Sabinene: A New Green Solvent Used in the Synthesis of Thiazolo[5,4-b]pyridines by Thermal or Microwave Activation.

Following the work already carried out in our laboratory on eucalyptol, a new green solvent derived from biomass, we are now looking at sabinene as another new green solvent. Sabinene is also derived from biomass, has no known toxicity and can be recycled by distillation. We have shown that it can be used as it is or distilled to synthesize thiazolo[5,4-b]pyridine heterocycles by thermal activation or microwave irradiation. This new solvent was compared with various conventional and green solvents. The conditions were optimised to enable us to carry out the syntheses in satisfactory yields, and we were able to show that sabinene, a natural bicyclic monoterpene, could be used effectively as a solvent.

Antioxidant Effects of Catechins (EGCG), Andrographolide, and Curcuminoids Compounds for Skin Protection, Cosmetics, and Dermatological Uses: An Update.

Here we have chosen to highlight the main natural molecules extracted from Camellia sinensis, Andrographis paniculata, and Curcuma longa that may possess antioxidant activities of interest for skin protection. The molecules involved in the antioxidant process are, respectively, catechins derivatives, in particular, EGCG, andrographolide, and its derivatives, as well as various curcuminoids. These plants are generally used as beverages for Camellia sinensis (tea tree), as dietary supplements, or as spices. The molecules they contain are known for their diverse therapeutic activities, including anti-inflammatory, antimicrobial, anti-cancer, antidiabetic, and dermatological treatment. Their common antioxidant activities and therapeutic applications are widely documented, but their use in cosmetics is more recent. We will see that the use of pharmacomodulated derivatives, the addition of co-antioxidants, and the use of various formulations enable better skin penetration and greater ingredient stability. In this review, we will endeavor to compile the cosmetic uses of these natural molecules of interest and the various structural modulations reported with the aim of improving their bioavailability as well as establishing their different mechanisms of action.

Design, Synthesis, and Biological Evaluation of Novel Tomentosin Derivatives in NMDA-Induced Excitotoxicity.

N-methyl-D-aspartate (NMDA) receptor stimulation may lead to excitotoxicity, which triggers neuronal death in brain disorders. In addition to current clinical therapeutic approaches, treatment strategies by phytochemicals or their derivatives are under investigation for neurodegenerative diseases. In the present study, novel amino and 1,2,3-triazole derivatives of tomentosin were prepared and tested for their protective and anti-apoptotic effects in NMDA-induced excitotoxicity. Amino-tomentosin derivatives were generated through a diastereoselective conjugate addition of several secondary amines to the α-methylene-γ-butyrolactone function, while the 1,2,3-triazolo-tomentosin was prepared by a regioselective Michael-type addition carried out in the presence of trimethylsilyl azide (TMSN3) and the α-methylene-γ-lactone function. The intermediate key thus obtained underwent 1,3-dipolar Huisgen cycloaddition using a wide range of terminal alkynes. The possible effects of the derivatives on cell viability and free-radical production following NMDA treatment were measured by Water-Soluble Tetrazolium Salts (WST-1) and Dichlorofluorescein Diacetate (DCF-DA) assays, respectively. The alterations in apoptosis-related proteins were examined by Western blot technique. Our study provides evidence that synthesized triazolo- and amino-tomentosin derivatives show neuroprotective effects by increasing cellular viability, decreasing ROS production, and increasing the Bcl-2/Bax ratio in NMDA-induced excitotoxicity. The findings highlight particularly 2e, 2g, and 6d as potential regulators and neuroprotective agents in NMDA overactivation.

Review on the Synthesis and Therapeutic Potential of Pyrido[2,3-d], [3,2-d], [3,4-d] and [4,3-d]pyrimidine Derivatives.

