cas 7459-33-8, LINOLEOYL CHLORIDE | Articles data

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Linoleic acid esters of hydroxy linoleic acids are anti-inflammatory lipids found in plants and mammals
Fatty acid esters of hydroxy fatty acids (FAHFAs) are a recently discovered class of biologically active lipids. Here we identify the linoleic acid ester of 13-hydroxy linoleic acid (13-LAHLA) as an anti-inflammatory lipid. An oat oil fraction and FAHFA-enriched extract from this fraction showed anti-inflammatory activity in a lipopolysaccharide-induced cytokine secretion assay. Structural studies identified three LAHLA isomers (15-, 13-, and 9-LAHLA) as being the most abundant FAHFAs in the oat oil fraction. Of these LAHLAs, 13-LAHLA is the most abundant LAHLA isomer in human serum after ingestion of liposomes made of fractionated oat oil, and it is also the most abundant endogenous LAHLA in mouse and human adipose tissue. As a result, we chemically synthesized 13-LAHLA for biological assays. 13-LAHLA suppresses lipopolysaccharide-stimulated secretion of cytokines and expression of pro-inflammatory genes. These studies identify LAHLAs as an evolutionarily conserved lipid with anti-inflammatory activity in mammalian cells.
Kolar, Matthew J.,Konduri, Srihari,Chang, Tina,Wang, Huijing,McNerlin, Clare,Ohlsson, Lena,H?rr?d, Magnus,Siegel, Dionicio,Saghatelian, Alan
p. 10698 - 10707
(2019)
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CATIONIC LIPIDS AND USES THEREOF
The present invention relates to novel cationic lipids of formula I, and more specifically formula IV. These are used, for example, in liposomes for the delivery of nucleic acids to cells.
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Page/Page column 152-153

(2021/01/23)

GLYCEROL DERIVATIVE, PREPARATION METHOD THEREFOR, AND IMMUNOMODULATOR COMPRISING SAME AS EFFECTIVE INGREDIENT
Disclosed are a glycerol derivative that is useful for improving, preventing or treating inflammation-related diseases by inhibiting overexpression of various inflammatory cytokines such as IL-4, IL-6 and so on, or chemokine CXCL8 and reducing migration of HL-60 cell lines, preparation method therefor, and an immunomodulator containing the same as active ingredient. It includes a glycerol derivative represented by Chemical formula 2 or 3 in the specification.
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Paragraph 0076-0077

(2021/07/02)

Pharmacological and structure-activity relationship studies of oleoyl-lysophosphatidylinositol synthetic mimetics
Metabolic diseases, such as obesity and type 2 diabetes, are relentlessly spreading worldwide. The beginning of the 21st century has seen the introduction of mechanistically novel types of drugs, aimed primarily at keeping these pathologies under control. In particular, an important family of therapeutics exploits the beneficial physiology of the gut-derived glucagon-like peptide-1 (GLP-1), with important clinical benefits, from glycaemic control to cardioprotection. Nonetheless, these protein-based drugs act systemically as exogenous GLP-1 mimetics and are not exempt from side effects. The food-derived lipid oleoyl-lysophosphatidylinositol (LPI) is a potent GPR119-dependent GLP-1 secreting agent. Here we present a structure-activity relationship (SAR) study of a synthetic library of oleoyl-LPI mimetics capable to induce the physiological release of GLP-1 from gastrointestinal enteroendocrine cells (EECs). The best lead compounds have shown potent and efficient release of GLP-1 in vitro from human and murine cells, and in vivo in diabetic db/db mice. We have also generated a molecular model of oleoyl-LPI, as well as its best performing analogues, interacting with the orthosteric site of GPR119, laying foundational evidence for their pharmacological activity.
Falasca, Marco,Keating, Damien J.,Kizilkaya, Hüsün Sheyma,Kokh, Elena,Mancera, Ricardo L.,Massi, Massimiliano,Paternoster, Silvano,Rosenkilde, Mette Marie,Simpson, Peter V.
(2021/08/30)

3-PYRROLIDINE-INDOLE DERIVATIVES AS SEROTONERGIC PSYCHEDELIC AGENTS FOR THE TREATMENT OF CNS DISORDERS
The present application relates to 3-cyclic amine-indole derivatives of general Formula (I), to processes for their preparation, to compositions comprising them and to their use in activation of a serotonin receptor in a cell, as well as to treating diseases, disorders or conditions by activation of a serotonin receptor in a cell. The diseases, disorders or conditions include, for example, psychosis, mental illnesses, and other neurological diseases, disorders and conditions. Formula (I)
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Paragraph 00286

(2021/08/14)

COMPOSITION AND METHODS FOR TREATMENT OF PRIMARY CILIARY DYSKINESIA
The present invention provides, among other things, methods and compositions for treating primary ciliary dyskinesia (PCD) based on mRNA therapy. The compositions used in treatment of PCD comprise an mRNA comprising a dynein axonemal intermediate chain 1 (DNAI1) coding sequence and are administered at an effective dose and an administration interval such that at least one symptom or feature of PCD is reduced in intensity, severity, or frequency or has a delayed onset. mRNAs with optimized DNAI1 coding sequences are provided that can be administered without the need for modifying the nucleotides of the mRNA to achieve sustained in vivo function.
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Paragraph 0321

(2021/11/13)

Unsaturation and Polar Head Effect on Gelation, Bioactive Release, and Cr/Cu Removal Ability of Glycolipids
Designing of multifunctional soft and smart materials from natural sources is a useful strategy for producing safer chemicals having potential applications in biomedical research and pharmaceutical industries. Herein, eight glycolipids with variation in unsaturation of hydrophobic tail and polar headgroup size were designed. The effect of unsaturation in the tail group and headgroup size on gelation ability, and mechanical and thermal stability of glycolipid hydro/organogels was studied to understand structure and property relationship. Glycolipids are functional amphiphilic molecules having potential applications in the field of drug delivery and metal removal. The encapsulation capacity and kinetic release behavior of hydrophobic/hydrophilic bioactives like curcumin/riboflavin from the hydrophobic/hydrophilic pockets of glycolipids hydro/organogels was examined. A significant observation was that the glucamine moiety of the glycolipid headgroup plays a vital role in removal of Cr and Cu from oil/water biphasic systems. Typical functions of the glycolipid hydrogels are metal chelation and enzyme-triggered release behavior, enabled them as promising material for Cr, Cu removal from edible oils and controlled release of water soluble/insoluble bioactives.
Bojja, Sreedhar,Holey, Snehal Ashokrao,Nayak, Rati Ranjan,Sekhar, Kanaparedu P. C.,Swain, Deepak Kumar
p. 3080 - 3088
(2020/08/06)

