attenuated total reflectance infrared spectroscopy (ATR-FTIR), and the rheological properties of photocrosslinked HA/Tyr hydrogel were investigated by rheometer. Results The HA/Tyr solution with 25% substitution formed a stable hydrogel via visible light irradiation in the presence of RF photoinitiator. Rheological data of HA/Tyr solution showed that the storage modulus (G’) was increased with increasing HA concentration. Additionally, it was found that RF initiated by visible light irradiation induced the degradation of HA molecular chain, and consequently reduced the viscosity of HA/Tyr solutions. Conclusion The results indicate that RF-based photoinitiator system caused the degradation of HA molecule by ROS generated in photochemical process as well as the crosslinking of HA/Tyr.