Hyaluronic acid from bluefin tuna by-product: Structural analysis and pharmacological activities.

The fishing and aquaculture industries generate a huge amount of waste during processing and preservation operations, especially those of tuna. Recovering these by-products is a major economic and environmental challenge for manufacturers seeking to produce new active biomolecules of interest. A new hyaluronic acid was extracted from bluefin tuna's vitreous humour to assess its antioxidant and pharmacological activities. The characterization by infrared spectroscopy (FT-IR), nuclear magnetic resonance ((1D1H) and 2D (1H COSY, 1H/13C HSQC)) and size exclusion chromatography (SEC/MALS/DRI/VD) revealed that the extracted polysaccharide was a hyaluronic acid with high uronic acid content (55.8 %) and a weight average molecular weight of 888 kDa. This polymer possesses significant anti-radical activity and ferrous chelating capacity. In addition, pharmacological evaluation of its anti-inflammatory and analgesic potential, using preclinical models, in comparison with reference drugs (Dexamethasone, diclofenac, and acetylsalicylate of lysine), revealed promising anti-inflammatory activity as well as interesting peripheral and central antinociceptive activity. Therefore, our new hyaluronic acid compound may therefore serve as a potential drug candidate for the treatment of pain sensation and inflammation of various pathological origins.

Thymoquinone-loaded self-nano-emulsifying drug delivery system against ischemia/reperfusion injury.

In the present study, a self-nano-emulsifying drug delivery system (SNEDDS) was developed to evaluate the efficiency of thymoquinone (TQ) in hepatic ischemia/reperfusion. SNEDDS was pharmaceutically characterized to evaluate droplet size, morphology, zeta potential, thermodynamic stability, and dissolution/diffusion capacity. Animals were orally pre-treated during 10 days with TQ-loaded SNEDDS. Biochemical analyses, hematoxylin-eosin staining, indirect immunofluorescence, and reverse transcription polymerase chain reaction (RT-PCR) were carried out to assess cell injury, oxidative stress, inflammation, and apoptosis. The TQ formulation showed good in vitro characteristics, including stable nanoparticle structure and size with high drug release rate. In vivo determinations revealed that TQ-loaded SNEDDS pre-treatment of rats maintained cellular integrity by decreasing transaminase (ALT and AST) release and preserving the histological characteristics of their liver. The antioxidant ability of the formulation was proven by increased SOD activity, reduced MDA concentration, and iNOS protein expression. In addition, this formulation exerted an anti-inflammatory effect evidenced by reduced plasma CRP concentration, MPO activity, and gene expressions of TLR-4, TNF-α, NF-κB, and IL-6. Finally, the TQ-loaded SNEDDS formulation promoted cell survival by enhancing the Bcl-2/Bax ratio. In conclusion, our results indicate that TQ encapsulated in SNEDDS significantly protects rat liver from I/R injury.

Eco-Friendly Homo- and Cross-Etherification of Benzyl Alcohols Catalyzed by Iron(II/III) Chloride in Propylene Carbonate as a Green and Recyclable Solvent.

A new catalytic approach toward the symmetrical and nonsymmetrical etherification of benzyl alcohols was developed. The symmetrical etherification reaction was carried out in the presence of FeCl3·6H2O (5 mol %) as the catalyst and propylene carbonate as a green and recyclable solvent and led to the corresponding symmetrical ethers in 53 to 91% yields. The nonsymmetrical etherification of benzylic alcohols was achieved by using FeCl2·4H2O (10 mol %) in the presence of a pyridine bis-thiazoline ligand (12 mol %) and allowed for high selectivity and in 52 to 89% yields. These methods take advantage of eco-friendly conditions.

