Influence of Oleacein, an Olive Oil and Olive Mill Wastewater Phenolic Compound, on Caenorhabditis elegans Longevity and Stress Resistance.

Oleacein, a bioactive compound of olive oil and olive mill wastewater, has one of the strongest antioxidant activities among olive phenolics. However, few reports explore the in vivo antioxidant activity of oleacein, with no clear identification of the biological pathway involved. Earlier studies have demonstrated a link between stress resistance, such as oxidative stress, and longevity. This study presents the effects of oleacein on Caenorhabditis elegans mean lifespan and stress resistance. A significant lifespan extension was observed with an increase of 20% mean lifespan at 5 µg/mL with a hormetic-like dose-dependent effect. DAF-16 and SIR-2.1 were involved in the effects of oleacein on the longevity of C. elegans, while the DAF-2 receptor was not involved. This study also shows the capacity of oleacein to significantly enhance C. elegans resistance to oxidative and thermal stress and allows a better understanding of the positive effects of olive phenolics on health.

A comparative ultrastructure study of the tardigrade Ramazzottius varieornatus in the hydrated state, after desiccation and during the process of rehydration.

Tardigrades can survive hostile environments such as desiccation by adopting a state of anhydrobiosis. Numerous tardigrade species have been described thus far, and recent genome and transcriptome analyses revealed that several distinct strategies were employed to cope with harsh environments depending on the evolutionary lineages. Detailed analyses at the cellular and subcellular levels are essential to complete these data. In this work, we analyzed a tardigrade species that can withstand rapid dehydration, Ramazzottius varieornatus. Surprisingly, we noted an absence of the anhydrobiotic-specific extracellular structure previously described for the Hypsibius exemplaris species. Both Ramazzottius varieornatus and Hypsibius exemplaris belong to the same evolutionary class of Eutardigrada. Nevertheless, our observations reveal discrepancies in the anhydrobiotic structures correlated with the variation in the anhydrobiotic mechanisms.

Water in cosmetics and Caenorhabditis elegans as an alternative model for lifespan assessment.

OBJECTIVE: Water, often considered a fundamental component of life, is the most commonly used ingredient in the formulation of dermocosmetic products, with waterless products being the exception. Dermocosmetic products can contain anywhere from 50% to 85% water, which contributes to their texture and specific characteristics. The chemical composition of water varies depending on its origin and can be categorized as highly mineralized or low mineralized. These compositions could impact the water's efficacy in anti-aging applications. In this study, the objective is evaluating the anti-aging properties of highly and low mineralized water with the model organism Caenorhabditis elegans. METHODS: In this article, we employed the alternative model organism C. elegans to assess the impact of 5 branded waters, one physiological water and one ultra-pure water on the model's lifespan, using the survival medium conventionally used for C. elegans as a comparison. RESULTS: Waters may have either a positive or a negative impact on the C. elegans lifespan expectancy. Our results indicate that only one of the water brands we assessed (Volvic®) had a significantly positive effect on worm longevity. In contrast, we found that two other brands (Hepar® and Contrex®) had a negative impact on the later stages of the worm's adulthood. Furthermore, we demonstrated that the impact of the brand water samples on lifespan expectancy varied depending on their physicochemical composition, in particular when ion concentrations were most extreme. CONCLUSION: This study shows that the highly mineralized waters studied have a detrimental effect on the survival of C. elegans, and a preliminary test with ultra-pure water could not be completed due to its deleterious effect on the worms. This suggests the hypothesis that both highly mineralized and completely demineralized waters may not be the most suitable for skin formulations.

OBJECTIF: L'eau, élément fondamental à la vie, est l'ingrédient le plus utilisé dans la formulation de produits dermocosmétiques, pour lesquels les produits sans eau restent des exceptions. Les produits dermocosmétiques contiennent 50% à 85% d'eau, contribuant à leurs textures et leurs caractéristiques spécifiques. La composition chimique de l'eau varie en fonction de son origine et peut être catégorisée comme hautement ou faiblement minéralisée. Cette composition peut impacter l'efficacité de l'eau pour ses applications anti-âge. Dans cette étude, l'objectif est d'évaluer les propriétés anti-âge d'eaux fortement ou faiblement minéralisées à l'aide de l'organisme modèle Caenorhabditis elegans. METHODES: Dans ce travail, nous avons utilisé le modèle alternatif C. elegans pour étudier l'impact de 5 marques d'eaux, du sérum physiologique et de l'eau ultrapure sur ce modèle, en utilisant le milieu de culture standard de C. elegans comme contrôle. RESULTATS: Les eaux peuvent avoir un impact positif ou négatif sur la longévité des C. elegans. Nos résultats indiquent que seule l'une des eaux étudiées (Volvic®) a un impact positif sur la longévité des nématodes. Au contraire, nous avons montré que 2 autres eaux (Hepar® and Contrex®) ont un impact négatif sur les derniers stades adultes. De plus, nous avons démontré que l'impact des eaux sur la longévité variait en fonction de leurs compositions physicochimiques, en particulier lorsque les concentrations ioniques sont extrêmes.