2, 4-dinitrophenol derivative and application thereof
The present invention relates to a 2, 4-dinitrophenol derivative represented by a general formula (I) or a pharmaceutically acceptable salt thereof, in which L and R are as described in the text, anda composition comprising an effective dose of a compound of general formula (I) or a pharmaceutically acceptable salt thereof. The compound with the general formula (I) or the pharmaceutical salt thereof is used for treating the non-alcoholic fatty liver disease. The invention also discloses application of the traditional Chinese medicine composition in medicines for treating non-alcoholic steatohepatitis, hepatic steatosis, type 2 diabetes mellitus, acquired dyslipidemia, dyslipidemia, local dyslipidemia, hypertriglyceridemia, obesity, metabolic syndrome, Rette's syndrome, aging-related metabolic syndrome or insulin resistance and the like.
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Paragraph 0128-0130

(2020/08/18)

Synthesis, characterization and corrosion inhibition studies of polyunsaturated fatty acid derivatives on the acidic corrosion of mild steel: Experimental and computational studies
In an effort to make an efficient and benign CI for the purpose of acidizing, a novel range of new derivatives of polyunsaturated fatty acids (PUFA) were prepared from a group of amines and Z-9,12-octadecadienoic acid with Excellent yields. Elemental analysis, FTIR, 13C NMR and 1H NMR was employed to realize a description for the newly manufactured compound. The inhibitive action of synthesized amides was examined by means of potentiodynamic polarization techniques and weight loss measurements in 1.00 M HCl. Derivatives of Z-9,12-octadecadienoic acid amides (DA) were found to obey the Langmuir adsorption model. The hydrophobic nature of mild steel (MS) was revealed by measurement of the contact angle in the presence of CI. The experimental findings were found to be supported by quantum chemical calculations. Inhibition efficiencies were computed for various DA concentrations for inhibition against the wear of MS in 100.00 ml of 1.00 M HCl, with exposure for four days at temperatures ranging from 298 to 333 K. For a DA concentration of 100 ppm, every inhibitor molecule showed outstanding percentage inhibition efficiencies in 1.00 M HCl. Compounds 2, 3, 4, 5, 6, 7, 8 and 9 offered a robust percentage inhibition efficiency of 92.90, 86.6, 49.8, 82.7, 85.9, 96.70, 94.30 and 91.30, correspondingly, at 100 ppm. The interaction of the p-electrons in compounds with low-energy, empty Fe d-orbitals helped the inhibitive molecules (IMs) to experience adsorption and inhibit the process of anodic dissolution. When Tafel plots were employed for the compounds used in the electrochemical method, similar findings were obtained for the percentage inhibition efficiencies. Compound adsorption on the MS surface was discovered to obey Arrhenius and Transition state plots in 1.00 M HCl.
Abdulazeez, Ismail,Abubshait, Haya A.,Abubshait, Samar A.,Elsharif, Asma M.
(2020/09/17)

Antiproliferative 3-deoxysphingomyelin analogs: Design, synthesis, biological evaluation and molecular docking of pyrrolidine-based 3-deoxysphingomyelin analogs as anticancer agents
Sphingomyelins and glycerophospholipids are structurally related phospholipids. Nevertheless, glycerophospholipids analogs are known as antitumor agents while sphingomyelin analogs were reported as cytoprotective agents. Herein, we have addressed the development of 3-deoxysphingomyelin analogs as cytotoxic agents possessing modified sphingobases. Thus, pyrrolidine-based 3-deoxysphingomyelin analogs were synthesized and evaluated against a panel of cell lines representing four major types of cancers. Compounds 3d, 4d and 6d elicited better GI50 values than the FDA approved drug miltefosine. Investigation of their impact on Akt phosphorylation as a possible mechanism for the antiproliferative activity of this class of compounds revealed that these compounds might elicit a concentration-dependent mechanism via inhibition of Akt phosphorylation at the lower concentration. Molecular docking predicted their binding modes to Akt to involve polar head binding to the Pleckstrin homology domain and hydrophobic tail extension into a hydrophobic pocket connecting the Pleckstrin homology domain and the kinase domain. As a whole, the described work suggests compounds 3d, 4d and 6d as promising pyrrolidine-based 3-deoxysphingomyelin analogs for development of novel cancer therapies.
Hassan, Ahmed H.E.,Park, Hye Rim,Yoon, Yoon Mi,Kim, Hye In,Yoo, Sung Yeun,Lee, Kun Won,Lee, Yong Sup
p. 444 - 455
(2019/01/03)

GEMCITABINE AMPHIPHILE PRODRUGS
The present invention relates to improved prodrugs, and compositions thereof. In particular, it relates to amphiphilic gemcitabine prodrugs or amphiphilic prodrugs of other biologically active molecules with the capacity to make liquid crystalline nanostructured nanoparticles, and uses thereof to treat animals, including humans.
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Page/Page column 52

(2019/11/12)

LINOLEIC ACID DERIVATIVES, PHARMACEUTICAL COMPOSITION OR FOOD COMPOSITION COMPRISING SAID LINOLEIC ACID DERIVATIVES, AND THEIR USES
This invention relates to linoleic acid derivative of Formula (I) below comprising a hydrophobic part C17H31 linked to a polar head part "A": wherein said polar head part A is selected from A1 to A4 below: wherein R1 and R2 are independently selected from the group composed of H or a saturated or unsaturated, straight or branched alkyl group containing 1 to 8 carbon atoms, or R1 and R2 are linked together to form a divalent radical of formula -R1-R2-, wherein -R1-R2- is preferably -CH2-CH2- or-(CH2)3-; R3 is independently selected from the group composed of:
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Paragraph 0137; 0146-0147; 0152; 0154-0155; 0157-0158; 0160