The objective of this review is to list the structures composed of a pyridopyrimidine moiety which have shown a therapeutic interest or have already been approved for use as therapeutics. We consider all the synthetic protocols to prepare these pyridopyrimidine derivatives. The review is organized into four sections, successively pyrido[2,3-d]pyrimidines, pyrido[3,4-d]pyrimidines, pyrido[4,3-d]pyrimidines and pyrido[3,2-d]pyrimidines. For each compound we present the biological activity and the synthetic route reported. To produce this manuscript, the bibliographic research was done using Reaxys and Scifinder for each kind of pyridopyrimidine.

A Review of Synthetic Access to Therapeutic Compounds Extracted from Psilocybe.

Psychedelics are used for various pathologies of the central nervous system and are currently the subject of much research, some of which relates to the compounds contained in various Psilocybe-type hallucinogenic mushrooms. It is difficult, however, to obtain and purify sufficient quantities of these compounds from fungi to carry out biological studies, hence the need to develop simple and efficient synthetic routes. We review here the various syntheses used to obtain these molecules, focusing first on the classic historical syntheses, then the use of more recent metallo-catalyzed couplings and finally the known biocatalytic methods for obtaining these molecules. Other access routes are certainly possible and should be the subject of future research given the therapeutic interest of these compounds.

Pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5-amines as Potential Cytotoxic Agents against Human Neuroblastoma.

We report herein the evaluation of various pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5-amines as potential cytotoxic agents. These molecules were obtained by developing the multicomponent Groebke-Blackburn-Bienaymé reaction to yield various pyrido[2',1':2,3]imidazo[4,5-c]quinolines which are isosteres of ellipticine whose biological activities are well established. To evaluate the anticancer potential of these pyrido[2',1':2,3]imidazo[4,5-c]isoquinolin-5-amine derivatives in the human neuroblastoma cell line, the cytotoxicity was examined using the WST-1 assay after 72 h drug exposure. A clonogenic assay was used to assess the ability of treated cells to proliferate and form colonies. Protein expressions (Bax, bcl-2, cleaved caspase-3, cleaved PARP-1) were analyzed using Western blotting. The colony number decrease in cells was 50.54%, 37.88% and 27.12% following exposure to compounds 2d, 2g and 4b respectively at 10 µM. We also show that treating the neuroblastoma cell line with these compounds resulted in a significant alteration in caspase-3 and PARP-1 cleavage.

Demonstration of Green Solvent Performance on O,S,N-Heterocycles Synthesis: Metal-Free Click Chemistry and Buchwald-Hartwig Coupling.

The development of new and greener approaches to organic synthesis has been a trend in recent years. Continuing the latest publications of our team, in this work, we demonstrate the efficiency of three solvents: eucalyptol (1,8-cineole), cyclopentyl methyl ether (CPME), and 2-methyltetrahydrofuran (2-MeTHF) for the synthesis of O,S,N-heterocyclic compounds.

Emerging Natural-Product-Based Treatments for the Management of Osteoarthritis.

Osteoarthritis (OA) is a complex degenerative disease in which joint homeostasis is disrupted, leading to synovial inflammation, cartilage degradation, subchondral bone remodeling, and resulting in pain and joint disability. Yet, the development of new treatment strategies to restore the equilibrium of the osteoarthritic joint remains a challenge. Numerous studies have revealed that dietary components and/or natural products have anti-inflammatory, antioxidant, anti-bone-resorption, and anabolic potential and have received much attention toward the development of new therapeutic strategies for OA treatment. In the present review, we provide an overview of current and emerging natural-product-based research treatments for OA management by drawing attention to experimental, pre-clinical, and clinical models. Herein, we review current and emerging natural-product-based research treatments for OA management.

Copper-catalyzed transformation of alkyl nitriles to N-arylacetamide using diaryliodonium salts.

This work reports a simple and efficient method for the copper-catalyzed redox-neutral transformation of alkyl nitriles using eco-friendly diaryliodonium salts and leading to N-arylacetamides. The method features high efficiency, broad substrate scope and good functional group tolerance.

Laser synthesis: a solvent-free approach for the preparation of phenylthiazolo[5,4-b]pyridine derivatives.

