- A Systematic Study of Unsaturation in Lipid Nanoparticles Leads to Improved mRNA Transfection In Vivo
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Lipid nanoparticles (LNPs) represent the leading concept for mRNA delivery. Unsaturated lipids play important roles in nature with potential for mRNA therapeutics, but are difficult to access through chemical synthesis. To systematically study the role of unsaturation, modular reactions were utilized to access a library of 91 amino lipids, enabled by the synthesis of unsaturated thiols. An ionizable lipid series (4A3) emerged from in vitro and in vivo screening, where the 4A3 core with a citronellol-based (Cit) periphery emerged as best. We studied the interaction between LNPs and a model endosomal membrane where 4A3-Cit demonstrated superior lipid fusion over saturated lipids, suggesting its unsaturated tail promotes endosomal escape. Furthermore, 4A3-Cit significantly improved mRNA delivery efficacy in vivo through Selective ORgan Targeting (SORT), resulting in 18-fold increased protein expression over parent LNPs. These findings provide insight into how lipid unsaturation promotes mRNA delivery and demonstrate how lipid mixing can enhance efficacy.
- Lee, Sang M.,Cheng, Qiang,Yu, Xueliang,Liu, Shuai,Johnson, Lindsay T.,Siegwart, Daniel J.
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supporting information
p. 5848 - 5853
(2021/02/05)
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- ROMATIC COMPOUNDS AND PHARMACEUTICAL USES THEREOF
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The present disclosure relates to compounds of the general formula (I): wherein R1, R2, R3, R4, R5, R6, and R7 may be chosen from different substituents; n is 0, 1, or 2; and X is a hydroxymethyl or a carboxylic acid or a derivative thereof, such as a carboxylate, such as a carboxylic ester, a glyceride, an anhydride, a phospholipid, a carboxamide, a phospholipid, or a prodrug thereof; or a pharmaceutically acceptable salt, solvate, solvate of such salt or a prodrug thereof. The present disclosure also relates to pharmaceutical compositions and lipid compositions comprising at least one compound according to the present disclosure, and to such compounds for use as medicaments or for use in therapy, in particular for the treatment of diseases related to metabolic diseases and liver diseases, such as non-alcoholic fatty liver disease and cholestasis diseases.
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Page/Page column 78
(2020/05/19)
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- Distal Alkenyl C-H Functionalization via the Palladium/Norbornene Cooperative Catalysis
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A distal-selective alkenyl C-H arylation method is reported through a directed palladium/norbornene (Pd/NBE) cooperative catalysis. The key is to use an appropriate combination of the directing group and the NBE cocatalyst. A range of acyclic and cyclic c
- Dong, Guangbin,Fatuzzo, Nina,Wu, Zhao
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supporting information
p. 2715 - 2720
(2020/03/10)
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- SYNTHESIS OF PHEROMONES AND RELATED MATERIALS VIA OLEFIN METATHESIS
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Methods for preparation of olefins, including 8- and 11-unsaturated monoenes and polyenes, via transition metathesis-based synthetic routes are described. Metathesis reactions in the methods are catalyzed by transition metal catalysts including tungsten-, molybdenum-, and ruthenium-based catalysts. The olefins include insect pheromones useful in a number of agricultural applications.
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Paragraph 0110; 0259
(2018/09/12)
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- Regioselective Epoxidations by Cytochrome P450 3A4 Using a Theobromine Chemical Auxiliary to Predictably Produce N-Protected β- or γ-Amino Epoxides
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N-Protected β- and γ-amino epoxides are useful chiral synthons. We report here that the enzyme cytochrome P450 3A4 can catalyze the formation of such compounds in a regio- and stereoselective manner, even in the presence of multiple double bonds or aromatic substituents. To this end, the theobromine chemical auxiliary is used not only to control the selectivity of the enzyme, but also as a masked amine, and to facilitate product recovery. Theobromine predictably directed epoxidation at the double bond of the fourth carbon from the theobromine group. Unlike with most catalysts, the selectivity did not depend on electronic or steric factors but rather on the position of the olefin relative to the theobromine group. (Figure presented.).