(2019/12/16)

Cationic lipids and transfection methods
The present invention relates in part to novel cationic lipids and their use, e.g., in delivering nucleic acids to cells.
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Page/Page column 17

(2020/01/08)

Discovery of Hydrolysis-Resistant Isoindoline N -Acyl Amino Acid Analogues that Stimulate Mitochondrial Respiration
N-Acyl amino acids directly bind mitochondria and function as endogenous uncouplers of UCP1-independent respiration. We found that administration of N-acyl amino acids to mice improves glucose homeostasis and increases energy expenditure, indicating that this pathway might be useful for treating obesity and associated disorders. We report the full account of the synthesis and mitochondrial uncoupling bioactivity of lipidated N-acyl amino acids and their unnatural analogues. Unsaturated fatty acid chains of medium length and neutral amino acid head groups are required for optimal uncoupling activity on mammalian cells. A class of unnatural N-acyl amino acid analogues, characterized by isoindoline-1-carboxylate head groups (37), were resistant to enzymatic degradation by PM20D1 and maintained uncoupling bioactivity in cells and in mice.
Lin, Hua,Long, Jonathan Z.,Roche, Alexander M.,Svensson, Katrin J.,Dou, Florence Y.,Chang, Mi Ra,Strutzenberg, Timothy,Ruiz, Claudia,Cameron, Michael D.,Novick, Scott J.,Berdan, Charles A.,Louie, Sharon M.,Nomura, Daniel K.,Spiegelman, Bruce M.,Griffin, Patrick R.,Kamenecka, Theodore M.
supporting information
p. 3224 - 3230
(2018/04/23)

Amides of N-Deacetyllappaconitine and Unsaturated Fatty Acids
Amides were prepared from N-deacetyllappaconitine and unsaturated oleic, linoleic, α-linolenic, and γ-linolenic fatty acids.
Gabbasov,Tsyrlina,Yunusova
p. 947 - 950
(2018/09/27)

A General Approach to Site-Specific, Intramolecular C?H Functionalization Using Dithiocarbamates
Intramolecular hydrogen atom transfer is an established approach for the site-specific functionalization of unactivated, aliphatic C?H bonds. Transformations using this strategy typically require unstable intermediates formed using strong oxidants and have mainly targeted C?H halogenations or intramolecular aminations. Herein, we report a site-specific C?H functionalization that significantly increases the synthetic scope and convergency of reactions proceeding via intramolecular hydrogen atom transfer. Stable, isolable N-dithiocarbamates are used as precursors to amidyl radicals formed via either light or radical initiation to efficiently deliver highly versatile alkyl dithiocarbamates across a wide range of complex structures.
Na, Christina G.,Alexanian, Erik J.
supporting information
p. 13106 - 13109
(2018/09/21)

Renewable Thermoplastics Based on Lignin-Derived Polyphenols
A series of renewable triphenylmethane-type polyphenols (TPs) were synthesized from lignin-derived guaiacols (methylguaiacol and propylguaiacol) and aldehydes (4-hydroxybenzaldehyde, vanillin, and syringaldehyde). By converting guaiacols to catechols through ortho-demethylation, the newly formed phenolic para site remarkably improved the reactivity as reflected by conversion of TPs. Optimized reagent molar ratios were aldehyde/catechol (1:4) and aldehyde/H2SO4 (1:3). A typical TP (VAN-M-CAT) was converted to glycidyl ether (GE-VAN-M-CAT) to examine its feasibility as precursor to epoxy thermosets. The resulting network exhibited excellent glassy modulus (12.3 GPa), glass transition temperature (167 °C), and thermal stability, which were attributed to the rigid triphenylmethane framework, high functionality (n = 5), and high cross-link density. A fully biobased epoxy comonomer (VAN-LIN-EPO), which was prepared by esterification of VAN-M-CAT with linoleic acid followed by epoxidation, could tune the material properties. This study widens the synthesis route of fully biobased polyphenols, which can yield polymers with excellent properties.
Zhao, Shou,Abu-Omar, Mahdi M.
p. 3573 - 3581
(2017/05/16)

LIPID-LINKED PRODRUGS
This invention provides lipid-linked prodrugs having structures as set out herein. Uses of such lipid-linked prodrug compounds for treatment of various indications, and methods for making and using lipid-linked prodrugs are also provided.
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Page/Page column 42

(2017/08/01)

Selective Modulation of Protein Kinase C α over Protein Kinase C by Curcumin and Its Derivatives in CHO-K1 Cells
Members of the protein kinase C (PKC) family of serine/threonine kinases regulate various cellular functions, including cell growth, differentiation, metabolism, and apoptosis. Modulation of isoform-selective activity of PKC by curcumin (1), the active constituent of Curcuma L., is poorly understood, and the literature data are inconsistent and obscure. The effect of curcumin (1) and its analogues, 4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl oleate (2), (9Z,12Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12-dienoate (3), (9Z,12Z,15Z)-4-[(2Z,6E)-3-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-5-oxohepta-2,6-dien-1-yl]-2-methoxyphenyl octadeca-9,12,15-trienoate (4), and (1E,6E)-1-[4-(hexadecyloxy)-3-methoxyphenyl]-7-(4-hydroxy-3-methoxyphenyl)hepta-1,6-diene-3,5-dione (5), and didemethylcurcumin (6) on the membrane translocation of PKCα, a conventional PKC, and PKC, a novel PKC, has been studied in CHO-K1 cells, in which these PKC isoforms are endogenously expressed. Translocation of PKC from the cytosol to the membrane was measured using immunoblotting and confocal microscopy. 1 and 6 inhibited the TPA-induced membrane translocation of PKCα but not of PKC. Modification of the hydroxyl group of curcumin with a long aliphatic chain containing unsaturated double bonds in 2-4 completely abolished this inhibition property. Instead, 2-4 showed significant translocation of PKCα but not of PKC to the membrane. No membrane translocation was observed with 1, 6, or the analogue 5 having a saturated long chain for either PKCα or PKC. 1 and 6 inhibited TPA-induced activation of ERK1/2, and 2-4 activated it. ERK1/2 is the downstream readout of PKC. These results show that the hydroxyl group of curcumin is important for PKC activity and the curcumin template can be useful in developing isoform specific PKC modulators for regulating a particular disease state.
Pany, Satyabrata,Majhi, Anjoy,Das, Joydip
p. 2135 - 2143
(2016/05/09)