We describe here a rapid and straightforward solvent-free method to access phenylthiazolo[5,4-b]pyridines using a Nd-YAG laser NANO-NY81-10 (λ = 355 nm, 10 Hz pulse frequency; 8 ns pulse duration). This newly presented method successfully brings several improvements to the laser assisted synthesis of N,S-heterocycles. We are able to provide a solvent-, metal- and base-free method with good yield and a substantial reduction in reaction time.

Design of new disubstituted imidazo[1,2-b]pyridazine derivatives as selective Haspin inhibitors. Synthesis, binding mode and anticancer biological evaluation.

Haspin is a mitotic protein kinase required for proper cell division by modulating Aurora B kinase localisation and activity as well as histone phosphorylation. Here a series of imidazopyridazines based on the CHR-6494 and Structure Activity Relationship was established. An assessment of the inhibitory activity of the lead structures on human Haspin and several other protein kinases is presented. The lead structure was rapidly optimised using a combination of crystal structures and effective docking models, with the best inhibitors exhibiting potent inhibitory activity on Haspin with IC50 between 6 and 100 nM in vitro. The developed inhibitors displayed anti-proliferative properties against various human cancer cell lines in 2D and spheroid cultures and significantly inhibited the migration ability of osteosarcoma U-2 OS cells. Notably, we show that our lead compounds are powerful Haspin inhibitors in human cells, and did not block G2/M cell cycle transition due to improved selectivity against CDK1/CyclinB.

Andrographis paniculata and Its Bioactive Diterpenoids Against Inflammation and Oxidative Stress in Keratinocytes.

Andrographis paniculata was widely used in traditional herbal medicine to treat various diseases. This study explored the potential anti-aging activity of Andrographis paniculata in cutaneous cells. Human, adult, low calcium, high temperature (HaCaT) cells were treated with methanolic extract (ME), andrographolide (ANDRO), neoandrographolide (NEO), 14-deoxyandrographolide (14DAP) and 14-deoxy-11,12-didehydroandrographolide (14DAP11-12). Oxidative stress and inflammation were induced by hydrogen peroxide and lipopolysaccharide/TNF-α, respectively. Reactive oxygen species (ROS) production was measured by fluorescence using a 2',7'-dichlorofluorescein diacetate (DCFH-DA) probe and cytokines were quantified by ELISA for interleukin-8 (IL-8) or reverse transcription-quantitative polymerase chain reaction (RT-qPCR) for tumor necrosis factor-α (TNF-α). Hyaluronic acid (HA) secretion was determined by an ELISA. Our results show a decrease in ROS production and TNF-α expression by ME (5 µg/mL) in HaCaT under pro-oxidant and pro-inflammatory conditions, respectively. ME protected HaCaT against oxidative stress and inflammation. Our findings confirm that ME can be used for the development of bioactive compounds against epidermal damage.

Andrographis Paniculata and Its Bioactive Diterpenoids Protect Dermal Fibroblasts Against Inflammation and Oxidative Stress.

Andrographis paniculata (Burm.f.) has long been used in ayurvedic medicine through its anti-inflammatory properties. However, its protective effect of skin aging has not been studied in vitro. This study aimed to investigate the anti-aging effects of methanolic extract (ME), andrographolide (ANDRO), neoandrographolide (NEO), 14-deoxyandrographolide (14DAP) and 14-deoxy-11,12-didehydroandrographolide (14DAP11-12) on human dermal fibroblasts (HDFa) under pro-oxidant or pro-inflammatory condition. The in vitro anti-aging capacity of ME, ANDRO, NEO, 14DAP, and 14DAP11-12 (1, 2.5 and 5 µg/mL) was performed in HDFa. Oxidative stress and inflammation were induced by hydrogen peroxide and lipopolysaccharide/TNF-α, respectively. Reactive oxygen species (ROS) production was measured by the fluorescence of DCF-DA probe and cytokines were quantified by ELISA (IL6 and IL8) or RTqPCR (TNF-α). Procollagen type I production was determined by an ELISA. Our results showed a decrease in ROS production with ME and 14DAP at 5 µg/mL and 1 µg/mL, respectively. Furthermore, IL-6 production and TNF-α expression decreased under ANDRO and ME at 5 µg/mL. Our data indicated that ME and 14DAP protect from oxidative stress. Additionally, ME and ANDRO decreased an inflammation marker, IL-6. This suggests their potential natural treatment against skin damage. Hence, their applications could be of interest in cosmetics for preventing skin ageing.