3-aminohydantoin derivate as a promising scaffold in dopaminergic neuroprotection and neurorescue in the in vivo and in vitro 6-hydroxydopamine models of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra, for which no disease-modifying treatments are available yet. Thus, developing new neuroprotective drugs with the potential to delay or stop the natural course of the disease is necessary. The aim of the present study was to evaluate the neuroprotective effects of a newly synthesized 3-aminohydantoin derivative named 3-amino-5-benzylimidazolidine-2,4-dione (PHAH). The possible neuroprotective and neurorescue effects of the synthesized compound were tested: (i) in N27 dopaminergic and BV-2 microglial cell lines treated with 6-hydroxydopamine (6-OHDA) and (ii) in the 6-OHDA rat model of PD. PHAH administration reduced proinflammatory markers, including nitric oxide synthase and interleukin-1ß, in BV-2 cells activated by lipopolysaccharide. Although PHAH did not restore cell death induced by 6-OHDA, it was not cytotoxic for dopaminergic cells since cell viability, under the effect of the two concentrations, remained comparable to that of the control cells. Most interestingly, PHAH restored 6-OHDA-induced dopaminergic neurodegeneration in the substantia nigra and striatum and ameliorated 6-OHDA-induced oxidative stress in the rat brain. In summary, we have proven that in PD models, PHAH has neuroprotective effects in vivo and anti-inflammatory effects in vitro; however, these effects remain to be confirmed by carrying out certain specific behavioural tests as well as by exploring other neuroinflammatory markers. The present work also suggests that PHAH is a promising scaffold that can serve as the basis for the design and synthesis of other derivatives that can be potent antiparkinsonian agents.

Eco-friendly and efficient catalyst-free synthesis of N-sulfonylimines from sulfonamides and aldehydes: crucial role of Al2O3 as a reusable dehydrating agent.

A green synthetic method for the synthesis of N-sulfonylimines was developed involving the straightforward condensation of sulfonamides with aldehydes under green and catalyst-free conditions, mediated by neutral Al2O3 as an efficient and reusable dehydrating agent. N-Sulfonylimines were produced in high yields and purity under simple experimental procedures.

Merging Grubbs second-generation catalyst with photocatalysis enables Z-selective metathesis of olefins: scope, limitations, and mechanism.

Olefin cross-metathesis is a cornerstone reaction in organic synthesis where stereoselectivity is typically governed by the structure of the catalyst. In this work, we show that merging Grubbs second generation catalyst, a classical E-selective catalyst, with a readily available photocatalyst, enables the exclusive formation of the contra-thermodynamic Z-isomer. The scope and limitations of this unprecedented approach are discussed based on both computational and experimental mechanistic data.

Cytotoxicity and Antiviral Activities of Haplophyllum tuberculatum Essential Oils, Pure Compounds, and Their Combinations against Coxsackievirus B3 and B4.

Haplophyllum tuberculatum is a plant commonly used in folk medicine to treat several diseases including vomiting, nausea, infections, rheumatism, and gastric pains. In the current study, H. tuberculatum essential oils, hydrosols, the pure compounds R-(+)-limonene, S-(-)-limonene, and 1-octanol, as well as their combinations R-(+)-limonene/1-octanol and S-(-)-limonene/1-octanol, were screened for their cytotoxicity on HEp-2 cells after 24, 48, and 72 h, and then tested for their activity against Coxsackievirus B3 and B4 (CV-B3 and CV-B4) at 3 different moments: addition of the plant compounds before, after, or together with virus inoculation. Results showed that the samples were more cytotoxic after 72 h than after 24 h or 48 h cell contact. However, the combinations R-(+)-limonene/1-octanol and S-(-)-limonene/1-octanol showed less effect on HEp-2 cells than pure R-(+)-limonene and S-(-)-limonene after 24 h, 48 h, and 72 h. 1-octanol exhibited the highest concentration causing 50% cytotoxicity (CC50) on HEp-2 cells after 24 h (CC50 = 93 µg/mL) and 48 h (CC50 = 83 µg/mL). The antiviral assays showed that the tested samples exhibited potent inhibition of CV-B. IC50 values ranged from 0.66 µg/mL to 28.4 µg/mL. In addition, CV-B3 was more sensitive than CV-B4. Both CV-B strains are more inhibited when cells were pretreated with the plant compounds. The hydrosols have no effect, neither on HEp-2 cells nor on the virus. 1-octanol, S-(-), and R-(+)-limonene/1-octanol had important selectivity indexes over time. Although essential oils had potent antiviral activity, they can be considered for application in the pretreatment of cells. However, 1-octanol and the combinations are within the safety limits, and thus, they can be used as an active natural antiviral agent for CV-B3 and CV-B4 inhibition.