Identification and synthesis of (Z,Z)-8,11-heptadecadienyl formate and (Z)-8-heptadecenyl formate: Unsaturated aliphatic formates found in the unidentified astigmatid mite, Sancassania sp. Sasagawa (Acari: Acaridae)
We identified two aliphatic formates, (Z,Z)-8,11-heptadecadienyl formate and (Z)-8-heptad ecenyl formate in the opisthonotal gland secretions of an unidentified acarid species, namely Sancassania sp. Sasagawa. Both compounds were isolated using silica gel column chromatography and the structures were elucidated by 1H-NMR and GC/FT-IR. Further information on the double bond positions was obtained by GC-MS analysis of the corresponding dimethyl disulfide derivatives. Based on the estimated structures of the two formates and using linoleic and oleic acids as the respective starting materials, a simple four-step synthesis was achieved via Barton decarboxylation as the key step. The aliphatic formates identified in acarids thus far are neryl formate ((Z)-3,7-dimethylocta-2,6-dienyl formate) and lardolure (1,3,5,7-tetramethyldecyl formate), and both have been reported to have pheromone functions. The biological function of the two formates isolated in this study is currently being investigated. Although we can speculate that the two compounds were biosynthesized from linoleic and oleic acid, there is a possibility that the synthetic processes featured a novel chain shortening and formic acid esterification mechanism.
Shimizu, Nobuhiro,Sakata, Daisuke,Miyazaki, Honami,Shimura, Yasuhiro,Kuwahara, Yasumasa
(2016/07/06)

Synthesis and biological evaluation of macamides derivatives as potent inhibitors of breast cancer cell MCF-7
A series of macamides (1-4) and their synthetic analogs (5-14) were synthesized and evaluated for in vitro inhibitory activities against breast cancer cell MCF-7. The results of bioactive assay showed that two of the macamides (compound 1 and 4) and one synthetic analog (compound 5) displayed comparable inhibitory activities against MCF-7 cell line, with IC50 values of 29.6, 36.2 and 27.2 μM, respectively.
Liang, Xiao Xia,Xiong, Cheng,He, Min,He, Changliang,Yin, Zhongqiong
p. 489 - 494
(2016/07/19)

IMPROVED COMPOSITIONS AND METHODS FOR THE DELIVERY OF NUCLEIC ACIDS
The present invention provides compositions and methods for the delivery of therapeutic agents to cells. In particular, these include novel lipids and nucleic acid-lipid particles that provide efficient encapsulation of nucleic acids and efficient delivery of the encapsulated nucleic acid to cells in vivo. The compositions of the present invention are highly potent, thereby allowing effective knock-down of specific target protein at relatively low doses. In addition, the compositions and methods of the present invention are less toxic and provide a greater therapeutic index compared to compositions and methods previously known in the art.
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Paragraph 0237

(2016/08/17)

Transdermal Penetration Enhancer and Their Uses
The present invention relates to a transdermal penetrating enhancer comprising an amino sugar-fatty acid conjugate. The conjugate included in the transdermal penetrating enhancer of the present invention can be industrially used in a cosmetic industry pursuing skin health and aesthetic enhancement of skin, and as well as used as a key material for a formulation of a transdermal drug delivery system. The transdermal penetrating enhancer of the present invention has effect of increasing permeability of a bioactive material or a drug into skin. Also, in some cases, the transdermal penetrating enhancer of the present invention can be applied as a single preparation for the therapeutic purpose by preparing a conjugate including a certain drug. Moreover, since the transdermal penetrating enhancer of the present invention uses a conjugate including a material in which skin safety is ensured, the transdermal penetrating enhancer can be applied to various fields besides a cosmetic or medicinal field.
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Paragraph 0095; 0096

(2019/08/07)

Synthesis and evaluation of fatty acid amides on the N-oleoylethanolamide-like activation of peroxisome proliferator activated receptor α
A series of fatty acid amides were synthesized and their peroxisome proliferator-activated receptor α (PPAR-α) agonistic activities were evaluated in a normal rat liver cell line, clone 9. The mRNAs of the PPAR-α downstream genes, carnitine-palmitoyltransferase-1 and mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase, were determined by real-time reverse transcription-polymerase chain reaction (RT-PCR) as PPAR-α agonistic activities. We prepared nine oleic acid amides. Their PPAR-α agonistic activities were, in decreasing order, N-oleoylhistamine (OLHA), N-oleoylglycine, Oleamide, N-oleoyltyramine, N-oleoylsertonin, and Olvanil. The highest activity was found with OLHA. We prepared and evaluated nine N-acylhistamines (N-acyl-HAs). Of these, OLHA, C16:0-HA, and C18:1Δ9-trans-HA showed similar activity. Activity due to the different chain length of the saturated fatty acid peaked at C16:0-HA. The PPAR-α antagonist, GW6471, inhibited the induction of the PPAR-α downstream genes by OLHA and N-oleoylethanolamide (OEA). These data suggest that N-acyl-HAs could be considered new PPAR-α agonists.
Takao, Koichi,Noguchi, Kaori,Hashimoto, Yosuke,Shirahata, Akira,Sugita, Yoshiaki
p. 278 - 285
(2015/04/22)

MULTI-DAY DELIVERY OF BIOLOGICALLY ACTIVE SUBSTANCES
Compositions and methods for modifying biologically active substances to achieve multi-day delivery of such substances, particularly through oral or parenteral administration, are disclosed. The compositions include the biologically active substance conjugated to a carrier having a suitably long half life, typically more than one day, wherein the conjugate optionally contains a spacer linking the carrier to the biologically active substance. Pharmaceutical formulations of the conjugates are also disclosed, as are methods of extending delivery of a single dose of a biologically active substance for more than one day.
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Paragraph 0112