[Resistance to BRAF inhibitors: A lesson from clinical observations]. / La résistance aux inhibiteurs de BRAF - Les leçons de la clinique.

The MAPK/ERK pathway is an essential intracellular signaling pathway. Its deregulation is involved in tumor transformation and progression. The discovery of activating mutations of BRAF in various cancers has opened new therapeutic avenues with BRAF protein kinase inhibitors. Depending on the type of cancers, these inhibitors have shown either insufficient efficacy due to primary resistance of tumor cells or transient efficacy due to the development of acquired resistance. In this review, we revisit the discoveries that led to the development of BRAF inhibitors and detail the molecular and cellular mechanisms of resistance in cancers treated with these inhibitors. Understanding these mechanisms is crucial for developing more efficient therapeutic strategies.

Title: La résistance aux inhibiteurs de BRAF - Les leçons de la clinique. Abstract: La voie de signalisation MAPK/ERK est une voie centrale de la signalisation intracellulaire. Sa dérégulation participe à la transformation et la progression tumorales. Dans plusieurs cancers, la découverte de mutations activatrices de BRAF, à l'origine de l'activation de cette voie, a ouvert de nouvelles perspectives thérapeutiques avec le développement d'inhibiteurs spécifiques de la protéine. Selon les cancers, ces inhibiteurs ont cependant montré soit une efficacité insuffisante, due à la résistance primaire des cellules tumorales, soit une efficacité transitoire, due à l'apparition d'une résistance acquise. Dans cette revue, nous revenons sur les découvertes qui ont conduit au développement de ces inhibiteurs de BRAF. Nous détaillons également les mécanismes moléculaires et cellulaires de la résistance à ces inhibiteurs observée dans différents types de cancers. Comprendre ces mécanismes est en effet primordial pour développer des stratégies thérapeutiques qui soient plus efficaces.

Perception of pharmacy students toward opioid-related disorders and roles of community pharmacists: A French nationwide cross-sectional study.

Background: Community pharmacists are among the frontline health professionals who manage patients with an opioid-related disorder (ORD). Pharmacists frequently have a negative attitude toward these patients, which could have a negative impact on their management. However, education on ORD may improve the attitude of future healthcare professionals. This cross-sectional study aimed to assess French pharmacy students' perceptions of ORD. Methods: This online survey was performed by emails sent to French pharmacy schools (between January 14, 2019 and May 31, 2019). The primary outcome was the perception (visual analogic scale) of ORD as a disease, the roles of community pharmacies (delivery of opioid agonist therapy-OAT and harm reduction kits), and the efficacy of OAT. The secondary outcomes assessed professional experience, university experience of and education on ORD, and the individual characteristics of students. Results: Among the 1,994 students included, 76.3% perceived ORD as a disease and felt that it was normal for pharmacists to deliver OAT (78.9%) and harm reduction kits (74.6%). However, only 46.9% perceived OAT as being effective. Multivariable analyses showed that females had a more positive perception in recognizing ORD as a disease. The progression through university years increased the positive perception of ORD as a disease and the delivery of OAT and harm reduction kits by pharmacists. Education on substance-related disorders had no impact on any scores. Students who had already delivered OAT had a negative perception of their efficacy. The students who had already performed pharmacy jobs or traineeships had a negative perception of harm reduction kit delivery. Conclusion: Education on substance-related disorders had no impact on students' perceptions. It seemed that the maturity acquired through university years had a stronger impact on the students' perceptions of ORD. Efforts must be made to improve our teaching methods and reinforce the confidence of students in the roles of community pharmacists.

Imidazo[1,2-a]quinoxalines for melanoma treatment with original mechanism of action.