Structure-activity relationship study of hypoxia-activated prodrugs for proteoglycan-targeted chemotherapy in chondrosarcoma.

Due to an abundant chondrogenic, poorly vascularized and particularly hypoxic extracellular matrix, chondrosarcoma, a malignant cartilaginous tumour, is chemo- and radio-resistant. Surgical resection with wide margins remains the mainstay of treatment. To address the lack of therapy, our strategy aims to increase anticancer drugs targeting and delivery in the tumour, by leveraging specific chondrosarcoma hallmarks: an extensive cartilaginous extracellular matrix, namely the high negative fixed charge density and severe chronic hypoxia. A dual targeted therapy for chondrosarcoma was investigated by conjugation of a hypoxia-activated prodrug (HAP) to quaternary ammonium (QA) functions which exhibit a high affinity for polyanionic sites of proteoglycans (PGs), the major components of the chondrosarcoma extracellular matrix. Based on preclinical results, an imidazole prodrug, ICF05016, was identified and provided the basis for a lead optimization study. A series of 27 QA-phosphoramide mustard conjugates, differing by the type of QA function and the length of the alkyl linker, was yielded by a common multi-step sequence involving phosphorylation of a key 2-nitroimidazole alcohol. Then, a screening was realized by surface plasmon resonance technology to assess biomolecular interactions between QA derivatives and aggrecan, the most abundant PG in chondrosarcoma. Results revealed that affinity depends more on the type of QA function, than on the linker length. Moreover, the presence of a benzyl group enhanced affinity to aggrecan. Twelve compounds were shortlisted and evaluated for antiproliferative activity (i.e., growth inhibiting concentration 50), under normoxic and hypoxic conditions using the human extraskeletal myeloid chondrosarcoma cell line (HEMC-SS). For all prodrugs, hypoxic selectivity was maintained and even increased, compared with the lead. From this study, compound 31f emerged as the most effective PG-targeted HAPs with a dissociation constant of 2.10 µM in the SPR experiment, a hypoxia cytotoxicity ratio of 24 and an efficient reductive cleavage under chemical and enzymatic conditions.

Synthesis and pharmacological profile of 6-methyl-3-isopropyl-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide derivatives: non-steroidal anti-inflammatory agents with reduced ulcerogenic effects in the rat.

The new anti-inflammatory agents 6-methyl-3-isopropyl-2H-1,2-benzothiazin-4(3H)-one 1,1-dioxide 6a and its analogues 6b-f were synthesized from L-valine. All compounds were characterized by physical, chemical and spectral studies. Preliminary pharmacological evaluation of the resulting products showed that compounds 6a-f (5-20 mg/kg, i.p.) are active anti-inflammatory agents in carrageenan-induced rat paw oedema assay in albino rats, and their effects are comparable to that of piroxicam (5 mg/kg, i.p.), used as a reference drug. The nature of the substituents on the sulfonamide nitrogen and those on position three had a pronounced effect on the anti-inflammatory activity. Studies of structure-activity relationships have led to selection of compound 2,6-dimethyl-3-isopropyl-1,2-benzothiazin-3,4-diol 1,1-dioxide 6 f which exhibited the most potent activity (61.7% inhibition at 5 mg/kg, i.p. and ED(50)=4.5 mg/kg, i.p.). Comparison of the gastrointestinal safety of compounds 6a-f with that of piroxicam showed a far better tolerability for our products. This comparison was based on the ulcer index and the pH of gastric content.