(2015/09/22)

DNA SYNTHASE INHIBITOR
PROBLEM TO BE SOLVED: To provide a compound having DNA synthase inhibitory activity, and a pharmaceutical composition comprising the compound as an active ingredient (DNA synthase inhibitor, anticancer agent and antiinflammatory agent). SOLUTION: A DNA synthase inhibitor comprises a compound represented by general formula (1) as an active ingredient. An example of the compound is carboxylate ester of plumbagin (5-hydroxy-2-methyl-1,4-naphthoquinone). COPYRIGHT: (C)2015,JPO&INPIT
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Paragraph 0112-0114

(2016/10/10)

LIPIDIC FURAN, PYRROLE, AND THIOPHENE COMPOUNDS FOR TREATMENT OF CANCER, NEUROLOGICAL DISORDERS, AND FIBROTIC DISORDERS
Compounds, methods, and compositions are provided for the treatment of cancer, neurological disorders, and fibrotic disorders. Specifically, the invention includes administering an effective amount of a compound of Formula I, II, or III, or a pharmaceutically acceptable composition, salt, isotopic analog, prodrug, or combination thereof, to a subject suffering from a cancer, neurological disorder, or fibrotic disorder.
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Page/Page column 41; 45

(2014/10/15)

Synthesis, molecular characterization and preliminary antioxidant activity evaluation of quercetin fatty esters
Quercetin shows interesting pharmacological effects, but its use in topical applications is limited by its low skin permeability and solubility. In this work, the synthesis of highly lipophilic quercetin esters with oleic, linoleic and linolenic acid useful as topical quercetin prodrugs is reported. Partial OH esterification is advisable to maintain the antioxidant activity of these compounds; tetraesters and triesters can be achieved by modulating the reaction conditions utilized for the total esterification of quercetin. The chemical structures of the esters were proven by spectroscopic techniques; quantum chemical NMR calculation were mandatory to unequivocally assign the free position in triesters. Finally, the antioxidant activity of all the synthesized compounds was determined by the 2,2-diphenyl-1-picryl-hydrazyl method and by 2,2-azinobis(3-ethyl-benzothiazoline-6-sulfonic acid) assay.
Mainini, Francesca,Contini, Alessandro,Nava, Donatella,Corsetto, Paola Antonia,Rizzo, Angela Maria,Agradi, Elisabetta,Pini, Elena
p. 1751 - 1759
(2013/11/19)

Analogs of 2-arachidonoylglycerin containing the no-donor group
1, 3-Dinitroglyceryl esters of fatty acids, analogs of endocannabinoid 2-arachidonoylglycerin, were synthesized. Various methods for esterifying fatty acids with glycerine dinitrate were developed.
Serkov,Gretskaya,Bezuglov
p. 367 - 370
(2012/10/30)

PROTEIN MODIFICATION FROM THE OXIDATION OF CLICKABLE POLYUNSATURATED FATTY ACID ANALOGS
Clickable polyunsaturated fatty acid analogs, methods of using these analogs and kits comprising these analogs.
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Page/Page column 94

(2011/07/09)

Improved LC-MS method for the determination of fatty acids in red blood cells by LC-orbitrap MS
We report a new method for fast and sensitive analyses of biologically relevant fatty acids (FAs) in red blood cells (RBC) by liquid chromatography mass spectrometry (LC-MS). A new chemical derivatization approach was developed forming picolylamides from FAs in a quantitative reaction. Fourteen derivatized FA standards, including saturated and unsaturated FAs from C14 to C22, were efficiently separated within 15 min. In addition, the use of a recently introduced benchtop orbitrap mass spectrometer under positive electrospray ionization (ESI) full scan mode showed a 2-10-fold improvement in sensitivity compared with a conventional tandem MS method, with a limit of detection in the low femtomole range for saturated and unsaturated FAs. The developed method was applied to determine FA concentrations in RBC with intra- and interday coefficients of variation below 10%.
Li, Xingnan,Franke, Adrian A.
experimental part
p. 3192 - 3198
(2011/11/04)

Inhibitory effect of novel 5-O-acyl juglones on mammalian DNA polymerase activity, cancer cell growth and inflammatory response
We previously found that vitamin K3 (menadione, 2-methyl-1,4-naphthoquinone) inhibits the activity of human mitochondrial DNA polymerase γ (pol γ). In this study, we focused on juglone (5-hydroxy-1,4-naphthoquinone), which is a 1,4-naphthoquinone derivative, and chemically synthesized novel juglones conjugated with C2:0 to C22:6 fatty acid (5-O-acyl juglones). The chemically modified juglones enhanced mammalian pol inhibition and their cytotoxic and anti-inflammatory activities. The juglone conjugated with oleic acid (C18:1-acyl juglone) showed the strongest inhibition of DNA replicative pol α activity and human colon carcinoma (HCT116) cell growth in 10 synthesized 5-O-acyl juglones. C12:0-Acyl juglone was the strongest inhibitor of DNA repair-related pol λ, as well as the strongest suppression of the production of tumor necrosis factor (TNF)-α production induced by lipopolysaccharide (LPS) in the compounds tested. Moreover, this compound caused the greatest reduction in 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced acute inflammation in mouse ears. C12:0- and C18:1-Acyl juglones selectively inhibited the activities of mammalian pol species, but did not influence the activities of other pols and DNA metabolic enzymes tested. These data indicate that the novel 5-O-acyl juglones target anti-cancer and/or anti-inflammatory agents based on mammalian pol inhibition. Moreover, the results suggest that acylation of juglone is an effective chemical modification to improve the anti-cancer and anti-inflammation of vitamin K3 derivatives, such as juglone.
Maruo, Sayako,Kuriyama, Isoko,Kuramochi, Kouji,Tsubaki, Kazunori,Yoshida, Hiromi,Mizushina, Yoshiyuki
experimental part
p. 5803 - 5812
(2011/11/05)