The malignant transformation of melanocytes causes several thousand deaths each year, making melanoma an important public health concern. Melanoma is the most aggressive skin cancer, which incidence has regularly increased over the past decades. We described here the preparation of new compounds based on the 1-(3,4-dihydroxyphenyl)imidazo[1,2-a]quinoxaline structure. Different positions of the quinoxaline moiety were screened to introduce novel substituents in order to study their influence on the biological activity. Several alkylamino or alkyloxy groups were also considered to replace the methylamine of our first generation of Imiqualines. Imidazo[1,2-a]pyrazine derivatives were also designed as potential minimal structure. The investigation on A375 melanoma cells displayed interesting in vitro low nanomolar cytotoxic activity. Among them, 9d (EAPB02303) is particularly remarkable since it is 20 times more potent than vemurafenib, the reference clinical therapy used on BRAF mutant melanoma. Contrary to the first generation, EAPB02303 does not inhibit tubulin polymerization, as confirmed by an in vitro assay and a molecular modelisation study. The mechanism of action for EAPB02303 highlighted by a transcriptomic analysis is clearly different from a panel of 12 well-known anticancer drugs. In vivoEAPB02303 treatment reduced tumor size and weight of the A375 human melanoma xenografts in a dose-dependent manner, correlated with a low mitotic index but not with necrosis.

Vegetable Oil-based Hybrid Submicron Particles Loaded with JMV5038: A Promising Formulation against Melanoma.

The aim of this work was to carry out a preformulation study on JMV5038 as a new potent cytotoxic agent, and to develop its formulation within vegetable oil-based hybrid submicron particles (HNP) in order to obtain a versatile dosage form against melanoma. JMV5038 was first characterized through physico-chemical tests and it exhibited high melting point and logP value, an important pH-sensitivity that led to the formation of well-identified degradation products at low pH, as well as a substantial solubility value in silylated castor oil (ICO). Then, JMV5038-loaded HNP were formulated through a thermostabilized emulsion process based on the sol-gel cross-linking of ICO. They showed high loading efficiency and their in vitro release kinetic assessed in a biorelevant PBS/octanol biphasic system showed a constant sustained release over one month. The cytotoxic activity and cytocompatibility of HNP were evaluated on A375 melanoma cells and NIH 3T3 cells, respectively. JMV5038-loaded HNP exhibited a slightly enhanced cytotoxic activity of JMV5038 on melanoma cells while demonstrating their safety on NIH 3T3 cells. In conclusion, JMV5038-loaded HNP proved to be an efficient and safe drug subcutaneous delivery system that will be interesting to evaluate through preclinical studies.

Substantial Cellular Penetration of Fluorescent Imidazoquinoxalines.

Fluorescent tools have revolutionized our capability to visualize, probe, study, and understand the biological cellular properties, processes and dynamics, enabling researchers to improve their knowledge for example in cancer field. In this paper, we use the peculiar properties of our Imiqualines derivatives to study their cellular penetration and distribution in a human melanoma cell line A375 using confocal microscopy. Preliminary results on colocalization with the potent protein target c-Kit of our lead are also described.

Imidazopyridine-fused [1,3]diazepinones: modulations of positions 2 to 4 and their impacts on the anti-melanoma activity.

A series of 19 novel pyrido-imidazodiazepinones, with modulations of positions 2, 3 and 4 of the diazepine ring were synthesised and screened for their in vitro cytotoxic activities against two melanoma cell lines (A375 and MDA-MB-435) and for their potential toxicity against NIH-3T3 non-cancerous cells. Selected compounds were also evaluated on the NCI-60 cell line panel. The SAR study revealed that the molecular volume and the cLogP of compounds modified at position 2 were significantly correlated with the activity of these compounds on melanoma cell lines. Moreover, introduction of a heterocyclic group at position 2 or an azido-alkyl chain at position 4 led to compounds displaying a significantly different activity profile on the NCI-60 cell line panel, compared to phenyl-substituted compounds at position 2 of the diazepinone. This study provides us crucial information for the development of new derivatives active against melanoma.

Ultrastructural analysis of the dehydrated tardigrade Hypsibius exemplaris unveils an anhydrobiotic-specific architecture.

Tardigrades can cope with adverse environmental conditions by turning into anhydrobiotes with a characteristic tun shape. Tun formation is an essential morphological adaptation for tardigrade entry into the anhydrobiotic state. The tun cell structure and ultrastructure have rarely been explored in tardigrades in general and never in Hypsibius exemplaris. We used transmission electron microscopy to compare cellular organization and ultrastructures between hydrated and anhydrobiotic H. exemplaris. Despite a globally similar cell organelle structure and a number of cells not significantly different between hydrated and desiccated tardigrades, reductions in the sizes of both cells and mitochondria were detected in dehydrated animals. Moreover, in anhydrobiotes, secretory active cells with a dense endoplasmic reticulum network were observed. Interestingly, these anhydrobiote-specific cells are in a close relationship with a specific extracellular structure surrounding each cell. It is possible that this rampart-like extracellular structure resulted from the accumulation of anhydrobiotic-specific material to protect the cells. Interestingly, after five hours of rehydration, the number of secretory cells decreased, and the specific extracellular structure began to disappear. Twenty-four hours after the beginning of rehydration, the cellular structure and ultrastructure were comparable to those observed in hydrated tardigrades.

Novel and Selective TLR7 Antagonists among the Imidazo[1,2-a]pyrazines, Imidazo[1,5-a]quinoxalines, and Pyrazolo[1,5-a]quinoxalines Series.

The Toll-like receptors (TLRs) 7 and 8 play an important role in the immune system activation, and their agonists may therefore serve as promising candidate vaccine adjuvants. However, the chronic immune activation by excessive TLR stimulation is a hallmark of several clinically important infectious and autoimmune diseases, which warrants the search for TLR antagonists. In this study, we have synthesized and characterized a variety of compounds belonging to three heterocyclic chemical series: imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline, and pyrazolo[1,5-a]quinoxaline. These compounds have been tested for their TLR7 or TLR8 agonistic and antagonistic activities. Several of them are shown to be selective TLR7 antagonists without any TLR7 or TLR8 agonistic activity. The selectivity was confirmed by a comparative ligand-docking study in TLR7 antagonist pocket. Two compounds of the pyrazolo[1,5-a]quinoxaline series (10a and 10b) are potent selective TLR7 antagonists and may be considered as promising starting points for the development of new therapeutic agents.

Carbonylation accumulation of the Hypsibius exemplaris anhydrobiote reveals age-associated marks.

Together with nematodes and rotifers, tardigrade belong to micrometazoans that can cope with environmental extremes such as UV and solar radiations, dehydration, supercooling or overheating. Tardigrade can resist the harshest conditions by turning to cryptobiosis, an anhydrobiotic state that results from almost complete dehydration and is characterized by an ametabolic status. Although reports have challenged the molecular basis of the mechanisms underlying genomic injury resistance, little is yet known regarding the possible involvement of other tardigrade macromolecules in injury during a stress experience. In this report, we show that the tardigrade Hypsibius exemplaris can accumulate molecular damages by means of in situ detection of carbonyls. Furthermore, we demonstrate that living tardigrade can accumulate carbonylation. Finally, we reveal that anhydrobiotic tardigrade can be constitutively affected by carbonylation that marks aging in other metazoans.

Imidazo[1,2-a]quinoxalines Derivatives Grafted with Amino Acids: Synthesis and Evaluation on A375 Melanoma Cells.

Imiqualines (imidazoquinoxaline derivatives) are anticancer compounds with high cytotoxic activities on melanoma cell lines. The first generation of imiqualines, with two lead compounds (EAPB0203 and EAPB0503), shows remarkable in vitro (IC50 = 1 570 nM and IC50 = 200 nM, respectively, on the A375 melanoma cell line) and in vivo activity on melanoma xenografts. The second generation derivatives, EAPB02302 and EAPB02303, are more active, with IC50 = 60 nM and IC50 = 10 nM, respectively, on A375 melanoma cell line. The aim of this study was to optimize the bioavailability of imiqualine derivatives, without losing their intrinsic activity. For that, we achieved chemical modulation on the second generation of imiqualines by conjugating amino acids on position 4. A new series of twenty-five compounds was efficiently synthesized by using microwave assistance and tested for its activity on the A375 cell line. In the new series, compounds 11a, 9d and 11b show cytotoxic activities less than second generation compounds, but similar to that of the first generation ones (IC50 = 403 nM, IC50 = 128 nM and IC50 = 584 nM, respectively). The presence of an amino acid leads to significant enhancement of the water solubility for improved drugability.

Use of Psychotropic Medications and Illegal Drugs, and Related Consequences Among French Pharmacy Students - SCEP Study: A Nationwide Cross-Sectional Study.

Background: The use of psychotropic medications and illegal drugs is a worldwide public health issue, leading to addiction, psychiatric and somatic disorders, and death. Pharmacy students are more exposed to psychotropic medications than other students (non-medical), which could lead to an overuse. The main objective of this study was to assess the prevalence of psychotropic drug use (medications and illegal drugs) by French pharmacy students, by carrying out a nationwide cross-sectional study. The relation of these medications and illegal drug use with several comorbidities and academic achievement was also assessed. Methods: This online survey was performed by emails sent to all French pharmacy faculties over a period of 66 days (March 16, 2016 to May 20, 2016). The survey assessed the prevalence of uses of psychotropic medications and illegal drugs during the last 3 months. These uses were compared to student characteristics (personal and university) and comorbidities (anxiety, depression, stress, and fatigue). Results: Of the 2,609 questionnaires received, 2,575 were completed and useable for the analysis. Among French pharmacy students and during the 3 last months, 9.4% have used psychotropic medications, 21.5% illegal drugs and 3.3% both psychotropic medications and illegal drugs. Psychotropic medications were used in the cases of a medical prescription (49.0%), a self-medication (42.4%) or a non-medical intent (26.3%). Stress scores of the last 7 days were higher for psychotropic medication users compared to non-users and illegal drug users. Proportions of anxiety and depression at the time of answer were higher for psychotropic medication users than for non-users and illegal drug users. Fatigue scores of the last 7 days were lower for illegal drug users compared to non-users and self-medicated students. Annual average marks of the last year, attendance and perception of study difficulty were lower for illegal drug users than for non-users. Conclusion: French pharmacy students were less exposed to psychotropic medications and illegal drugs than the general French population. However, in comparison to other students in other countries, the use of psychotropic medications seemed to be lower, but with a proportionally higher use of anxiety/sedative medications and a lower use of opioid medications.

Liquid chromatography-electrospray ionization-tandem mass spectrometry method for quantitative estimation of new imiqualine leads with potent anticancer activities in rat and mouse plasma. Application to a pharmacokinetic study in mice.

Imidazoquinoxaline derivatives (imiqualines) are a new series of anticancer compounds. Two lead compounds (EAPB0203 and EAPB0503) with remarkable in vitro and in vivo activity on melanoma and T-cell lymphomas have been previously identified. The modulation of the chemical structure of the most active compound, EAPB0503, has led to the synthesis of two compounds, EAPB02302 and EAPB02303, 7 and 40 times more active than EAPB0503 against A375 human melanoma cancer cell line, respectively. The aim of this study was to develop and validate a sensitive and accurate liquid chromatography-electrospray ionization-tandem mass spectrometry method to simultaneously quantify EAPB02303 and its potential active metabolite, EAPB02302, in rat and mouse plasma. Analytes were detected in multiple reaction monitoring acquisition mode using an electrospray ionization detector in positive ion mode. Following a liquid-liquid extraction with ethyl acetate, analytes and internal standard were separated by HPLC reversed-phase on a C18 RP18 Nucleoshell column (2.7µm, 4.6×100mm). The method was validated according to FDA and EMA Bioanalytical Method Validation guidelines. The robustness of the method was assessed by introducing small variations in nine nominal analytical parameters. Statistical interpretation was performed by mean of the Student's t-test. Standard curves were generated via unweighted quadratic regression of calibrators (EAPB02303: 1.95-1000ng/mL, EAPB02302: 7.81-1000ng/mL in rat plasma; EAPB02303: 0.98-1000ng/mL, EAPB02302: 1.95-1000ng/mL in mouse plasma). From the analysis of QC samples, intra- and inter-assay precision and accuracy studies demonstrated %R.S.Ds. <12.5% and percent deviation from nominal concentration <7%. Matrix effects (mean matrix factors from 91.8-108.5% in rat plasma; and from 90.4-102.4% in mouse plasma) and stability assays (recoveries >87%) were acceptable and in accordance with the guidelines. No quantifiable carryover effect was observed. The LLOQs were 1.95ng/mL for EAPB02303 and 7.81ng/mL for EAPB02302 in rat plasma, and 0.98ng/mL and 1.95ng/mL for the two compounds in mouse plasma, respectively. This method was successfully implemented to support a mouse pharmacokinetic study following a single intraperitoneal administration of EAPB02303 in male C57Bl/6 mice. The obtained pharmacokinetic parameters of EAPB02303 would be useful to optimize the dosing and the rhythm of administration for subsequent preclinical in vivo activity studies.