- Polic, Vanja,Cheong, Kin Jack,Hammerer, Fabien,Auclair, Karine
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supporting information
p. 3983 - 3989
(2017/11/30)
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- Exhaustive Suzuki-Miyaura reactions of polyhalogenated heteroarenes with alkyl boronic pinacol esters
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A novel Suzuki-Miyaura protocol is described that enables the exhaustive alkylation of polychlorinated pyridines. This method facilitates a formal synthesis of normuscopyridine and the rapid assembly of a dumbbell shaped portion of a [2]rotaxane.
- Laulhé, Sébastien,Blackburn, J. Miles,Roizen, Jennifer L.
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supporting information
p. 7270 - 7273
(2017/07/11)
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- Design and Synthesis of 2-Alkylpyrimidine-4,6-diol and 6-Alkylpyridine-2,4-diol as Potent GPR84 Agonists
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A series of alkylpyrimidine-4,6-diol derivatives were designed and synthesized as novel GRP84 agonists based on a high-throughput screening (HTS) hit 1. 6-Nonylpyridine-2,4-diol was identified as the most potent agonist of GPR84 reported so far, with an EC50 of 0.189 nM. These novel GPR84 agonists will provide valuable tools for the study of the physiological functions of GPR84.
- Liu, Yang,Zhang, Qing,Chen, Lin-Hai,Yang, Hui,Lu, Wei,Xie, Xin,Nan, Fa-Jun
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supporting information
p. 579 - 583
(2016/07/06)
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- ITRACONAZOLE ANALOGS AND USE THEREOF
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Provided herein are Itraconazole analogs. Also provided herein are methods of inhibition of Hedgehog pathway, vascular endothelial growth factor receptor 2 (VEGFR2) glycosylation, angiogenesis and treatment of disease with Itraconazole analogs.
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Paragraph 0282
(2013/03/26)
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- Itraconazole Side Chain Analogues: Structure-Activity Relationship Studies for Inhibition of Endothelial Cell Proliferation, Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) Glycosylation, and Hedgehog Signaling
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Itraconazole is an antifungal drug that was recently found to possess potent antiangiogenic activity and anti-hedgehog (Hh) pathway activity. To search for analogues of itraconazole with greater potency and to understand the structure-activity relationship in both antiangiogenic and Hh targeting activity, 25 itraconazole side chain analogues were synthesized and assayed for inhibition of endothelial cell proliferation and Gli1 transcription in a medulloblastoma (MB) culture. Through this analysis, we have identified analogues with increased potency for inhibiting endothelial cell proliferation and the Hh pathway, as well as VEGFR2 glycosylation that was recently found to be inhibited by itraconazole. An SAR analysis of these activities revealed that potent activity of the analogues against VEGFR2 glycosylation was generally driven by side chains of at least four carbons in composition with branching at the α or β position. SAR trends for targeting the Hh pathway were divergent from those related to HUVEC proliferation or VEGFR2 glycosylation. These results also suggest that modification of the sec-butyl side chain can lead to enhancement of the biological activity of itraconazole.
- Shi, Wei,Nacev, Benjamin A.,Aftab, Blake T.,Head, Sarah,Rudin, Charles M.,Liu, Jun O.
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supporting information; experimental part
p. 7363 - 7374
(2011/12/04)
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- A detailed investigation of the aza-prins reaction
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The development of a Lewis acid-promoted aza-Prins reaction to form piperidines and pyrrolidines is described. Indium trichloride has been found to be a highly successful and mild Lewis acid for promoting this reaction. A thorough mechanistic investigation is described, including the factors that influence the formation of the 5- or 6-membered ring product(s). The Royal Society of Chemistry.
- Dobbs, Adrian P.,Guesne, Sebastien J. J.,Parker, Robert J.,Skidmore, John,Stephenson, Richard A.,Hursthouse, Mike B.
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supporting information; experimental part
p. 1064 - 1080
(2010/06/13)
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- Amphiphilic organocatalyst for schotten-baumann-type tosylation of alcohols under organic solvent free condition
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A Tosylation of primary alcohol with tosyl chloride was performed effectively with an W-hexadecylimidazole catalyst in water containing K 2CO3 aggregation of the catalyst carrying a hydrophobic methylene chain worked as a substitute for organic solvent.
- Asano, Keisuke,Matsubara, Seijiro
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supporting information; experimental part
p. 1757 - 1759
(2009/09/06)
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- The first total synthesis of iPF4α-VI and its deuterated analog
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The total and stereospecific syntheses of iPF4α-VI and d4-iPF4α-VI have been accomplished. iPF4α-VI is a docosahexanenoic acid (DHA)-derived isoprostane. DHA is the most abundant polyunsaturated fatty acid in the brain. Different synthetic designs have been used for the two syntheses. In the d4-iPF4α-VI design, the deuterated part of the molecule was introduced last in the synthesis.
- Kim, Seongjin,Lawson, John A.,Praticò, Domenico,FitzGerald, Garret A.,Rokach, Joshua
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p. 2801 - 2805
(2007/10/03)
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- Enantioselective intramolecular cyclopropanation of N-allylic-and N-homoallylic diazoacetamides catalyzed by chiral dirhodium(II) catalysts
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Diazodecomposition of N-(tert-butyl)-N-(3-buten-1-yl)diazoacetamides catalyzed by dirhodium(II) tetrakis[methyl 2-pyrrolidone-5(S)-carboxylate], Rh2(5S-MEPY)4, and tetrakis[methyl 2-oxazolidinone-4(S)-carboxylate], Rh2(4S-
- Doyle, Michael P.,Eismont, Michail Y.,Protopopova, Marina N.,Kwan, Michelle M. Y.
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p. 1665 - 1674
(2007/10/02)
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- New Routes to cis-Jasmone and Dihydrojasmone via 1,4-Diketones Exploiting the Mobile Activating Sulfonyl Group
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cis-Jasmone(1a) and dihydrojasmone(1b) are synthesized starting from cis-3-hexen-1-yl phenyl sulfone (6a) and n-hexyl phenyl sulfone (6b), respectively, through 1,4-diketones 3a,b.The key intermediates in these syntheses are the diketo sulfones 7a,b, which are prepared by two methods.The reaction of dilithiosulfones 12a,b with γ-valerolactone in tetrahydrofuran in the presence of hexamethylphosphoramide at -78 deg C gives the hydroxy keto sulfones 13a,b in satisfactory yields and the successive oxidation of these compounds with Jones reagent in acetone affords 7a,b in very good yields.On the other hand, the reaction of 12a,b with ethyl levulinate ethylene ketal gives the partially protected diketo sulfones 17a,b, from which 7a,b are obtained by removal of the protecting group.Cleavage of the carbon-sulfur bond in 7a,b, accomplished by aluminum amalgam in aqueous tetrahydrofuran, affords 3a,b which are then cyclized to 1a,b by heating over basic alumina in benzene.
- Mussatto, Maria Cristina,Savoia, Diego,Trombini, Claudio,Umani-Ronchi, Achille
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p. 4002 - 4005
(2007/10/02)
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- Potassium on Alumina as a Reagent for Reductive Decyanation of Alkylnitriles.
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Highly dispersed potassium over neutral alumina (K/Al2O3), easily prepared by melting potassium over alumina in an inert atmosphere, is capable of effecting reductive cleavage of the cyano group in alkylnitriles in hexane at room temperature in 70-91percent yield.This decyanation method is applied in the key step of a novel synthesis of (Z)-9-dodecen-1-yl acetate, the sex pheromone of Paralobesia viteana.
- Savoia, Diego,Tagliavini, Emilio,Trombini, Claudio,Umani-Ronchi, Achille
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p. 3227 - 3229
(2007/10/02)
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