Nonionic diethanolamide amphiphiles with unsaturated C18 hydrocarbon chains: Thermotropic and lyotropic liquid crystalline phase behavior
The neat and lyotropic liquid crystalline phase behavior of three nonionic diethanolamide amphiphiles with C18 hydrocarbon chains containing one, two or three unsaturated bonds has been examined. This has allowed the effect of degree of unsaturation on the phase behavior of diethanolamide amphiphiles to be investigated. Neat linoleoyl and linolenoyl diethanolamide undergo a transition from a glassy liquid crystal to a liquid crystal at ～-85 °C, while neat oleoyl diethanolamide undergoes a transition at ～-60 °C to a liquid crystalline material before re-crystallizing at -34 °C. Oleoyl diethanolamide then undergoes a third transition from a crystalline phase to a smectic liquid crystalline phase at ～5 °C. In the absence of water, the transition temperature from a smectic liquid crystal to an isotropic liquid decreases with increasing unsaturation. The addition of water results in the formation of a lamellar phase (Lα) for all three amphiphiles. The lamellar phase is stable under excess water conditions up to temperatures of at least 70 °C. Approximate partial binary amphiphile-water phase diagrams generated for the three unsaturated C18 amphiphiles indicate that the excess water point for each amphiphile occurs at ～60% (w/w) amphiphile. the Owner Societies 2011.
Sagnella, Sharon M.,Conn, Charlotte E.,Krodkiewska, Irena,Drummond, Calum J.
experimental part
p. 13370 - 13381
(2012/05/19)

Synthesis and biological evaluation of isoflavone fatty acid esters with potential weight loss and hypolipidemic activities
A series of isoflavone fatty acid esters were designed on the basis of endogenous oleoyl-estrone using estrogen moiety modification strategy. Ten new compounds were synthesized, and their body weight loss and hypolipidemic bioactivities were assayed. Some of these novel compounds could effectively inhibit the differentiation of 3T3-L1 preadipocytes in vitro. The most potent compound 1a significantly decreased the body weight and white adipose tissue weight in a high-fat diet-induced rat model. Also, compound 1a showed good hypolipidemic activity and low toxicity.
Xiang, Hua,Zhao, Wei,Xiao, Hong,Qian, Lei,Yao, Yao,Li, Xiao-Bo,Liao, Qing-Jiang
experimental part
p. 3036 - 3042
(2010/07/06)

Tryptamine-derived alkaloids from Annonaceae exerting neurotrophin-like properties on primary dopaminergic neurons
N-fatty acyl tryptamines constitute a scarce group of natural compounds mainly encountered in Annonaceous plants. No biological activity was reported so far for these rare molecules. This study investigated the neurotrophic properties of these natural tryptaminic derivatives on dopaminergic (DA) neurons in primary mesencephalic cultures. A structure-activity relationships study led us to precise the role of a nitrogen atom into the aliphatic chain conferring to the compounds a combined neuroprotective and neuritogenic activity in the nanomolar range. The potent antioxidant activity of these natural products seems to be involved in part of their mechanism of action. This study provides the first description of natural neurotrophin mimetics present in Annonaceae extracts, and led to the biological characterization of compounds, which present a potential interest in neurodegenerative diseases such as Parkinson's disease.
Schmidt, Fanny,Douaron, Gael Le,Champy, Pierre,Amar, Majid,Seon-Meniel, Blandine,Raisman-Vozari, Rita,Figadere, Bruno
experimental part
p. 5103 - 5113
(2010/09/11)

Pitfalls in the sample preparation and analysis of N-acylethanolamines
N-acylethanolamines (NAEs) are a group of lipid mediators synthesized in response to a number of physiological and pathological stimuli. Because of the low tissue concentrations of NAEs, analyses often include liquid extraction followed by solid-phase extraction and subsequent quantitation by LC/MS or GC/MS. Reported levels of NAEs vary considerably, however, and often no explanation is given for these discrepancies. Brought on by difficulties encountered during method development, the effects of using four different brands of silica-containing solid phase extraction (SPE) columns and five different brands of chloroform for sample preparation were investigated. Considerable variation in the retention and recoveries of seven NAEs and 2-arachidonoylglycerol existed between the SPE columns. Furthermore, it was found that some chloroforms contained quantifiable amounts of N-palmitoylethanolamine and N-stearoylethanolamine. Finally, it was found that use of one of the chloroforms resulted in a loss of N-oleoylethanolamine from solution due to addition of chlorine to the ω-9 bond. The identity of this reaction product was confirmed by LC-MS/MS and NMR. It is recommended that these aspects of sample preparation and analysis should be thoroughly validated during method development and the relevant information on specific brands used be reported in future communications in order to better estimate the validity of reported quantitative data. Copyright
Skonberg, Christian,Artmann, Andreas,Cornett, Claus,Hansen, Steen Honore,Hansen, Harald S.
body text
p. 3062 - 3073
(2011/02/22)

Heterofibrins: Inhibitors of lipid droplet formation from a deep-water southern Australian marine sponge, Spongia (Heterofibria) sp.
A bioassay-guided search for inhibitors of lipid droplet formation in a deep-water southern Australian marine sponge, Spongia (Heterofibria) sp., yielded six new compounds, fatty acids heterofibrins A1 (1) and B1 (4), along with related monolactyl and dilactyl esters, heterofibrins A2 (2), B2 (5), A3 (3) and B3 (6). Heterofibrin structures were assigned on the basis of detailed spectroscopic analysis, with comparison to chiral synthetic model compounds. All heterofibrins possess a diyne-ene moiety, while the monolactyl and dilactyl moiety featured in selected heterofibrins is unprecedented in the natural products literature. SAR by co-metabolite studies on the heterofibrins confirmed them to be non-cytotoxic, with the carboxylic acids 1 and 4 inhibiting lipid droplet formation in A431 fibroblast cell lines. Such inhibitors have potential application in the management of obesity, diabetes and atherosclerosis. The Royal Society of Chemistry 2010.
Salim, Angela A.,Rae, James,Fontaine, Frank,Conte, Melissa M.,Khalil, Zeinab,Martin, Sally,Parton, Robert G.,Capon, Robert J.
experimental part
p. 3188 - 3194
(2010/08/21)

Creatine-fatty acids
The present invention describes compounds produced from a creatine molecule and a fatty acid molecule. The compounds being in the form of creatine-fatty acid compounds being bound by an anhydride linkage, or mixtures thereof made by reacting creatine or derivatives thereof with an appropriate fatty acid previously reacted with a thionyl halide. The administration of such molecules provides supplemental creatine with enhanced bioavailability and the additional benefits conferred by the specific fatty acid.
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(2008/06/13)

CREATINE-FATTY ACIDS
The present invention describes compounds produced from a creatine molecule and a fatty acid molecule. The compounds being in the form of creatine-fatty acid compounds being bound by an anhydride linkage, or mixtures thereof made by reacting creatine or derivatives thereof with an appropriate fatty acid previously reacted with a thionyl halide. The administration of such molecules provides supplemental creatine with enhanced bioavailability and the additional benefits conferred by the specific fatty acid. Formula (I).
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(2008/12/08)

Self-assembling structures of long-chain sugar-based amphiphiles influenced by the introduction of double bonds
Nine phenyl glucoside or galactoside amphiphiles possessing a saturated or unsaturated long alkyl-chain group as the self-assembling unit of a highly organized molecular architecture were synthesized. Their self-assembly properties were investigated by using energy-filtering TEM (EF-TEM), SEM, CD, XRD, and FT-IR techniques. Compound 2, possessing one cis double bond in the lipophilic portion, exhibited twisted helical fibers, which formed a bilayered structure with a 3.59 nm period, while 3 exhibited helical ribbons and left-handed nanotubu-lar structures with 150-200 nm inner diameters and a wall thickness of approximately 20 nm. Very interestingly, 4, possessing three cis double bonds, exhibited a nanotubular structure with an inner diameter of approximately 70 nm and a d spacing value of 4.62 nm. On the other hand, 7, possessing two trans double bonds in the lipophilic region, exhibited crystal- or plate-like structures, which formed a bilayer structure with a d spacing value of 3.93 nm. These results indicate that the self-assembly properties are strongly dependent on the type of double bond. Furthermore, 8 and 9, with the galactopyr anose moiety, revealed helical ribbon and well-defined double helical fiber structures, respectively. These findings support the view that the orientation of the intermolecular hydrogen-bonding interaction between the sugar moieties plays a critical role in producing the nanotubular structures. According to CD and powder XRD experiments, the relatively strong intermolecular hydrogen-bonding interaction of the glucopyranoside moiety in 3 and 4 provided a highly ordered chiral packing structure. Even though these compounds formed a weak hydrophobic interaction between lipophilic groups, it led to the formation of the nanotubular structure.
Jung, Jong Hwa,Do, Youngkyu,Lee, Young-A.,Shimizu, Toshimi
p. 5538 - 5544
(2007/10/03)

Acyl-CoA: Cholesterol acyltransferase inhibitory activities of fatty acid amides isolated from Mylabris phalerate Pallas
Unsaturated fatty acid amides, 9(Z)-octadecenamide (2) and 9(Z),12(Z)-octadecadienamide (4) as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT) were isolated from the ethyl acetate extracts of the insect, Mylabris phalerate Pallas, and elucidated by their spectroscopic data analysis. Compounds 2 and 4 inhibited rat liver microsomal ACAT, hACAT-1, and hACAT-2 with IC50 values of 170, 85, and 63μM for 2 and of 151, 53, and 45μM for 4, respectively.
Xu, Ming-Zhe,Lee, Woo Song,Kim, Mi Jeong,Park, Doo-Sang,Yu, Hana,Tian, Guan-Rong,Jeong, Tae-Sook,Park, Ho-Yong
p. 4277 - 4280
(2007/10/03)

Hemisynthesis and preliminary evaluation of novel endocannabinoid analogues
Three new endocannabinoid analogues in which amide moiety was replaced either by oxomethylene group or ester moiety with simultaneous substitution of both α-hydrogens with methyl groups were synthesized and their abilities to interact with CB1-receptor and FAAH were investigated.
El Fangour, Siham,Balas, Laurence,Rossi, Jean-Claude,Fedenyuk, Andrey,Gretskaya, Natalia,Bobrov, Mikhail,Bezuglov, Vladimir,Hillard, Cecilia J.,Durand, Thierry
p. 1977 - 1980
(2007/10/03)

A divergent synthesis of [1-14C]-mono-E isomers of fatty acids
A convenient synthesis of [1-14C]-mono-trans fatty acid using olefin inversion as a key-step is described. This methodology allows for a facile synthesis of [1-14C]-labelled mono-trans analogues of oleic, linoleic and linolenic acids. As an example, only eleven steps were necessary to obtain the [1-14C]-mono-E isomers of linolenic acid from its commercial all-Z form. In the first step, Barton's decarboxylation procedure yielded a bromo intermediate. Epoxidation of this compound resulted in the formation of three monoepoxides, which could be separated by HPLC. After identification by 1H NMR and MS, the pure monoepoxides were then subjected to inversion consisting of a stereospecific deoxygenation followed by a β-elimination step. Finally, the labelling was introduced by substitution of the bromine by a [14C]-cyano group followed by hydrolysis.
Georgin,Taran,Mioskowski
p. 83 - 91
(2007/10/03)

Addition of organocerium reagents to morpholine amides: synthesis of important pheromone components of Achaea janata.
Readily preparable morpholine amides hitch in good yields with organocerium reagents to produce ketones. Even in the presence of substrates and reagents with high steric hindrance, the organometallic compounds prepared from dry cerium(III) chloride and organomagnesium or organolithium compounds at -78 degrees C add cleanly to morpholine amides. The low cost of starting materials makes this new scheme of synthesis very interesting for the preparation of biologically important pheromones.
Badioli, Michele,Ballini, Roberto,Bartolacci, Massimo,Bosica, Giovanna,Torregiani, Elisabetta,Marcantoni, Enrico
p. 8938 - 8942
(2007/10/03)