Quantitative Determination of Andrographolide and Related Compounds in Andrographis paniculata Extracts and Biological Evaluation of Their Anti-Inflammatory Activity.

Extraction, isolation and characterization of Andrographis paniculata (A.p.) products were developed. Three natural diterpenes compounds were obtained and one was used for chemical modifications. Evaluation of their inhibition of TNFα induced NFκB transcriptional activity. A rapid analytical method for the determination and quantitation of three diterpenoid lactones (andrographolide 1, didehydroandrographolide 2, neoandrographiside 3) found in A. paniculata extracts was investigated. After some optimizations on column type and injection solvent, the separation was achieved in 9 min on a monolithic Chromolith Performance RP18e column (100 mm × 4.6 mm ID, 2 µm), with a gradient solvent system of water and methanol, UV detection at 220 nm and ELSD detection. The method was proved to be suitable for the quantitation of these three diterpenes in four different commercial Andrographis dietary supplements. The anti-inflammatory activities of a mixture of known composition have been evaluated showing differences in activity depending on the relative ratio of various diterpenes and also a possible synergic activity for some of them.

Andrographolide, a Natural Antioxidant: An Update.

Traditionally, Andrographis paniculata has been used as an herbal remedy for lung infection treatments. Its leaves contain a diterpenoid labdane called andrographolide responsible for a wide range of biological activities such as antioxidant, anti-inflammatory, and anti-cancer properties. This manuscript is a brief review of the antioxidant mechanisms and the regulation of the Nrf2 (nuclear factor (erythroid-derived 2)-like 2) signaling pathway by andrographolide.

First Metal-Free Synthesis of Tetracyclic Pyrido and Pyrazino Thienopyrimidinone Molecules.

We report herein a new metal free synthetic pathway to generate tetracyclic compounds from 3-aminothieno[3,2-b]pyridine-2-carboxylate. To enlarge the molecular diversity, we studied the Suzuki coupling of 9-chloro-6H-pyrido[1,2-a]pyrido[2',3':4,5]thieno[3,2-d]pyrimidin-6-one and several boronic acids were easily introduced.

A Greener and Efficient Method for Nucleophilic Aromatic Substitution of Nitrogen-Containing Fused Heterocycles.

A simple and efficient methodology for the nucleophilic aromatic substitution of nitrogen-containing fused heterocycles with interesting biological activities has been developed in an environmentally sound manner using polyethylene glycol (PEG-400) as the solvent, leading to the expected compounds in excellent yields in only five minutes.

Modification of Natural Eudesmane Scaffolds via Mizoroki-Heck Reactions.

The Mizoroki-Heck reaction was applied to substrates derived from isocostic and ilicic acids, important sesquiterpene components of Dittrichia viscosa L. Greuter that were extracted directly from plant material collected in Morocco. After optimization of the metallo-catalysis conditions, various aryl-groups were successfully introduced on the exocyclic double bond with an exclusive E-configuration and without racemization.

Perindopril and ramipril phosphonate analogues as a new class of angiotensin converting enzyme inhibitors.

A series of phosphonate analogues related to perindopril and ramipril were prepared and tested to estimate their ability to inhibit angiotensin converting enzyme. These new synthesized compounds were active ACE inhibitors with a promising activity.

Efficient metal-free synthesis of various pyrido[2',1':2,3]imidazo- [4,5-b]quinolines.

Dancing with diversity: The synthesis of diverse pyrido[2',1':2,3]imidazo[4,5-b]quinolines bearing several substitution patterns was developed based on combining a multicomponent reaction (Groebke-Blackburn-Bienaymé reaction) with an original cyclization as a secondary transformation (see scheme; DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene).