56 results on '"Philippe Diaz"'
Search Results
2. Cannabinoids Activate the Insulin Pathway to Modulate Mobilization of Cholesterol in C. elegans
- Author
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Bruno Hernandez-Cravero, Sofia Gallino, Jeremy Florman, Cecilia Vranych, Philippe Diaz, Ana Belén Elgoyhen, Mark J. Alkema, and Diego de Mendoza
- Abstract
The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early development arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is critical. Previously, we demonstrated that the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) plays a key role in C. elegans modulating sterol mobilization, but the mechanism is unknown. Here we show that mutations in the ocr-2 and osm-9 genes coding for transient receptors potential V (TRPV) ion channels, dramatically reduces the effect of 2-AG in cholesterol mobilization. Through genetic analysis combined with the rescuing of larval arrest induced by sterol starvation we found that the insulin/IGF-1signaling (IIS) pathway and UNC-31/CAPS, a calcium-activated regulator of neural dense-core vesicles release, are essential for 2-AG-mediated stimulation of cholesterol mobilization. These findings indicate that 2-AG-dependent cholesterol trafficking requires the release of insulin peptides and signaling through the DAF-2 insulin receptor. These results suggest that 2-AG acts as an endogenous modulator of TRPV signal transduction to control intracellular sterol traffic through modulation of the IGF-1 signaling pathway.Author summaryAlthough cannabis extracts have been used in folklore medicine for centuries, the past few years have seen an increased interest in the medicinal uses of cannabinoids, the bioactive components of the cannabis plant, for treatment of many diseases of the nervous system. However, the human body naturally produces endocannabinoids that are similar to the cannabinoids present in Cannabis sativa. Our goal is to understand how endocannabinoids maintain cholesterol homeostasis in animals, underscoring the importance of cholesterol balance for healthy life. Both cholesterol excess and cholesterol deficiency can have detrimental effects on health, and a myriad of regulatory processes have thus evolved to control the metabolic pathways of sterol metabolism. The nematode C. elegans is auxotroph for sterols, that is; contrary to mammals they cannot synthesize sterols, therefore, dietary supply is essential for survival. The aim of our study was to elucidate the mechanism by which endocannabinoids abolish larval arrest of C. elegans induced by cholesterol depletion. We discovered that endocannabinoids stimulate the insulin pathway, which affects development, reproduction and life span, to modulate mobilization of cholesterol in C. elegans. Our studies have important implications for a better understanding of human pathological conditions associated with impaired cholesterol homeostasis.
- Published
- 2022
3. Cannabinoids activate the insulin pathway to modulate mobilization of cholesterol in C. elegans
- Author
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Bruno Hernandez-Cravero, Sofia Gallino, Jeremy Florman, Cecilia Vranych, Philippe Diaz, Ana Belén Elgoyhen, Mark J. Alkema, and Diego de Mendoza
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Cancer Research ,Sterols ,Cholesterol ,Cannabinoids ,Genetics ,Animals ,Insulin ,Caenorhabditis elegans ,Molecular Biology ,Genetics (clinical) ,Ecology, Evolution, Behavior and Systematics - Abstract
The nematode Caenorhabditis elegans requires exogenous cholesterol to survive and its depletion leads to early developmental arrest. Thus, tight regulation of cholesterol storage and distribution within the organism is critical. Previously, we demonstrated that the endocannabinoid (eCB) 2-arachidonoylglycerol (2-AG) plays a key role in C. elegans since it modulates sterol mobilization. However, the mechanism remains unknown. Here we show that mutations in the ocr-2 and osm-9 genes, coding for transient receptors potential V (TRPV) ion channels, dramatically reduce the effect of 2-AG in cholesterol mobilization. Through genetic analysis in combination with the rescue of larval arrest induced by sterol starvation, we found that the insulin/IGF-1signaling (IIS) pathway and UNC-31/CAPS, a calcium-activated regulator of neural dense-core vesicles release, are essential for 2-AG-mediated stimulation of cholesterol mobilization. These findings indicate that 2-AG-dependent cholesterol trafficking requires the release of insulin peptides and signaling through the DAF-2 insulin receptor. These results suggest that 2-AG acts as an endogenous modulator of TRPV signal transduction to control intracellular sterol trafficking through modulation of the IGF-1 signaling pathway Fil: Hernández Cravero, Bruno. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana (IBR-CONICET); Argentina. Fil: Vranych, Cecilia V. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana (IBR-CONICET); Argentina. Fil: De Mendoza, Diego. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario. Laboratorio de Fisiología Microbiana (IBR-CONICET); Argentina. Fil: GallinoI, Sofía. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres". Laboratorio de Fisiología y Genética de la Audición (INGEBI-CONICET); Argentina. Fil: Elgoyhen, Ana Belén. Instituto de Investigaciones en Ingeniería Genética y Biología Molecular "Dr. Héctor N. Torres". Laboratorio de Fisiología y Genética de la Audición (INGEBI-CONICET); Argentina. Fil: Florman, Jeremy. University of Massachusetts Medical School. Department of Neurobiology; United States. Fil: AlkemaI, Mark J. University of Massachusetts Medical School. Department of Neurobiology; United States. Fil: Diaz, Philippe. University of Montana. Department of Biomedical and Pharmaceutical Sciences; United States.
- Published
- 2022
4. Definition of functionally and structurally distinct repressive states in the nuclear receptor PPARγ
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Michelle D. Nemetchek, Desiree E. Mendes, Philippe Diaz, Ian M. Chrisman, Trey Patton, Anne-Laure Blayo, Travis S. Hughes, Zahra Heidari, Scott J. Novick, Theodore M. Kamenecka, and Patrick R. Griffin
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0301 basic medicine ,Protein Conformation, alpha-Helical ,Magnetic Resonance Spectroscopy ,Pyridines ,Science ,General Physics and Astronomy ,Hydrogen Deuterium Exchange-Mass Spectrometry ,Molecular Dynamics Simulation ,Ligands ,01 natural sciences ,General Biochemistry, Genetics and Molecular Biology ,Article ,Rosiglitazone ,03 medical and health sciences ,Protein structure ,Nuclear receptors ,Biophysical chemistry ,0103 physical sciences ,Inverse agonist ,Anilides ,Receptor ,lcsh:Science ,Multidisciplinary ,Binding Sites ,010304 chemical physics ,Chemistry ,Omega loop ,Mutagenesis ,General Chemistry ,Nuclear magnetic resonance spectroscopy ,Ligand (biochemistry) ,Molecular conformation ,Cell biology ,PPAR gamma ,030104 developmental biology ,Nuclear receptor ,Benzamides ,Mutagenesis, Site-Directed ,lcsh:Q ,Molecular modelling ,Peptides ,Solution-state NMR ,Co-Repressor Proteins - Abstract
The repressive states of nuclear receptors (i.e., apo or bound to antagonists or inverse agonists) are poorly defined, despite the fact that nuclear receptors are a major drug target. Most ligand bound structures of nuclear receptors, including peroxisome proliferator-activated receptor γ (PPARγ), are similar to the apo structure. Here we use NMR, accelerated molecular dynamics and hydrogen-deuterium exchange mass spectrometry to define the PPARγ structural ensemble. We find that the helix 3 charge clamp positioning varies widely in apo and is stabilized by efficacious ligand binding. We also reveal a previously undescribed mechanism for inverse agonism involving an omega loop to helix switch which induces disruption of a tripartite salt-bridge network. We demonstrate that ligand binding can induce multiple structurally distinct repressive states. One state recruits peptides from two different corepressors, while another recruits just one, providing structural evidence of ligand bias in a nuclear receptor., The repressive states of peroxisome proliferator-activated receptor γ (PPARγ) are ill-defined, despite nuclear receptors being a major drug target. Here authors demonstrate multiple structurally distinct repressive states, providing a structural rationale for ligand bias in a nuclear receptor.
- Published
- 2019
5. Characterization of CYP26B1-selective inhibitor, DX314, as a potential therapeutic for keratinization disorders
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Valérie De Glas, Benoît Balau, Haoming Liu, Yves Poumay, J. Veit, Philippe Diaz, Florence Bourlond, and Amy S. Paller
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0301 basic medicine ,Keratinocytes ,medicine.drug_class ,Retinoic acid ,Context (language use) ,Dermatology ,Biochemistry ,Skin Diseases ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Congenital ichthyosis ,Medicine ,Cytochrome P-450 Enzyme Inhibitors ,Humans ,Liarozole ,Retinoid ,Benzothiazoles ,Molecular Biology ,Epidermis (botany) ,business.industry ,Cell Differentiation ,Cell Biology ,Retinoic Acid 4-Hydroxylase ,Triazoles ,Talarozole ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,Epidermis ,business ,Keratinocyte - Abstract
Inhibition of CYP450-mediated retinoic acid (RA) metabolism by RA metabolism blocking agents increases endogenous retinoids and is an alternative to retinoid therapy. Currently available RA metabolism blocking agents (i.e., liarozole and talarozole) tend to have fewer adverse effects than traditional retinoids but lack target specificity. Substrate-based inhibitor DX314 has enhanced selectivity for RA-metabolizing enzyme CYP26B1 and may offer an improved treatment option for keratinization disorders such as congenital ichthyosis and Darier disease. In this study, we used RT-qPCR, RNA sequencing, pathway, upstream regulator, and histological analyses to demonstrate that DX314 can potentiate the effects of all-trans-RA in healthy and diseased reconstructed human epidermis. We unexpectedly discovered that DX314, but not all-trans-RA or previous RA metabolism blocking agents, appears to protect epidermal barrier integrity. In addition, DX314-induced keratinization and epidermal proliferation effects are observed in a rhino mice model. Altogether, the results indicate that DX314 inhibits all-trans-RA metabolism with minimal off-target activity and shows therapeutic similarity to topical retinoids in vitro and in vivo. Findings of a barrier-protecting effect require further mechanistic study but may lead to a unique strategy in barrier-reinforcing therapies. DX314 is a promising candidate compound for further study and development in the context of keratinization disorders.
- Published
- 2021
6. Preclinical assessment of dual CYP26[A1/B1] inhibitor, DX308, as an improved treatment for keratinization disorders
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F. Zolezzi, J. Kreitinger, J. Veit, L. Walker, A. Paquet, D. Mendes, Amy S. Paller, Philippe Diaz, C. Menigot, and Yves Poumay
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chemistry.chemical_classification ,integumentary system ,Chemistry ,RL1-803 ,Keratin ,Cancer research ,Dermatology ,General Medicine ,DUAL (cognitive architecture) - Abstract
BackgroundRetinoid‐based therapies are commonly used in the treatment of disorders of keratinization and other skin disorders but can result in non‐specific effects and adverse reactions. Use of retinoic acid metabolism blocking agents (RAMBAs) such as DX308 may address these shortcomings.ObjectivesCharacterize the therapeutic potential of recently discovered, CYP26‐selective RAMBA, DX308.Materials and MethodsPreliminary in vitro assessment of potential off‐target activity, metabolic and toxicologic profiling. Studies to assess safety and efficacy of topical treatment in correcting abnormal skin morphology in rhino mice. Extensive gene expression profiling by RNA sequencing and qPCR in 3D epidermis grown with keratinocytes (KCs) from keratinization disorders and healthy controls, to investigate modulation of retinoid biopathways.ResultsIn vitro, DX308 does not interact with off‐target nuclear receptors or CYP450s, is not genotoxic, and is stable in skin, despite vigorous hepatic metabolism. In vivo, topical DX308 induces comedolysis and epidermal thickening without apparent adverse effects. Gene expression profiling shows potent modulation of retinoid‐responsive genes by DX308 in both healthy and keratinization disorder KCs. Pathway analysis suggests DX308 may inhibit inflammatory and immune responses in KCs.ConclusionsThese preliminary studies suggest that DX308 is an efficacious topical therapeutic with a favourable metabolic and safety profiles. DX308 may present an improved therapeutic alternative for the treatment of keratinization disorders and other retinoid‐responsive skin ailments.
- Published
- 2020
7. A brain-penetrant microtubule-targeting agent that disrupts hallmarks of glioma tumorigenesis
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Eric A. Horne, Patrick J. Cimino, Eric C. Holland, N. Wageling, Debra K. Kumasaka, Linda Wordeman, Daniel D Azorín, Ernest Hamel, Cong Xu, Michael Wagenbach, Philippe Diaz, Frank Winkler, Nephi Stella, and Erik Jung
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0301 basic medicine ,Programmed cell death ,DNA damage ,Blood–brain barrier ,medicine.disease_cause ,microtubules ,03 medical and health sciences ,0302 clinical medicine ,In vivo ,Glioma ,medicine ,AcademicSubjects/MED00300 ,tumor microtubes ,Temozolomide ,DNA-damage ,Cell growth ,Chemistry ,interphase ,medicine.disease ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,Basic and Translational Investigations ,Cancer research ,AcademicSubjects/MED00310 ,Surgery ,Neurology (clinical) ,Carcinogenesis ,medicine.drug - Abstract
BackgroundGlioma is sensitive to microtubule-targeting agents (MTAs), but most MTAs do not cross the blood brain barrier (BBB). To address this limitation, we developed the new chemical entity, ST-401, a brain-penetrant MTA.MethodsSynthesis of ST-401. Measures of MT assembly and dynamics. Cell proliferation and viability of patient-derived (PD) glioma in culture. Measure of tumor microtube (TM) parameters using immunofluorescence analysis and machine learning-based workflow. Pharmacokinetics (PK) and experimental toxicity in mice. In vivo antitumor activity in the RCAS/tv-a PDGFB-driven glioma (PDGFB-glioma) mouse model.ResultsWe discovered that ST-401 disrupts microtubule (MT) function through gentle and reverisible reduction in MT assembly that triggers mitotic delay and cell death in interphase. ST-401 inhibits the formation of TMs, MT-rich structures that connect glioma to a network that promotes resistance to DNA damage. PK analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft flank tumor mouse model demonstrates significant antitumor activity and no over toxicity in mice. In the PDGFB-glioma mouse model, ST-401 enhances the therapeutic efficacies of temozolomide (TMZ) and radiation therapy (RT).ConclusionOur study identifies hallmarks of glioma tumorigenesis that are sensitive to MTAs and reports ST-401 as a promising chemical scaffold to develop brain-penetrant MTAs.
- Published
- 2020
8. EXTH-53. A BRAIN-PENETRANT MICROTUBULE-TARGETING AGENT THAT DISRUPTS HALLMARKS OF GLIOMA TUMORIGENESIS
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Michael Wagenbach, Erik Jung, Eric A. Horne, Eric C. Holland, Cong Xu, Juan Ruiz, Frank Winkler, Ernest Hamel, Linda Wordeman, Philippe Diaz, Nephi Stella, Patrick J. Cimino, and Debra K. Kumasaka
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Cancer Research ,Chemistry ,medicine.disease ,medicine.disease_cause ,Preclinical Experimental Therapeutics ,chemistry.chemical_compound ,Oncology ,Microtubule ,Glioma ,medicine ,Cancer research ,Neurology (clinical) ,Penetrant (biochemical) ,Carcinogenesis - Abstract
Most cancer therapeutics developed to date are excluded from the brain and are therefore ineffective in treating glioma, the most devastating type of brain cancer in adults. Microtubule targeting agents (MTAs) are indispensable medicines to treat a wide range of solid and hematopoietic tumors, and evidence suggests that glioma is sensitive to MTAs; but most MTAs do not cross the blood-brain-barrier. To address this limitation, we developed a brain-penetrant MTA, ST-401, that inhibited the growth of human glioma in culture at nanomolar concentrations. ST-401 bound to the colchicine site, inhibited tubulin assembly and reversibly reduced microtubule (MT) dynamics. Testing of ST-401 on the NCI 60 cancer cell panel indicated that its anti-tumor activity does not correlate with any of the compounds tested thus far through this platform but showed weak correlations for two MTA that work through distinct mechanisms: taxol (p=0.46) and vinblastine (p=0.34). Thus, ST-401 may kill cancer cells through a novel mechanism related to disruption of MT function. We discovered that ST-401 killed patient-derived (PD) glioma isolates in both mitosis and interphase, and inhibited the formation of tumor microtubes, MT-rich structures that connects glioma cells to a network that is resistant to standard therapies. Pharmacokinetic analysis of ST-401 in mice shows brain penetration reaching antitumor concentrations, and in vivo testing of ST-401 in a xenograft model demonstrated significant antitumor activity. In an immunocompetent mouse model of platelet-derived growth factor B-driven glioma, ST-401 significantly enhanced the therapeutic efficacies of standard care therapies temozolomide and radiation therapy. Our study identified novel aspects of glioma tumorigenesis that exhibit enhanced sensitivity to MTAs and shows that the brain-penetrant MTA, ST-401, represents a promising chemical scaffold to develop therapeutics for the treatment of patients diagnosed with glioma.
- Published
- 2020
9. Cav3.2 T-type calcium channels control acute itch in mice
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N. Wageling, Philippe Diaz, Dylan Budke, Vinicius M. Gadotti, Gerald W. Zamponi, and Joanna M. Kreitinger
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0301 basic medicine ,Male ,medicine.drug_class ,Calcium channel blocker ,Pharmacology ,Itch ,lcsh:RC346-429 ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Calcium Channels, T-Type ,0302 clinical medicine ,Chloroquine ,medicine ,Animals ,skin and connective tissue diseases ,Molecular Biology ,lcsh:Neurology. Diseases of the nervous system ,Voltage-dependent calcium channel ,Behavior, Animal ,business.industry ,Cav3.2 T-type channel ,Research ,Pruritus ,T-type calcium channel ,Wild type ,Scratching ,eye diseases ,3. Good health ,Mice, Inbred C57BL ,030104 developmental biology ,Nociception ,chemistry ,Acute Disease ,Female ,business ,030217 neurology & neurosurgery ,Histamine ,medicine.drug - Abstract
Cav3.2 T-type calcium channels are important mediators of nociceptive signaling, but their roles in the transmission of itch remains poorly understood. Here we report a key involvement of these channels as key modulators of itch/pruritus-related behavior. We compared scratching behavior responses between wild type and Cav3.2 null mice in models of histamine- or chloroquine-induced itch. We also evaluated the effect of the T-type calcium channel blocker DX332 in male and female wild-type mice injected with either histamine or chloroquine. Cav3.2 null mice exhibited decreased scratching responses during both histamine- and chloroquine-induced acute itch. DX332 co-injected with the pruritogens inhibited scratching responses of male and female mice treated with either histamine or chloroquine. Altogether, our data provide strong evidence that Cav3.2 T-type channels exert an important role in modulating histamine-dependent and -independent itch transmission in the primary sensory afferent pathway, and highlight these channels as potential pharmacological targets to treat pruritus.
- Published
- 2020
10. DDIS-14. MODIFIED CARBAZOLES DESTABILIZE MICROTUBULES AND KILL GLIOBLASTOMA MULTIFORM CELLS
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Eric A. Horne, Ernest Hamel, Philippe Diaz, Mike Wagenbach, Hothi Parvinder, Cong Xu, Ravil R. Petrov, Brian Hass, Rick Gussio, Linda Wordeman, and Nephi Stella
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Cancer Research ,Abstracts ,Oncology ,Chemistry ,Microtubule ,medicine ,Cancer research ,Neurology (clinical) ,medicine.disease ,Glioblastoma - Abstract
Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC50 values from 67 to > 10,000 nM. Measures of the activity of modified carbazoles with tubulin and microtubules coupled to molecular docking studies show that these compounds bind to the colchicine site of tubulin in a unique low interaction space that inhibits tubulin assembly. The modified carbazoles reported here represent novel chemical tools to better understand how small molecules disrupt MT functions and kill devastating cancers such as GBM.
- Published
- 2018
11. Development and Characterization of Novel and Selective Inhibitors of Cytochrome P450 CYP26A1, the Human Liver Retinoic Acid Hydroxylase
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Frank R. Fronczek, Fanny Astruc-Diaz, Weize Huang, Charles M. Keyari, Brian Buttrick, Philippe Diaz, Lauren S L Price, Vanessa G. Sperandio, Nicolas Guilloteau, Nina Isoherranen, and Sasmita Tripathy
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0301 basic medicine ,Drug Resistance ,Retinoic acid ,Tretinoin ,Pharmacology ,Article ,Substrate Specificity ,Structure-Activity Relationship ,03 medical and health sciences ,chemistry.chemical_compound ,CYP26A1 ,0302 clinical medicine ,Cytochrome P-450 Enzyme System ,Cell Line, Tumor ,Drug Discovery ,Animals ,Humans ,Potency ,Enzyme Inhibitors ,neoplasms ,IC50 ,chemistry.chemical_classification ,biology ,Chemistry ,organic chemicals ,Cytochrome P450 ,Metabolism ,Retinoic Acid 4-Hydroxylase ,biological factors ,Rats ,Isoenzymes ,Kinetics ,030104 developmental biology ,Enzyme ,Liver ,Biochemistry ,Drug Design ,Enzyme Induction ,030220 oncology & carcinogenesis ,embryonic structures ,biology.protein ,Molecular Medicine ,Lead compound ,Algorithms - Abstract
Cytochrome P450 CYP26 enzymes are responsible for all-trans-retinoic acid (atRA) clearance. Inhibition of CYP26 enzymes will increase endogenous atRA concentrations and is an attractive therapeutic target. However, the selectivity and potency of the existing atRA metabolism inhibitors towards CYP26A1 and CYP26B1 is unknown, and no selective CYP26A1 or CYP26B1 inhibitors have been developed. Here the synthesis and potent inhibitory activity of the first CYP26A1 selective inhibitors is reported. A series of non-azole CYP26A1 selective inhibitors was identified with low nM potency. The lead compound 3-{4-[2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-1,3-dioxolan-2-yl] phenyl}4 propanoic acid (24) had 43-fold selectivity towards CYP26A1 with an IC50 of 340 nM. Compound 24 and its two structural analogs also inhibited atRA metabolism in HepG2 cells resulting in increased potency of atRA towards RAR activation. The identified compounds have potential to become novel treatments aiming to elevate endogenous atRA concentrations and may be useful as cotreatment with atRA to combat therapy resistance.
- Published
- 2016
12. Identification of Tazarotenic Acid as the First Xenobiotic Substrate of Human Retinoic Acid Hydroxylase CYP26A1 and CYP26B1
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Robert S. Foti, Alex Zelter, Leslie J. Dickmann, Brian Buttrick, Nina Isoherranen, Philippe Diaz, Dominique Douguet, Amgen Inc. USA, University of Washington [Seattle], University of Montana, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (... - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Models, Molecular ,0301 basic medicine ,Receptors, Retinoic Acid ,Stereochemistry ,Metabolite ,Molecular Sequence Data ,Retinoic acid ,Tretinoin ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,Metabolism, Transport, and Pharmacogenomics ,Substrate Specificity ,Xenobiotics ,03 medical and health sciences ,CYP26A1 ,chemistry.chemical_compound ,Cytochrome P-450 Enzyme System ,Catalytic Domain ,Humans ,Amino Acid Sequence ,Heme ,ComputingMilieux_MISCELLANEOUS ,Pharmacology ,chemistry.chemical_classification ,biology ,Nicotinic Acids ,Cytochrome P450 ,Active site ,Retinoic Acid 4-Hydroxylase ,[SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences ,Kinetics ,030104 developmental biology ,Enzyme ,Pharmaceutical Preparations ,chemistry ,Biochemistry ,embryonic structures ,biology.protein ,Molecular Medicine ,[INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM] ,Xenobiotic ,[CHIM.CHEM]Chemical Sciences/Cheminformatics - Abstract
Cytochrome P450 (CYP) 26A1 and 26B1 are heme-containing enzymes responsible for metabolizing all-trans retinoic acid (at-RA). No crystal structures have been solved, and therefore homology models that provide structural information are extremely valuable for the development of inhibitors of cytochrome P450 family 26 (CYP26). The objectives of this study were to use homology models of CYP26A1 and CYP26B1 to characterize substrate binding characteristics, to compare structural aspects of their active sites, and to support the role of CYP26 in the metabolism of xenobiotics. Each model was verified by dockingat-RA in the active site and comparing the results to known metabolic profiles ofat-RA. The models were then used to predict the metabolic sites of tazarotenic acid with results verified by in vitro metabolite identification experiments. The CYP26A1 and CYP26B1 homology models predicted that the benzothiopyranyl moiety of tazarotenic acid would be oriented toward the heme of each enzyme and suggested that tazarotenic acid would be a substrate of CYP26A1 and CYP26B1. Metabolite identification experiments indicated that CYP26A1 and CYP26B1 oxidatively metabolized tazarotenic acid on the predicted moiety, with in vitro rates of metabolite formation by CYP26A1 and CYP26B1 being the highest across a panel of enzymes. Molecular analysis of the active sites estimated the active-site volumes of CYP26A1 and CYP26B1 to be 918 Å(3)and 977 Å(3), respectively. Overall, the homology models presented herein describe the enzyme characteristics leading to the metabolism of tazarotenic acid by CYP26A1 and CYP26B1 and support a potential role for the CYP26 enzymes in the metabolism of xenobiotics.
- Published
- 2016
13. 606 Small molecule blockade of T-type calcium channels by DX416 inhibits itch and reduces corresponding inflammation in acute and chronic itch mouse models
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F. Diaz, N. Wageling, J. Kreitinger, Philippe Diaz, Gerald W. Zamponi, Vinicius M. Gadotti, and L. Walker
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Chemistry ,T-type calcium channel ,medicine ,Inflammation ,Cell Biology ,Dermatology ,Pharmacology ,medicine.symptom ,Chronic itch ,Molecular Biology ,Biochemistry ,Small molecule ,Blockade - Published
- 2020
14. 254 AKR1B10 inhibition in keratinocytes as a strategy to improve retinaldehyde efficacy and increase endogenous atRA
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L. Walker, N. Wageling, J. Kreitinger, C. Crane, T. Falla, Katie Rodan, Philippe Diaz, Kathy Fields, and J.S. Craw
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Chemistry ,Retinaldehyde ,Endogeny ,Cell Biology ,Dermatology ,Molecular Biology ,Biochemistry ,Cell biology - Published
- 2020
15. DDIS-29. BRAIN-PENETRANT MICROTUBULE-TARGETING AGENT, ST-401, KILLS GLIOBLASTOMA THROUGH A NOVEL MECHANISM
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Michael Wagenbach, Philippe Diaz, Patrick J. Cimino, Juan-Jesus Vicente, Ernest Hamel, Linda Wordeman, Nephi Stella, Rick Gussio, Eric A. Horne, Thomas Deckwerth, Cong Xu, Eric C. Holland, and Benjamin Uhlenbruck
- Subjects
Cancer Research ,biology ,business.industry ,Mechanism (biology) ,Binding (Molecular Function) ,Blood–brain barrier ,medicine.disease ,chemistry.chemical_compound ,medicine.anatomical_structure ,Tubulin ,Oncology ,chemistry ,Microtubule ,Drug Discovery ,biology.protein ,Cancer research ,Medicine ,Tumor growth ,Neurology (clinical) ,business ,Penetrant (biochemical) ,Glioblastoma - Abstract
Glioblastomas are particularly sensitive to mitotic disruption when compared with nonmalignant cells and thus microtubule-targeting agents (MTA) represent promising therapeutics to treat patients with glioblastomas; but few such compounds pass the blood brain barrier. We developed a series of modified carbazoles, evaluated their anti-cancer activity in glioblastoma cells in culture and identified ST-401 as the most potent compound (IC50, 10 – 102 nM, depending on the cell line). Testing of ST-401 on the NCI 60 cancer cell panel indicated that its anti-tumor activity does not correlate with any of the compounds tested thus far through this platform but showed weak correlations for taxol (p=0.46) and vinblastine (p=0.34). Thus, ST-401 may kill cancer cells through a novel mechanism related to disruption of MT function. Biochemical analysis indicates that ST-401 binds to the colchicine site of tubulin and inhibits tubulin assembly. Real-time imaging of MT dynamics in cells in culture shows that ST-401 reduces MT assembly rates but in a reversible fashion. ST-401 potently blocks mitotic progression and triggers cell death in multiple glioblastoma lines in culture, including patient-derived glioblastomas of the proneural, mesenchymal and classical subtypes. We established the maximum tolerated dose (MTD) of ST-401 in mice (20 mg/kg/bdip) and found that its acute i.p. injection results in micromolar amounts of ST-401 in mouse brain. Using this treatment regimen, we found that ST-401 reduces tumor growth and doubles overall survival in a human tumor xenograft mouse model system. ST-401 also increases by 2-fold overall survival in the genetic RCAS-PDGF glioblastomas mouse model treated with standard care (radiation and Temodar® treatments). Histological analysis of RCAS-PDGF glioblastoma tissue shows that ST-401 triggers mitotic arrest of glioblastoma cells. ST-401 represents a promising lead compound for the treatments for patients diagnosed with glioblastomas.
- Published
- 2019
16. Modified carbazoles destabilize microtubules and kill glioblastoma multiform cells
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Michael Wagenbach, Rick Gussio, Eric Horne, Parvinder Hothi, Philippe Diaz, Brian Haas, Nephi Stella, Benjamin Uhlenbruck, Cong Xu, Ravil R. Petrov, Ernest Hamel, and Linda Wordeman
- Subjects
0301 basic medicine ,Cell Survival ,Carbazoles ,Antineoplastic Agents ,Microtubules ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,Structure-Activity Relationship ,Microtubule ,Cell Line, Tumor ,Drug Discovery ,Colchicine ,Moiety ,Structure–activity relationship ,Humans ,Cell Proliferation ,Pharmacology ,biology ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Cell growth ,Organic Chemistry ,General Medicine ,Small molecule ,Molecular Docking Simulation ,030104 developmental biology ,Tubulin ,Cell culture ,biology.protein ,Biophysics ,Drug Screening Assays, Antitumor ,Glioblastoma - Abstract
Small molecules that target microtubules (MTs) represent promising therapeutics to treat certain types of cancer, including glioblastoma multiform (GBM). We synthesized modified carbazoles and evaluated their antitumor activity in GBM cells in culture. Modified carbazoles with an ethyl moiety linked to the nitrogen of the carbazole and a carbonyl moiety linked to distinct biaromatic rings exhibited remarkably different killing activities in human GBM cell lines and patient-derived GBM cells, with IC50 values from 67 to >10,000 nM. Measures of the activity of modified carbazoles with tubulin and microtubules coupled to molecular docking studies show that these compounds bind to the colchicine site of tubulin in a unique low interaction space that inhibits tubulin assembly. The modified carbazoles reported here represent novel chemical tools to better understand how small molecules disrupt MT functions and kill devastating cancers such as GBM.
- Published
- 2018
17. Characterization of Novel Cannabinoid Based T-Type Calcium Channel Blockers with Analgesic Effects
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N. Daniel Berger, Vinicius M. Gadotti, Gerald W. Zamponi, Chris Bladen, Steven W. McDaniel, Ravil R. Petrov, and Philippe Diaz
- Subjects
Male ,Cannabinoid receptor ,carbazole scaffold ,Physiology ,medicine.drug_class ,Cognitive Neuroscience ,medicine.medical_treatment ,Pain ,Calcium channel blocker ,Motor Activity ,Pharmacology ,Biochemistry ,Cell Line ,Receptor, Cannabinoid, CB2 ,Calcium Channels, T-Type ,Receptor, Cannabinoid, CB1 ,medicine ,Cannabinoid receptor type 2 ,Animals ,Humans ,Cannabinoid Receptor Antagonists ,inflammatory pain ,neuropathic pain ,Mice, Knockout ,Analgesics ,Dose-Response Relationship, Drug ,Voltage-dependent calcium channel ,Chemistry ,Calcium channel ,T-type calcium channel ,Cell Biology ,General Medicine ,electrophysiology ,Calcium Channel Blockers ,Sciatic Nerve ,3. Good health ,Mice, Inbred C57BL ,hCav 3.2 ,Disease Models, Animal ,Hyperalgesia ,Touch ,Cannabinoid receptor antagonist ,Cannabinoid ,Research Article - Abstract
Low-voltage-activated (T-type) calcium channels are important regulators of the transmission of nociceptive information in the primary afferent pathway and finding ligands that modulate these channels is a key focus of the drug discovery field. Recently, we characterized a set of novel compounds with mixed cannabinoid receptor/T-type channel blocking activity and examined their analgesic effects in animal models of pain. Here, we have built on these previous findings and synthesized a new series of small organic compounds. We then screened them using whole-cell voltage clamp techniques to identify the most potent T-type calcium channel inhibitors. The two most potent blockers (compounds 9 and 10) were then characterized using radioligand binding assays to determine their affinity for CB1 and CB2 receptors. The structure-activity relationship and optimization studies have led to the discovery of a new T-type calcium channel blocker, compound 9. Compound 9 was efficacious in mediating analgesia in mouse models of acute inflammatory pain and in reducing tactile allodynia in the partial nerve ligation model. This compound was shown to be ineffective in Cav3.2 T-type calcium channel null mice at therapeutically relevant concentrations, and it caused no significant motor deficits in open field tests. Taken together, our data reveal a novel class of compounds whose physiological and therapeutic actions are mediated through block of Cav3.2 calcium channels.
- Published
- 2014
18. 6. La médiation dans le catalogue enrichi et participatif du portail de l’Astrolabe
- Author
-
Philippe Diaz
- Published
- 2017
19. Novel di-aryl-substituted isoxazoles act as noncompetitive inhibitors of the system xc- cystine/glutamate exchanger
- Author
-
Jayme L. Newell, Steven W. McDaniel, Nicholas R. Natale, Richard J. Bridges, Charles M. Keyari, Sarjubhai A. Patel, and Philippe Diaz
- Subjects
Chemistry ,Stereochemistry ,Aryl ,Antiporter ,Glutamate receptor ,Transporter ,Context (language use) ,Cell Biology ,Glutathione ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Non-competitive inhibition ,Biochemistry ,Isoxazole - Abstract
The system xc(-) antiporter is a plasma membrane transporter that mediates the exchange of extracellular l-cystine with intracellular l-glutamate. This exchange is significant within the context of the CNS because the import of l-cystine is required for the synthesis of the antioxidant glutathione, while the efflux of l-glutamate has the potential to contribute to either excitatory signaling or excitotoxic pathology. Changes in the activity of the transport system have been linked to the underlying pathological mechanisms of a variety of CNS disorders, one of the most prominent of which is its highly enriched expression in glial brain tumors. In an effort to produce more potent system xc(-) blockers, we have been using amino-3-carboxy-5-methylisoxazole propionic acid (ACPA) as a scaffold for inhibitor development. We previously demonstrated that the addition of lipophilic aryl groups to either the #4 or #5 position on the isoxazole ring markedly increased the inhibitory activity at system xc(-). In the present work a novel series of analogues has been prepared in which aryl groups have been introduced at both the #4 and #5 positions. In contrast to the competitive action of the mono-substituted analogues, kinetic analyses indicate that the di-substituted isoxazoles block system xc(-)-mediated uptake of (3)H-l-glutamate into SNB-19 cells by a noncompetitive mechanism. These new analogues appear to be the first noncompetitive inhibitors identified for this transport system, as well as being among the most potent blockers identified to date. These diaryl-isoxazoles should be of value in assessing the physiological roles and molecular pharmacology of system xc(-).
- Published
- 2014
20. 717 Peripheral blockade of T-type calcium channels by DX416 inhibits acute itch and modulates immune response
- Author
-
Vinicius M. Gadotti, Gerald W. Zamponi, N. Wageling, Philippe Diaz, B. Uhlenbruck, and J. Kreitinger
- Subjects
Immune system ,Chemistry ,T-type calcium channel ,Cell Biology ,Dermatology ,Pharmacology ,Molecular Biology ,Biochemistry ,Peripheral ,Blockade - Published
- 2019
21. 357 Deciphering biosynthesis of all-trans-retinoic acid from retinaldehyde and the regulation of retinoid homeostasis in skin
- Author
-
Katie Rodan, Philippe Diaz, E. Berglund, J. Kreitinger, T. Falla, J. Veit, Kathy Fields, and S. Craw
- Subjects
medicine.drug_class ,Retinoic acid ,All trans ,Cell Biology ,Dermatology ,Biochemistry ,Cell biology ,chemistry.chemical_compound ,chemistry ,Biosynthesis ,Retinaldehyde ,medicine ,Retinoid ,Molecular Biology ,Homeostasis - Published
- 2019
22. Mastering tricyclic ring systems for desirable functional cannabinoid activity
- Author
-
Shao Rui Chen, Fanny Diaz, Ken Mackie, Philippe Diaz, Steven W. McDaniel, Jim Wager-Miller, Ravil R. Petrov, Hui Lin Pan, Claudio N. Cavasotto, Lindsay K. Knight, and Francis Barth
- Subjects
Models, Molecular ,Agonist ,Cannabinoid receptor ,medicine.drug_class ,medicine.medical_treatment ,media_common.quotation_subject ,Carbazoles ,Homology Modelling ,Cannabinoid Receptor ,Pharmacology ,Article ,purl.org/becyt/ford/1 [https] ,Receptor, Cannabinoid, CB2 ,Structure-Activity Relationship ,Receptor, Cannabinoid, CB1 ,Drug Discovery ,purl.org/becyt/ford/1.4 [https] ,medicine ,Radioligand ,Cannabinoid receptor type 2 ,Animals ,Humans ,Structure–activity relationship ,Internalization ,media_common ,G protein-coupled receptor ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Otras Ciencias Químicas ,Organic Chemistry ,Ciencias Químicas ,Tricycling Ring System ,General Medicine ,Rats ,Flexible Docking ,Neuralgia ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,CIENCIAS NATURALES Y EXACTAS - Abstract
There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain and other indications. In continuation of our ongoing program aiming for the development of new small molecule cannabinoid ligands, we have synthesized a novel series of carbazole and γ-carboline derivatives. The affinities of the newly synthesized compounds were determined by a competitive radioligand displacement assay for human CB2 cannabinoid receptor and rat CB1 cannabinoid receptor. Functional activity and selectivity at human CB1 and CB2 receptors were characterized using receptor internalization and [35S]GTP-γ-S assays. The structure–activity relationship and optimization studies of the carbazole series have led to the discovery of a non-selective CB1 and CB2 agonist, compound 4. Our subsequent research efforts to increase CB2 selectivity of this lead compound have led to the discovery of CB2 selective compound 64, which robustly internalized CB2 receptors. Compound 64 had potent inhibitory effects on pain hypersensitivity in a rat model of neuropathic pain. Other potent and CB2 receptor–selective compounds, including compounds 63 and 68, and a selective CB1 agonist, compound 74 were also discovered. In addition, we identified the CB2 ligand 35 which failed to promote CB2 receptor internalization and inhibited compound CP55,940-induced CB2 internalization despite a high CB2 receptor affinity. The present study provides novel tricyclic series as a starting point for further investigations of CB2 pharmacology and pain treatment. Fil: Petrov, Ravil R.. University Of Montana; Estados Unidos Fil: Knight, Lindsay. Indiana University; Estados Unidos Fil: Chen, Shao Rui . University Of Texas; Estados Unidos Fil: Wager Miller, Jim. Indiana University; Estados Unidos Fil: McDaniel, Steven W.. University Of Montana; Estados Unidos Fil: Diaz, Fanny. University Of Montana; Estados Unidos Fil: Barth, Francis. Sanofi-aventis R&D; Francia Fil: Pan, Hui Lin. University Of Texas; Estados Unidos Fil: Mackie, Ken . Indiana University; Estados Unidos Fil: Cavasotto, Claudio Norberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigación en Biomedicina de Buenos Aires; Argentina Fil: Diaz, Philippe. University Of Montana; Estados Unidos
- Published
- 2013
23. Prevention of Paclitaxel-Induced Neuropathy Through Activation of the Central Cannabinoid Type 2 Receptor System
- Author
-
Suzanne Craig, David L. Brown, Mohamed Naguib, Bihua Bie, Jijun J. Xu, Jianhua Hu, Walter N. Hittelman, Philippe Diaz, and David Cogdell
- Subjects
Lipopolysaccharides ,Male ,medicine.medical_treatment ,Pharmacology ,Rats, Sprague-Dawley ,Receptor, Cannabinoid, CB2 ,Mice ,Piperidines ,Cricetinae ,Image Processing, Computer-Assisted ,Cannabinoid receptor type 2 ,Mice, Knockout ,CD11b Antigen ,Microscopy, Confocal ,Microglia ,Peripheral Nervous System Diseases ,Flow Cytometry ,Immunohistochemistry ,Neuroprotective Agents ,medicine.anatomical_structure ,Allodynia ,Spinal Cord ,Hyperalgesia ,lipids (amino acids, peptides, and proteins) ,medicine.symptom ,Neuroglia ,Agonist ,medicine.medical_specialty ,Paclitaxel ,medicine.drug_class ,Blotting, Western ,Down-Regulation ,Enzyme-Linked Immunosorbent Assay ,Real-Time Polymerase Chain Reaction ,Neuroprotection ,Article ,Proinflammatory cytokine ,Physical Stimulation ,Internal medicine ,Glial Fibrillary Acidic Protein ,medicine ,Animals ,Humans ,Benzofurans ,business.industry ,Gene Expression Profiling ,medicine.disease ,Antineoplastic Agents, Phytogenic ,Toll-Like Receptor 2 ,Rats ,Anesthesiology and Pain Medicine ,Endocrinology ,Peripheral neuropathy ,Astrocytes ,Cannabinoid ,business - Abstract
BACKGROUND: Peripheral neuropathy is a major dose-limiting toxicity of chemotherapy, especially after multiple courses of paclitaxel. The development of paclitaxel-induced neuropathy is associated with the activation of microglia followed by the activation and proliferation of astrocytes, and the expression and release of proinflammatory cytokines in the spinal dorsal horn. Cannabinoid type 2 (CB2) receptors are expressed in the microglia in neurodegenerative disease models. METHODS: To explore the potential of CB2 agonists for preventing paclitaxel-induced neuropathy, we designed and synthesized a novel CB2-selective agonist, namely, MDA7. The effect of MDA7 in preventing paclitaxel-induced allodynia was assessed in rats and in CB2 / and CB 2 / mice. We hypothesized that the CB2 receptor functions in a negative-feedback loop and that early MDA7 administration can blunt the neuroinflammatory response to paclitaxel and prevent mechanical allodynia through interference with specific signaling pathways. RESULTS: We found that MDA7 prevents paclitaxel-induced mechanical allodynia in rats and mice in a dose- and time-dependent manner without compromising paclitaxel’s antineoplastic effect. MDA7’s neuroprotective effect was absent in CB2 / mice and was blocked by CB2 antagonists, suggesting that MDA7’s action directly involves CB 2 receptor activation. MDA7 treatment was found to interfere with early events in the paclitaxel-induced neuroinflammatory response as evidenced by relatively reduced toll-like receptor and CB2 expression in the lumbar spinal cord, reduced levels of extracellular signal-regulated kinase 1/2 activity, reduced numbers of activated microglia and astrocytes, and reduced secretion of proinflammatory mediators in vivo and in in vitro models. CONCLUSIONS: Our findings suggest an innovative therapeutic approach to prevent chemotherapyinduced neuropathy and may permit more aggressive use of active chemotherapeutic regimens with reduced long-term sequelae. (Anesth Analg 2012;114:1104–20)
- Published
- 2012
24. Design and evaluation of a novel fluorescent CB2 ligand as probe for receptor visualization in immune cells
- Author
-
Zeina Jaffar, Ravil R. Petrov, Maria Ferrini, Philippe Diaz, Kevan Roberts, and Charles M. Thompson
- Subjects
Isatin ,Clinical Biochemistry ,Drug Evaluation, Preclinical ,Pharmaceutical Science ,CHO Cells ,Ligands ,Biochemistry ,Fluorescence ,Article ,Flow cytometry ,law.invention ,Receptor, Cannabinoid, CB2 ,Mice ,Structure-Activity Relationship ,Confocal microscopy ,law ,Cricetinae ,Drug Discovery ,medicine ,Cannabinoid receptor type 2 ,Animals ,Humans ,Structure–activity relationship ,Receptor ,Lung ,Molecular Biology ,Fluorescent Dyes ,Pyrans ,G protein-coupled receptor ,B-Lymphocytes ,Mice, Inbred BALB C ,Oxadiazoles ,Microscopy, Confocal ,Molecular Structure ,medicine.diagnostic_test ,Chemistry ,Chinese hamster ovary cell ,Organic Chemistry ,Hydrazones ,Hydrazines ,Pyrimidines ,Drug Design ,Biophysics ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Protein Binding - Abstract
Cannabinoid CB2 receptor has emerged as a very promising target over the last decades. We have synthesized and evaluated a new fluorescent probe designated NMP6 based on 6-methoxyisatin scaffold, which exhibited selectivity and K(i) value at hCB2 of 387 nM. We have demonstrated its ability to be an effective probe for visualization of CB2 receptor binding using confocal microscopy and a flow cytometry probe for the analysis of CB2 protein expression. Furthermore, NMP6 was easily obtained in two chemical steps from commercially available building blocks.
- Published
- 2011
25. Functional Characterization and Analgesic Effects of Mixed Cannabinoid Receptor/T-Type Channel Ligands
- Author
-
Haitao You, Vinicius M. Gadotti, Ravil R. Petrov, Gerald W. Zamponi, and Philippe Diaz
- Subjects
Cannabinoid receptor ,Analgesic ,Carbazoles ,CHO Cells ,Pharmacology ,Ligands ,Depolarization-induced suppression of inhibition ,Receptor, Cannabinoid, CB2 ,Calcium Channels, T-Type ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Cricetulus ,0302 clinical medicine ,Receptor, Cannabinoid, CB1 ,Cricetinae ,lcsh:Pathology ,Cannabinoid receptor type 2 ,Animals ,Humans ,030304 developmental biology ,Analgesics ,0303 health sciences ,Voltage-dependent calcium channel ,Chemistry ,Research ,Calcium channel ,HEK 293 cells ,Rats ,HEK293 Cells ,Anesthesiology and Pain Medicine ,Molecular Medicine ,GPR18 ,lipids (amino acids, peptides, and proteins) ,030217 neurology & neurosurgery ,lcsh:RB1-214 ,Carbolines - Abstract
Background: Both T-type calcium channels and cannabinoid receptors modulate signalling in the primary afferent pain pathway. Here, we investigate the analgesics activities of a series of novel cannabinoid receptor ligands with T-type calcium channel blocking activity. Results: Novel compounds were characterized in radioligand binding assays and in vitro functional assays at human and rat CB1 and CB2 receptors. The inhibitory effects of these compounds on transient expressed human T-type calcium channels were examined in tsA-201 cells using standard whole-cell voltage clamp techniques, and their analgesic effects in response to various administration routes (intrathecally, intraplantarly, intraperitoneally) assessed in the formalin model. A series of compounds were synthesized and evaluated for channel and receptor activity. Compound NMP-7 acted as non-selective CB1/CB2 agonist while NMP4 was found to be a CB1 partial agonist and CB2 inverse agonist. Furthermore, NMP-144 behaved as a selective CB2 inverse agonist. All of these three compounds completely inhibited peak Cav3.2 currents with IC50 values in the low micromolar range. All compounds mediated analgesic effects in the formalin model, but depending on the route of administration, could differentially affect phase 1 and phase 2 of the formalin response. Conclusions: Our results reveal that a set of novel cannabinioid receptor ligands potently inhibit T-type calcium channels and show analgesic effects in vivo. Our findings suggest possible novel means of mediating pain relief through mixed T-type/cannabinoid receptor ligands.
- Published
- 2011
26. 726 Novel CYP26B1-selective inhibitor increases measures of epidermal barrier function in healthy, darier’s, and ichthyotic econstructed human epidermis
- Author
-
F. Astruc-Diaz, Haoming Liu, Philippe Diaz, V. De Glas, Amy S. Paller, K. Bagnowski, J. Veit, Yves Poumay, Benoît Balau, and D. Mendes
- Subjects
Epidermal barrier ,Epidermis (botany) ,Chemistry ,Cell Biology ,Dermatology ,Molecular Biology ,Biochemistry ,Function (biology) ,Cell biology - Published
- 2018
27. 722 Combination of retinaldehyde and hydroxylapatite mimics the effects of all-trans retinoic acid in reconstructed human epidermis
- Author
-
J. Veit, E. Berglund, and Philippe Diaz
- Subjects
chemistry.chemical_compound ,Epidermis (botany) ,chemistry ,Retinaldehyde ,Retinoic acid ,All trans ,Cell Biology ,Dermatology ,Hydroxylapatite ,Molecular Biology ,Biochemistry ,Cell biology - Published
- 2018
28. 2,3-Dihydro-1-Benzofuran Derivatives as a Series of Potent Selective Cannabinoid Receptor 2 Agonists: Design, Synthesis, and Binding Mode Prediction through Ligand-Steered Modeling
- Author
-
Mohamed Naguib, Charles M. Thompson, Fanny Astruc-Diaz, Frank R. Fronczek, Jijun Xu, Philippe Diaz, Claudio N. Cavasotto, and Sharangdhar S. Phatak
- Subjects
Male ,Models, Molecular ,Stereochemistry ,CHO Cells ,Ligands ,Biochemistry ,Article ,Rats, Sprague-Dawley ,Receptor, Cannabinoid, CB2 ,Structure-Activity Relationship ,Cricetulus ,Cricetinae ,Drug Discovery ,Cannabinoid receptor type 2 ,Animals ,Humans ,Structure–activity relationship ,Molecule ,General Pharmacology, Toxicology and Pharmaceutics ,Receptor ,Benzofurans ,Pharmacology ,Molecular Structure ,Chemistry ,Ligand ,Organic Chemistry ,Analgesics, Non-Narcotic ,Rats ,Hyperalgesia ,Asymmetric carbon ,Drug Design ,Molecular Medicine ,Racemic mixture ,Enantiomer - Abstract
We recently discovered and reported a series of N-alkyl-isatin acylhydrazone derivatives that are potent cannabinoid receptor 2 (CB(2)) agonists. In an effort to improve the druglike properties of these compounds and to better understand and improve the treatment of neuropathic pain, we designed and synthesized a new series of 2,3-dihydro-1-benzofuran derivatives bearing an asymmetric carbon atom that behave as potent selective CB(2) agonists. We used a multidisciplinary medicinal chemistry approach with binding mode prediction through ligand-steered modeling. Enantiomer separation and configuration assignment were carried out for the racemic mixture for the most selective compound, MDA7 (compound 18). It appeared that the S enantiomer, compound MDA104 (compound 33), was the active enantiomer. Compounds MDA42 (compound 19) and MDA39 (compound 30) were the most potent at CB(2). MDA42 was tested in a model of neuropathic pain and exhibited activity in the same range as that of MDA7. Preliminary ADMET studies for MDA7 were performed and did not reveal any problems.
- Published
- 2009
29. MDA7: a novel selective agonist for CB2 receptors that prevents allodynia in rat neuropathic pain models
- Author
-
Philippe Diaz, Jijun Xu, Pablo E. Vivas-Mejia, Suzanne Craig, Mohamed Naguib, David L. Brown, and Fanny Astruc-Diaz
- Subjects
Pharmacology ,Agonist ,medicine.drug_class ,Chemistry ,medicine.medical_treatment ,Allodynia ,Opioid receptor ,Neuropathic pain ,Hyperalgesia ,medicine ,Cannabinoid receptor type 2 ,lipids (amino acids, peptides, and proteins) ,Cannabinoid ,medicine.symptom ,Receptor - Abstract
Background and purpose: There is growing interest in using cannabinoid type 2 (CB2) receptor agonists for the treatment of neuropathic pain. In this report, we describe the pharmacological characteristics of MDA7 (1-[(3-benzyl-3-methyl-2,3-dihydro-1-benzofuran-6-yl)carbonyl]piperidine), a novel CB2 receptor agonist. Experimental approach: We characterized the pharmacological profile of MDA7 by using radioligand-binding assays and in vitro functional assays at human cannabinoid type 1 (CB1) and CB2 receptors. In vitro functional assays were performed at rat CB1 and CB2 receptors. The effects of MDA7 in reversing neuropathic pain were assessed in spinal nerve ligation and paclitaxel-induced neuropathy models in rats. Key results: MDA7 exhibited selectivity and agonist affinity at human and rat CB2 receptors. MDA7 treatment attenuated tactile allodynia produced by spinal nerve ligation or by paclitaxel in a dose-related manner. These effects were selectively antagonized by a CB2 receptor antagonist but not by CB1 or opioid receptor antagonists. MDA7 did not affect rat locomotor activity. Conclusion and implications: MDA7, a novel selective CB2 agonist, was effective in suppressing neuropathic nociception in two rat models without affecting locomotor behaviour. These results confirm the potential for CB2 agonists in the treatment of neuropathic pain. British Journal of Pharmacology (2008) 155, 1104–1116; doi:10.1038/bjp.2008.340; published online 1 September 2008
- Published
- 2008
30. Design and Synthesis of a Novel Series of N-Alkyl Isatin Acylhydrazone Derivatives that Act as Selective Cannabinoid Receptor 2 Agonists for the Treatment of Neuropathic Pain
- Author
-
Jijun Xu, Mohamed Naguib, Hao Min Pan, Fanny Astruc-Diaz, David L. Brown, and Philippe Diaz
- Subjects
Isatin ,Agonist ,Cannabinoid receptor ,medicine.drug_class ,Stereochemistry ,CHO Cells ,Chemical synthesis ,Receptor, Cannabinoid, CB2 ,Structure-Activity Relationship ,chemistry.chemical_compound ,Cricetulus ,Receptor, Cannabinoid, CB1 ,X-Ray Diffraction ,Cricetinae ,Drug Discovery ,Cannabinoid receptor type 2 ,medicine ,Animals ,Humans ,Structure–activity relationship ,Chemistry ,Hydrazones ,Rats ,Drug Design ,Neuropathic pain ,Neuralgia ,Molecular Medicine ,lipids (amino acids, peptides, and proteins) ,Lead compound - Abstract
There is growing interest in using cannabinoid receptor 2 (CB2) agonists for the treatment of neuropathic pain. We have synthesized a novel series of N-alkyl isatin acylhydrazone derivatives and have identified and characterized several of them as novel analogues with high functional activity and selectivity at human CB2 receptors using [(35)S]GTP-gamma-S assays. Binding affinities at human CB2 and CB1 were determined for compounds 28, 33, 40, 48, and 58. Structure-activity relationship studies of this novel series led to optimization of our lead compound, compound 33 (MDA19). Compound 33 possessed potent antiallodynic effects in a rat model of neuropathic pain but did not affect rat locomotor activity. More potent and more CB2-receptor-selective compounds, including compounds 37, 40, and 48, were also discovered.
- Published
- 2008
31. 529 Novel CYP26 inhibitors potentiate the effects of all- trans -retinoic acid on phenotype of normal and Darier disease keratinocytes in reconstructed human epidermis
- Author
-
J. Veit, V. De Glas, N. Guilloteau, Benoît Balau, D. Mendes, F. Astruc-Diaz, Yves Poumay, and Philippe Diaz
- Subjects
Genetics ,Epidermis (botany) ,Retinoic acid ,All trans ,Cell Biology ,Dermatology ,Biology ,Biochemistry ,Phenotype ,Molecular biology ,chemistry.chemical_compound ,chemistry ,Darier Disease ,Molecular Biology - Published
- 2017
32. NMP-7 inhibits chronic inflammatory and neuropathic pain via block of Cav3.2 T-type calcium channels and activation of CB2 receptors
- Author
-
N Daniel, Berger, Vinicius M, Gadotti, Ravil R, Petrov, Kevin, Chapman, Philippe, Diaz, and Gerald W, Zamponi
- Subjects
Inflammation ,Male ,Mice, Knockout ,Analgesics ,Inflammatory pain ,Research ,Body Weight ,Freund's Adjuvant ,Carbazoles ,Pain ,Ligands ,Neuropathic pain ,Sciatic Nerve ,Mice, Inbred C57BL ,Receptor, Cannabinoid, CB2 ,Calcium Channels, T-Type ,Mice ,Hyperalgesia ,Animals ,Neuralgia ,T-type calcium channels ,Analgesia ,Cannabinoid receptors ,Pain Measurement - Abstract
Background T-type calcium channels and cannabinoid receptors are known to play important roles in chronic pain, making them attractive therapeutic targets. We recently reported on the design, synthesis and analgesic properties of a novel T-type channel inhibitor (NMP-7), which also shows mixed agonist activity on CB1 and CB2 receptors in vitro. Here, we analyzed the analgesic effect of systemically delivered NMP-7 (intraperitoneal (i.p.) or intragstric (i.g.) routes) on mechanical hypersensitivity in inflammatory pain induced by Complete Freund’s Adjuvant (CFA) and neuropathic pain induced by sciatic nerve injury. Results NMP-7 delivered by either i.p. or i.g. routes produced dose-dependent inhibition of mechanical hyperalgesia in mouse models of inflammatory and neuropathic pain, without altering spontaneous locomotor activity in the open-field test at the highest active dose. Neither i.p. nor i.g. treatment reduced peripheral inflammation per se, as evaluated by examining paw edema and myeloperoxidase activity. The antinociception produced by NMP-7 in the CFA test was completely abolished in CaV3.2-null mice, confirming CaV3.2 as a key target. The analgesic action of intraperitoneally delivered NMP-7 was not affected by pretreatment of mice with the CB1 antagonist AM281, but was significantly attenuated by pretreatment with the CB2 antagonist AM630, suggesting that CB2 receptors, but not CB1 receptors are involved in the action of NMP-7 in vivo. Conclusions Overall, our work shows that NMP-7 mediates a significant analgesic effect in a model of persistent inflammatory and chronic neuropathic pain by way of T-type channel modulation and CB2 receptor activation. Thus, this study provides a novel therapeutic avenue for managing chronic pain conditions via mixed CB ligands/T-type channel blockers.
- Published
- 2014
33. Coupling reaction of chalcogenyl halides with alkynes on a solid support. Synthesis of new selenium-containing retinoids
- Author
-
Philippe Diaz and Fabrice Gendre
- Subjects
animal structures ,Chemistry ,Organic Chemistry ,Halide ,chemistry.chemical_element ,Biochemistry ,Copper ,Coupling reaction ,Solid-phase synthesis ,Wang resin ,Drug Discovery ,Polymer chemistry ,Organic chemistry ,Selenium - Abstract
A new series of selenium-containing acetylenic retinoids has been prepared by a copper assisted reaction of selenyl bromides with terminal alkynes bound to Wang resin.
- Published
- 2000
34. Solution-Phase Synthesis of Diaryl Selenides Using Polymer-Supported Borohydride
- Author
-
Corinne Millois and Philippe Diaz
- Subjects
inorganic chemicals ,Polymers ,Receptors, Retinoic Acid ,Chemistry ,Organic Chemistry ,chemistry.chemical_element ,Borohydrides ,Borohydride ,Biochemistry ,Diselenide ,Coupling (electronics) ,Retinoids ,chemistry.chemical_compound ,Nickel ,Retinoid X Receptors ,Neoplasms ,Organoselenium Compounds ,Polymer chemistry ,Psoriasis ,Physical and Theoretical Chemistry ,Polymer supported ,Solution phase synthesis ,Transcription Factors - Abstract
[reaction: see text] A new series of selenium-containing diaryl retinoids have been prepared by a new direct nickel(II)-catalyzed coupling of a diselenide with an iodoaryl in the presence of polymer-supported borohydride.
- Published
- 2000
35. New selenium-containing acetylenic retinoids by direct coupling of alkynylsilanes with selenylhalides
- Author
-
Fabrice Gendre, Philippe Diaz, and Jean-Michel Bernardon
- Subjects
chemistry ,Organic Chemistry ,Drug Discovery ,Halide ,chemistry.chemical_element ,Organic chemistry ,Direct coupling ,Biochemistry ,Selenium ,Copper iodide - Abstract
A new series of alkynylselenide-containing retinoids has been synthesized by reacting phenylchalcogenyl halides with trimethylsilylalkynes in the presence of copper iodide.
- Published
- 1998
36. New synthetic retinoids obtained by palladium-catalyzed tandem cyclisation-hydride capture process
- Author
-
Bruno Charpentier, Lucien Stella, Philippe Diaz, and Fabrice Gendre
- Subjects
inorganic chemicals ,Tandem ,Hydride ,Bioactive molecules ,Organic Chemistry ,Enantioselective synthesis ,chemistry.chemical_element ,Nanotechnology ,Biochemistry ,Combinatorial chemistry ,Catalysis ,Enantiopure drug ,chemistry ,Scientific method ,Drug Discovery ,Palladium - Abstract
A new series of conformationally restricted retinoids (3-aryl-3-methyl-2,3-dihydro-benzofurans) have been prepared through a palladium-catalyzed tandem cyclisation-hydride capture. The use of enantiopure BINAP-Pd catalyst allowed asymmetric synthesis of bioactive molecules.
- Published
- 1998
37. Synthesis and biological activities of new heterocyclic aromatic retinoids
- Author
-
Lucien Stella, Philippe Diaz, Bruno Charpentier, and S. Michel
- Subjects
chemistry.chemical_classification ,Bicyclic molecule ,Chemistry ,Stereochemistry ,Carboxylic acid ,Cellular differentiation ,Organic Chemistry ,Clinical Biochemistry ,Retinoic acid ,Pharmaceutical Science ,Biochemistry ,Affinities ,Chemical synthesis ,In vitro ,Retinoic acid receptor ,chemistry.chemical_compound ,Drug Discovery ,Molecular Medicine ,Molecular Biology - Abstract
A series of 3-aryl-2H-1-benzopyrancarboxylic acid derivatives was synthesized and evaluated as Retinoic Acid Receptor (RAR) agonists. By modifications of the 3-aryl group, we have obtained new retinoids exhibiting potent cellular differentiating activities and high affinities for RARs. Moreover, hydrogenation of the 2H-1-benzopyran ring led to the 3-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-naphthalen-2-yl)-3,4-dihydro-2H-1-benzopyran-7-yl carboxylic acid, characterized by a RARs binding profile.
- Published
- 1997
38. Up-regulation of mRNA ventricular PRNP prion protein gene expression in air pollution highly exposed young urbanites: endoplasmic reticulum stress, glucose regulated protein 78, and nanosized particles
- Author
-
Hongtu Zhu, Rodolfo Villarreal-Calderon, Qiang Sun, Dan Drecktrah, Maricela Franco-Lira, Lou Harritt, Beatriz Pérez-Guillé, Lara Ferreira-Azevedo, Ricardo Torres-Jardón, Mariana Aragón-Flores, Rafael Reynoso-Robles, Ana Laura Calderón-Garcidueñas, Angélica González-Maciel, Philippe Diaz, and Lilian Calderón-Garcidueñas
- Subjects
Male ,Pathology ,Erythrocytes ,Glucose-regulated protein ,air pollution ,medicine.disease_cause ,lcsh:Chemistry ,oxidative stress ,Child ,lcsh:QH301-705.5 ,Endoplasmic Reticulum Chaperone BiP ,Spectroscopy ,BiP ,children ,endoplasmic reticulum stress ,GRP78 ,sarcoplasmic reticulum ,myocardial damage ,nanoparticles ,particulate matter ,PRNP ,Heat-Shock Proteins ,Air Pollutants ,biology ,General Medicine ,Endoplasmic Reticulum Stress ,Computer Science Applications ,Up-Regulation ,Female ,Adult ,medicine.medical_specialty ,Adolescent ,Prions ,Heart Ventricles ,Real-Time Polymerase Chain Reaction ,Catalysis ,Prion Proteins ,Article ,Inorganic Chemistry ,Young Adult ,Dogs ,Downregulation and upregulation ,Internal medicine ,Heat shock protein ,medicine ,Animals ,Humans ,RNA, Messenger ,Physical and Theoretical Chemistry ,Particle Size ,Molecular Biology ,Endoplasmic reticulum ,Organic Chemistry ,Endocrinology ,lcsh:Biology (General) ,lcsh:QD1-999 ,biology.protein ,Unfolded protein response ,Nanoparticles ,Homeostasis ,Oxidative stress - Abstract
Mexico City Metropolitan Area children and young adults exposed to high concentrations of air pollutants including fine and ultrafine particulate matter (PM) vs. clean air controls, exhibit myocardial inflammation and inflammasome activation with a differential right and left ventricular expression of key inflammatory genes and inflammasomes. We investigated the mRNA expression levels of the prion protein gene PRNP, which plays an important role in the protection against oxidative stress and metal toxicity, and the glucose regulated protein 78, a key protein in endoplasmic reticulum (ER) stress signaling, in ventricular autopsy samples from 30 children and young adults age 19.97 ± 6.8 years with a lifetime of low (n:4) vs. high (n:26) air pollution exposures. Light microscopy and transmission electron microscopy studies were carried out in human ventricles, and electron microscopy studies were also done in 5 young, highly exposed Mexico City dogs. There was significant left ventricular PRNP and bi-ventricular GRP78 mRNA up-regulation in Mexico City young urbanites vs. controls. PRNP up-regulation in the left ventricle was significantly different from the right, p < 0.0001, and there was a strong left ventricular PRNP and GRP78 correlation (p = 0.0005). Marked abnormalities in capillary endothelial cells, numerous nanosized particles in myocardial ER and in abnormal mitochondria characterized the highly exposed ventricles. Early and sustained cardiac ER stress could result in detrimental irreversible consequences in urban children, and while highly complex systems maintain myocardial homeostasis, failure to compensate for chronic myocardial inflammation, oxidative and ER stress, and particles damaging myocardial organelles may prime the development of pathophysiological cardiovascular states in young urbanites. Nanosized PM could play a key cardiac myocyte toxicity role.
- Published
- 2013
39. Spinal gene expression profiling and pathways analysis of a CB2 agonist (MDA7)-targeted prevention of paclitaxel-induced neuropathy
- Author
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David L. Brown, Bihua Bie, Philippe Diaz, Fanny Astruc-Diaz, Hui Yang, Mohamed Naguib, Jiang Wu, and Jijun J. Xu
- Subjects
Agonist ,MAPK/ERK pathway ,Pain Threshold ,Paclitaxel ,medicine.drug_class ,Pharmacology ,Receptor, Cannabinoid, CB2 ,Mice ,Piperidines ,medicine ,Animals ,Neuroinflammation ,Benzofurans ,ATF3 ,biology ,business.industry ,General Neuroscience ,Gene Expression Profiling ,Lumbosacral Region ,Transforming growth factor beta ,medicine.disease ,Rats ,Peripheral neuropathy ,Allodynia ,Spinal Cord ,Hyperalgesia ,Immunology ,biology.protein ,medicine.symptom ,Signal transduction ,business ,Signal Transduction - Abstract
Aims Patients receiving paclitaxel often develop peripheral neuropathies. We found that a novel selective cannabinoid CB 2 receptor agonist (MDA7) prevents paclitaxel-induced mechanical allodynia in rats and mice. Here we investigated gene expression profiling in the lumbar spinal cord after 14-day treatment of MDA7 in paclitaxel animals and analyzed possible signaling pathways underlying the preventive effect of MDA7 on paclitaxel-induced neuropathy. Methods Peripheral mechanical allodynia was induced in rats or mice receiving intraperitoneal (i.p.) injection of paclitaxel at a dose of 1 mg/kg daily for four consecutive days. MDA7 was administered at a dose of 15 mg/kg 15 min before paclitaxel and then continued daily for another 10 days. Whole-genome gene expression profiling in the lumbar spinal cord of MDA7 and paclitaxel-treated rats was investigated using microarray analysis. The Ingenuity pathway analysis was performed to determine the potential relevant canonical pathways responsible for the effect of MDA7 on paclitaxel-induced peripheral neuropathy. Results We observed that the inflammatory molecular networks including tumor necrosis factor (TNF), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), transforming growth factor beta (TGFβ), and mitogen-activated protein kinases (MAPK) signaling are most relevant to the preventive effect of MDA7 on paclitaxel-induced peripheral neuropathy. In addition, genes encoding molecules that are important in central sensitization such as glutamate transporters and N -methyl- d -aspartate receptor 2B (NMDAR2B), and neuro-immune-related genes such as neuronal nitric oxide synthase (nNOS1), chemokine CX3CL1 (a mediator for microglial activation), toll-like receptor 2 (TLR2), and leptin were differentially modulated by MDA7. Conclusion The preventive effect of MDA7 on paclitaxel-induced peripheral allodynia in rats may be associated with genes involved in signal pathways in central sensitization, microglial activation, and neuroinflammation in the spinal cord.
- Published
- 2013
40. Synthesis of New Quinolinequinone Derivatives and Preliminary Exploration of their Cytotoxic Properties
- Author
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Charles M. Keyari, Emily A. Eickholt, Nathan S. Duncan, Philippe Diaz, Alison K. Kearns, Howard D. Beall, and Geoffrey Abbott
- Subjects
Models, Molecular ,Magnetic Resonance Spectroscopy ,Stereochemistry ,Cell Survival ,Tetrazolium Salts ,Antineoplastic Agents ,Article ,chemistry.chemical_compound ,Structure-Activity Relationship ,Oxygen Consumption ,Cell Line, Tumor ,Drug Discovery ,Electrochemistry ,NAD(P)H Dehydrogenase (Quinone) ,Cytotoxic T cell ,Structure–activity relationship ,Humans ,Lavendamycin ,Cytotoxicity ,Coloring Agents ,Microwaves ,Chemistry ,Aryl ,Cytochromes c ,Thiazoles ,Cancer cell ,Quinolines ,Molecular Medicine ,Indicators and Reagents ,NAD+ kinase ,Drug Screening Assays, Antitumor - Abstract
A series of 7-amino- and 7-acetamidoquinoline-5,8-diones with aryl substituents at the 2-position were synthesized, characterized, and evaluated as potential NAD(P)H:quinone oxidoreductase (NQO1) -directed antitumor agents. The synthesis of lavendamycin analogues is illustrated. Metabolism studies demonstrated that 7-amino analogues were generally better substrates for NQO1 than 7-amido analogues, as were compounds with smaller heteroaromatic substituents at the C-2 position. Surprisingly, only two compounds, 7-acetamido-2-(8'-quinolinyl)quinoline-5,8-dione (11) and 7-amino-2-(2-pyridinyl)quinoline-5,8-dione (23), showed selective cytotoxicity toward the NQO1-expressing MDA468-NQ16 breast cancer cells versus the NQO1-null MDA468-WT cells. For all other compounds, NQO1 protected against quinoline-5,8-dione cytotoxicity. Compound 22 showed potent activity against human breast cancer cells expressing or not expressing NQO1, with respective IC50 values of 190 nM and 140 nM and a low NQO1-mediated reduction rate, which suggests that the mode of action of 22 differs from that of lavendamycin and involves an unidentified target(s).
- Published
- 2013
41. In Vivo Efficacy of Enabling Formulations Based on Hydroxypropyl-β-Cyclodextrins, Micellar Preparation, and Liposomes for the Lipophilic Cannabinoid CB2 Agonist, MDA7
- Author
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Jijun J. Xu, David L. Brown, Steven W. McDaniel, Mohamed Naguib, Stephane Parola, Philippe Diaz, Fanny Astruc-Diaz, University of Montana, Laboratoire de Chimie - UMR5182 (LC), Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École normale supérieure - Lyon (ENS Lyon)-Institut de Chimie du CNRS (INC), Cleveland Clinic, École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,Chemistry, Pharmaceutical ,[SDV]Life Sciences [q-bio] ,Dispersity ,Population ,Pharmaceutical Science ,02 engineering and technology ,01 natural sciences ,Micelle ,Article ,Rats, Sprague-Dawley ,Receptor, Cannabinoid, CB2 ,Dynamic light scattering ,Piperidines ,Animals ,Solubility ,education ,Micelles ,Benzofurans ,education.field_of_study ,Liposome ,Chromatography ,010405 organic chemistry ,Chemistry ,[CHIM.ORGA]Chemical Sciences/Organic chemistry ,beta-Cyclodextrins ,[CHIM.MATE]Chemical Sciences/Material chemistry ,021001 nanoscience & nanotechnology ,0104 chemical sciences ,Bioavailability ,2-Hydroxypropyl-beta-cyclodextrin ,Rats ,Treatment Outcome ,Liposomes ,Racemic mixture ,0210 nano-technology - Abstract
International audience; Enabling formulations based on hydroxypropyl-β-cyclodextrins (HPβCD), micellar preparation, and liposomes have been designed to deliver the racemic mixture of a lipophilic cannabinoid type 2 agonist, MDA7. The antiallodynic effects of MDA7 formulated in these three different systems were compared after intravenous (i.v.) administration in rats. Stoichiometry of the inclusion complex formed by MDA7 in HPβCD was determined by continuous variation plot, electrospray ionization–mass spectrometry (ESI–MS) analysis, phase solubility, and nuclear magnetic resonance studies and indicate formation of exclusively 1:1 adduct. Morphology and particle sizes determined by dynamic light scattering and transmission electron microscopy show the presence of a homogeneous population of closed round-shaped oligolamellar MDA7 containing liposomes, with an average size of 117 nm [polydispersity index (PDI)
- Published
- 2013
42. Chemoenzymatic synthesis of enantiomers of a new retinoid to investigate the role of chirality in the biological response
- Author
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Philippe Diaz, Jean-Michel Bernardon, Michele Vion, Braham Shroot, Corinne Millois, Bruno Charpentier, and Bruno F Antibes Fr Bernard
- Subjects
Lanthanide ,biology ,Chemistry ,Stereochemistry ,medicine.drug_class ,Organic Chemistry ,Clinical Biochemistry ,Absolute configuration ,Pharmaceutical Science ,Biochemistry ,Teratocarcinoma ,Drug Discovery ,biology.protein ,medicine ,Molecular Medicine ,Retinoid ,Enantiomer ,Lipase ,Chirality (chemistry) ,Molecular Biology - Abstract
We have prepared both enantiomers of a new retinoid ( IIa and IIb ) partly by using lipase resolution of 1-acetoxy-1-(5, 6, 7, 8 - tetrahydro - 5, 5, 8, 8-tetramethyl-2-naphthyl) ethane. Absolute configuration of resulting secondary carbinols ( 4a and 4b ) was assigned using lanthanide induced shifts NMR experiments on MTPA esters of 4a and 4b . Only the enantiomer (R-(−)- IIa ) is active on the differentiation of F9 embryonal teratocarcinoma cells (F9 cells).
- Published
- 1995
43. Palladium-catalyzed cascade allylation/carbopalladation/cross coupling: a novel three-component reaction for the synthesis of 3,3-disubstituted-2,3-dihydrobenzofurans
- Author
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Magali Szlosek-Pinaud, Jean Martinez, Philippe Diaz, Frédéric Lamaty, Institut des Biomolécules Max Mousseron [Pôle Chimie Balard] (IBMM), and Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Montpellier (UM)-Ecole Nationale Supérieure de Chimie de Montpellier (ENSCM)
- Subjects
Component (thermodynamics) ,010405 organic chemistry ,Stereochemistry ,Organic Chemistry ,chemistry.chemical_element ,General Medicine ,010402 general chemistry ,01 natural sciences ,Biochemistry ,Combinatorial chemistry ,3. Good health ,0104 chemical sciences ,Catalysis ,Coupling (electronics) ,chemistry ,Cascade ,Drug Discovery ,[CHIM]Chemical Sciences ,ComputingMilieux_MISCELLANEOUS ,Palladium - Abstract
A novel one-pot palladium-catalyzed cascade between 2-iodophenol, methyl bromomethylacrylate and an arylboronic acid provides an efficient access to heterocycles possessing the 3,3-disubstituted-2,3-dihydrobenzofuran skeleton via allylation/carbopalladation/Suzuki cross-coupling.
- Published
- 2003
44. ChemInform Abstract: Suzuki-Miyaura Cross-Coupling of Benzylic Bromides under Microwave Conditions
- Author
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Kevin C. Rider, Charles M. Keyari, Steven W. McDaniel, Philippe Diaz, and Nicholas R. Natale
- Subjects
body regions ,Coupling ,chemistry.chemical_compound ,Field (physics) ,chemistry ,Chemical physics ,fungi ,General Medicine ,respiratory system ,Isoxazole ,skin and connective tissue diseases ,human activities ,Microwave - Abstract
The optimized conditions allow the preparation of a library of structurally diverse products what is of interest for SAR studies in the field of isoxazole drugs.
- Published
- 2012
45. Suzuki-Miyaura Cross-Coupling of Benzylic Bromides Under Microwave Conditions
- Author
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Steven W. McDaniel, Charles M. Keyari, Philippe Diaz, Kevin C. Rider, and Nicholas R. Natale
- Subjects
chemistry.chemical_classification ,Coupling ,Base (chemistry) ,Chemistry ,Ligand ,Organic Chemistry ,chemistry.chemical_element ,Biochemistry ,Article ,Catalysis ,Potassium carbonate ,Solvent ,chemistry.chemical_compound ,Drug Discovery ,Polymer chemistry ,Microwave ,Palladium - Abstract
A procedure for benzylic Suzuki-Miyaura cross-coupling under microwave conditions has been developed. These conditions allowed for heterocyclic compounds to be coupled. Optimum conditions found were Pd(OAc)(2), JohnPhos as the catalyst and ligand, potassium carbonate as base, and DMF as the solvent. Using these conditions, a library of structurally diverse compounds was synthesized.
- Published
- 2011
46. Neuroinflammation, hyperphosphorylated tau, diffuse amyloid plaques, and down-regulation of the cellular prion protein in air pollution exposed children and young adults
- Author
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Zhaowei Hua, Michelle L. Block, Philippe Diaz, Rafael Reynoso-Robles, Norma Osnaya, Ruixin Guo, Angélica González-Maciel, Hongtu Zhu, George Perry, Lilian Calderón-Garcidueas, Michael P. Kavanaugh, Ricardo Delgado-Chávez, Rodolfo Villarreal-Calderon, Ricardo Torres-Jardón, and Amedeo D'Angiulli
- Subjects
Apolipoprotein E ,Adult ,Male ,Adolescent ,Prions ,Down-Regulation ,Inflammation ,Plaque, Amyloid ,tau Proteins ,Neuropathology ,medicine.disease_cause ,Neuroprotection ,Cohort Studies ,Young Adult ,Air Pollution ,medicine ,Humans ,Gene Regulatory Networks ,Phosphorylation ,Child ,Mexico ,Neuroinflammation ,Regulation of gene expression ,business.industry ,General Neuroscience ,Neurodegeneration ,Age Factors ,Infant ,General Medicine ,medicine.disease ,Frontal Lobe ,Psychiatry and Mental health ,Clinical Psychology ,Child, Preschool ,Immunology ,Encephalitis ,Female ,Geriatrics and Gerontology ,medicine.symptom ,business ,Oxidative stress - Abstract
Air pollution exposures have been linked to neuroinflammation and neuropathology. Autopsy samples of the frontal cortex from control (n = 8) and pollution-exposed (n = 35) children and young adults were analyzed by RT-PCR (n = 43) and microarray analysis (n = 12) for gene expression changes in oxidative stress, DNA damage signaling, NFκB signaling, inflammation, and neurodegeneration pathways. The effect of apolipoprotein E (APOE) genotype on the presence of protein aggregates associated with Alzheimer's disease (AD) pathology was also explored. Exposed urbanites displayed differential (>2-fold) regulation of 134 genes. Forty percent exhibited tau hyperphosphorylation with pre-tangle material and 51% had amyloid-β (Aβ) diffuse plaques compared with 0% in controls. APOE4 carriers had greater hyperphosphorylated tau and diffuse Aβ plaques versus E3 carriers (Q = 7.82, p = 0.005). Upregulated gene network clusters included IL1, NFκB, TNF, IFN, and TLRs. A 15-fold frontal down-regulation of the prion-related protein (PrP(C)) was seen in highly exposed subjects. The down-regulation of the PrP(C) is critical given its important roles for neuroprotection, neurodegeneration, and mood disorder states. Elevation of indices of neuroinflammation and oxidative stress, down-regulation of the PrP(C) and AD-associated pathology are present in young megacity residents. The inducible regulation of gene expression suggests they are evolving different mechanisms in an attempt to cope with the constant state of inflammation and oxidative stress related to their environmental exposures. Together, these data support a role for air pollution in CNS damage and its impact upon the developing brain and the potential etiology of AD and mood disorders.
- Published
- 2011
47. ChemInform Abstract: Synthesis of Bridged Bicyclic β-Trifluoroacetoxy β- Trifluoromethyl α-Amino Acid Derivatives by an Original Dakin- West/Diels-Alder Tandem Sequence
- Author
-
Philippe Diaz, Thierry Cufos, and Lucien Stella
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,Trifluoromethyl ,Tandem ,chemistry ,Bicyclic molecule ,Stereochemistry ,Diels alder ,General Medicine ,Amino acid ,Sequence (medicine) - Published
- 2010
48. ChemInform Abstract: Chemoenzymatic Synthesis of Enantiomers of a New Retinoid to Investigate the Role of Chirality in the Biological Response
- Author
-
Corinne Millois, Bruno Charpentier, Michele Vion, Jean-Michel Bernardon, Braham Shroot, Philippe Diaz, and Bruno F Antibes Fr Bernard
- Subjects
Lanthanide ,biology ,Chemistry ,medicine.drug_class ,Stereochemistry ,Absolute configuration ,General Medicine ,Teratocarcinoma ,biology.protein ,medicine ,Retinoid ,Lipase ,Enantiomer ,Chirality (chemistry) - Abstract
We have prepared both enantiomers of a new retinoid ( IIa and IIb ) partly by using lipase resolution of 1-acetoxy-1-(5, 6, 7, 8 - tetrahydro - 5, 5, 8, 8-tetramethyl-2-naphthyl) ethane. Absolute configuration of resulting secondary carbinols ( 4a and 4b ) was assigned using lanthanide induced shifts NMR experiments on MTPA esters of 4a and 4b . Only the enantiomer (R-(−)- IIa ) is active on the differentiation of F9 embryonal teratocarcinoma cells (F9 cells).
- Published
- 2010
49. ChemInform Abstract: Synthesis and Biological Activities of New Heterocyclic Aromatic Retinoids
- Author
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S. Michel, Lucien Stella, Bruno Charpentier, and Philippe Diaz
- Subjects
chemistry.chemical_classification ,Binding profile ,Retinoic acid receptor ,Chemistry ,Stereochemistry ,Carboxylic acid ,General Medicine ,Ring (chemistry) ,Affinities - Abstract
A series of 3-aryl-2H-1-benzopyrancarboxylic acid derivatives was synthesized and evaluated as Retinoic Acid Receptor (RAR) agonists. By modifications of the 3-aryl group, we have obtained new retinoids exhibiting potent cellular differentiating activities and high affinities for RARs. Moreover, hydrogenation of the 2H-1-benzopyran ring led to the 3-(5,6,7,8-tetrahydro-5,5,8,8,-tetramethyl-naphthalen-2-yl)-3,4-dihydro-2H-1-benzopyran-7-yl carboxylic acid, characterized by a RARs binding profile.
- Published
- 2010
50. ChemInform Abstract: New Synthetic Retinoids Obtained by Palladium-Catalyzed Tandem Cyclization-Hydride Capture Process
- Author
-
Lucien Stella, Fabrice Gendre, Bruno Charpentier, and Philippe Diaz
- Subjects
Tandem ,Hydride ,Chemistry ,Scientific method ,chemistry.chemical_element ,General Medicine ,Combinatorial chemistry ,Palladium ,Catalysis - Published
- 2010
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