Imidazo[1,2-a]pyrazine, Imidazo[1,5-a]quinoxaline and Pyrazolo[1,5-a]quinoxaline derivatives as IKK1 and IKK2 inhibitors.

The transcription nuclear factor NF-κB plays a pivotal role in chronic and acute inflammatory diseases. Among the several and diverse strategies for inhibiting NF-κB, one of the most effective approach considered by the pharmaceutical industry seems to be offered by the development of IKK inhibitors. In a former study, two potential IKK2 inhibitors have been highlighted among a series of imidazo[1,2-a]quinoxaline derivatives. In order to enhance this activity, we present herein the synthesis of twenty-one new compounds based on the imidazo[1,2-a]pyrazine, imidazo[1,5-a]quinoxaline or pyrazolo[1,5-a]quinoxaline structures. Their potential to inhibit IKK1 and IKK2 activities is also tested.

Fluorescence Study of Imidazoquinoxalines.

The fluorescence properties of eleven novel derivatives based on the imidazo[1,2-a]quinoxaline structures have been studied. The absorption and emission spectra of these compounds have been recorded in dimethylsulfoxide solution. The phenyl substituting group on position 1 gives them particular properties thanks to the diverse hydroxy or methoxy decorating moieties, especially when they are multiplied or mixed. The investigated fluorescence auto-quenching revealed that the decreasing fluorescence intensity correlated only with the chemical structures of the aromatic compounds.

Lipid nanocapsules formulation and cellular activities evaluation of a promising anticancer agent: EAPB0503.

OBJECTIVE: EAPB0503, lead compound of imiqualines, presented high antitumor activities but also a very low water solubility which was critical for further preclinical studies. To apply to EAPB0503, a robust and safe lipid formulation already used for poor soluble anticancer agents for injectable administration at a concentration higher than 1 mg/mL. MATERIALS AND METHODS: Physicochemical properties of EAPB0503 were determined to consider an adapted formulation. In a second time, lipid nanocapsules (LNC) formulations based on the phase-inversion process were developed for EAPB0503 encapsulation. Then, EAPB0503 loaded-LNC were tested in vitro on different cell lines and compared to standard EAPB0503 solutions. RESULTS: Optimized EAPB0503 LNC displayed an average size of 111.7 ± 0.9 nm and a low polydispersity index of 0.059 ± 0.002. The obtained loading efficiency was higher than 96% with a drug loading of 1.7 mg/mL. A stability study showed stability during 4 weeks stored at 25°C. In vitro results highlighted similar efficiencies between LNC and standard EAPB0503 solutions prepared in dimethyl sulfoxide. CONCLUSION: In view of results obtained for loading efficiency and drug loading, the use of a LNC formulation is very interesting to permit the solubilization of a lipophilic drug and to improve its bioavailability. Preliminary tested pharmaceutical formulation applied to EAPB0503 significantly improved its water solubility and will be soon considered for future preclinical in vivo studies.

New imidazoquinoxaline derivatives: Synthesis, biological evaluation on melanoma, effect on tubulin polymerization and structure-activity relationships.

Microtubules are considered as important targets of anticancer therapy. EAPB0503 and its structural imidazo[1,2-a]quinoxaline derivatives are major microtubule-interfering agents with potent anticancer activity. In this study, the synthesis of several new derivatives of EAPB0503 is described, and the anticancer efficacy of 13 novel derivatives on A375 human melanoma cell line is reported. All new compounds show significant antiproliferative activity with IC50 in the range of 0.077-122µM against human melanoma cell line (A375). Direct inhibition of tubulin polymerization assay in vitro is also assessed. Results show that compounds 6b, 6e, 6g, and EAPB0503 highly inhibit tubulin polymerization with percentages of inhibition of 99%, 98%, 90%, and 84% respectively. Structure-activity relationship studies within the series are also discussed in line with molecular docking studies into the colchicine-binding site of tubulin.

New IKK inhibitors: Synthesis of new imidazo[1,2-a]quinoxaline derivatives using microwave assistance and biological evaluation as IKK inhibitors.

The inhibition of the NF-κB-dependent pathways by IKK inhibitors plays an important role in immunity, inflammation, and cancer. New imidazoquinoxalines tricyclic derivatives are prepared using microwave assistance and their biological activities as IKK inhibitors are described. Compounds 6a present a potent inhibition activity and selectivity for IKK2. Docking studies in the IKK2 binding site allowed identification of residues most likely to interact with theses inhibitors and explain their potent IKK2 inhibition activity and selectivity.