Studies on selectin blocker. 9. SARs of non-sugar selectin blocker against E-, P-, L-selectin bindings
As a part of study of selectin blockers, we have already reported that a non-sugar selectin antagonist (3) was successfully discovered using a computational screening (Hiramatsu, Y.; Tsukida, T.; Nakai, Y.; Inou, Y.; Kondo, H.J. Med. Chem. 2000, 43, 1476). To investigate the SARs of compound 3 against E-, P-, and L-selectins, we synthesized the derivatives of compound 3 and evaluated their inhibitory activities toward selectin bindings. The structural diversity of compound 3 contained the following: (1) and modification of the spacer unit (4-7), (2) a modification of the tail (8-11), (3), a modification of the head unit (12-18). As a result, it was found that a non-sugar based selectin blocker (3) could be a potential lead compound for E-, P-, and L-selectin blockers and wome of the derivatives showed broad and/or selective inhibitory activities toward the E-, P-, and L-selectins. In addition, it was found that the experimental evidence well supported that the computational screening using 3D-pharmacophore model could be useful methodology to find out a new lead for the several type of selectin blockers, which included a broad and/or a selective inhibitor. Copyright
Moriyama, Hideki,Hiramatsu, Yasuyuki,Kiyoi, Takao,Achiha, Toshio,Inoue, Yoshimasa,Kondo, Hirosato
p. 1479 - 1491
(2007/10/03)

Large-scale preparation of (9Z,12E)-[1-13C]-octadeca-9,12-dienoic acid, (9Z,12Z,15E)-[1-13C]-octadeca-9,12,15-trienoic acid and their [1-13C] all-cis isomers
Several grams of labelled trans linoleic and linolenic acids with high chemical and isomeric purities (>97%) have been prepared for human metabolism studies. A total of 12.5 g of (9Z,12E)-[1-13C]-octadeca-9,12-dienoic acid and 6.3 g of (9Z,12Z,15E)-[1-13C]-octadeca-9,12,15-trienoic acid were obtained in, respectively, seven steps (7.8% overall yield) and 11 steps (7% overall yield) from 7-bromo-heptan-1-ol. The trans bromo precursors used for the labelling were synthesised by using copper-catalysed couplings. The trans fatty acids were then obtained via the nitrile derivatives. A total of 23.5 g of (9Z,12Z)-[1-13C]-octadeca-9,12-dienoic acid and 10.4 g of (9Z,12Z,15Z)-[1-13C]-octadeca-9,12,15-trienoic acid were prepared in five steps in, respectively, 32 and 18% overall yield. Large quantities of bromo and chloro precursors were synthesised from the commercially available acid according to Barton's procedure. In all cases, the main impurities (>0.5%) of each labelled fatty acid have been characterised. Copyright (C) 2000 Elsevier Science Ireland Ltd.
Loreau,Maret,Poullain,Chardigny,Sebedio,Beaufrere,Noel
p. 65 - 78
(2007/10/03)

Polyunsaturated fatty acid anilides as inhibitors of acyl- COA:Cholesterol acyltransferase (ACAT)
A series of polyunsaturated fatty acid anilides were synthesized and evaluated as ACAT inhibitors. Compound 24 had potent inhibitory activity against microsomal ACAT derived from U937, HepG2 and Caco-2 cell lines. Therefore, it might be expected to act as an antiarteriosclerotic and hypocholesterolemic agent. Interestingly, the ACAT inhibitory potency of 24 varied significantly depending on the source of the enzyme.
Matsuyama, Naoto,Kosaka, Tetsuya,Fukuhara, Mina,Soda, Yasuji,Mizuno, Koji
p. 2039 - 2042
(2007/10/03)

Phytosphingosine-based ceramide I analogs
The present invention describes phytospringosine-based analogs of ceramides I, as well as cosmetics and pharmaceutical compositions containing these novel compounds and their use.
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(2008/06/13)

Novel analogues of arachidonylethanolamide (anandamide): Affinities for the CB1 and CB2 cannabinoid receptors and metabolic stability
Several analogues of the endogenous cannabinoid receptor ligand arachidonylethanolamide (anandamide) were synthesized and evaluated in order to study (a) the structural requirements for high-affinity binding to the CB1 and CB2 cannabinoid receptors and (b) their hydrolytic stability toward anandamide amidase. The series reported here was aimed at exploring structure-activity relationships (SAR) primarily with regard to stereoelectronic requirements of ethanolamido headgroup for interaction with the cannabinoid receptor active site. Receptor affinities, reported as K(i) values, were obtained by a standard receptor binding assay using [3H]CP- 55,940 as the radioligand, while stability toward the amidase was evaluated by comparing the K(i) of each analogue in the presence and absence of phenylmethanesulfonyl fluoride (PMSF), a serine protease blocker and inhibitor of anandamide amidase. Introduction of a methyl group in the 1'- and 2'-positions or substitution of the ethanolamido headgroup with a butylamido group gave analogues with vastly improved biochemical stability. This is accomplished in some cases with increased receptor affinity. Conversely, oxazolyl and methyloxazolyl headgroups led to low-affinity analogues. Substitution of the hydroxyl group with electronegative substituents such as fluoro, chloro, allyl, and propargyl groups significantly increased receptor affinity but did not influence the biochemical stability. The 2'-chloro analogue of anandamide was found to have the highest affinity for CB1. Additionally, reversing the positions of the carbonyl and NH in the amido group produces retro-anandamides possessing considerably higher metabolic stability. Replacement of the arachidonyl tail with oleyl or linoleyl results in analogues with low affinities for both receptors. All of the analogues in this study showed high selectivity for the CB1 receptor over the peripheral CB2 receptor. The most potent analogues were tested for their ability to stimulate the binding of [35S]GTPγS to G- proteins and were shown to be potent cannabimimetic agonists. The results are discussed in terms of pharmacophoric features affecting receptor affinity and enzymatic stability.
Lin, Sonyuan,Khanolkar, Atmaram D.,Fan, Pusheng,Goutopoulos, Andreas,Qin, Ce,Papahadjis, Demetris,Makriyannis, Alexandras
p. 5353 - 5361
(2007/10/03)

Two New Unsaturated Fatty Acid Ethanolamides in Brain That Bind to the Cannabinoid Receptor
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Hanus, Lumir,Gopher, Asher,Almog, Shlomo,Mechoulam, Raphael
p. 3032 - 3034
(2007/10/02)