- PHOSPHOLIPID-FLAVAGLINE CONJUGATES AND METHODS OF USING THE SAME FOR TARGETED CANCER THERAPY
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Disclosed herein are phospholipid ether (PLE) molecules. Further provided are phospholipid-flavagline conjugates. The phospholipid-flavagline conjugate may include a PLE conjugated to a flavagline via a linker. Further provided herein are methods of treating cancer in a subject and methods of targeting a drug to a tumor or cancer cell in a subject.
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Paragraph 000140
(2021/04/17)
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- Synthetic Fluorogenic Peptides Reveal Dynamic Substrate Specificity of Depalmitoylases
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Palmitoylation is a post-translational modification involving the thioesterification of cysteine residues with a 16-carbon-saturated fatty acid. Little is known about rates of depalmitoylation or the parameters that dictate these rates. Here we report a modular strategy to synthesize quenched fluorogenic substrates for the specific detection of depalmitoylase activity and for mapping the substrate specificity of individual depalmitoylases. We demonstrate that human depalmitoylases APT1 and APT2, and TgPPT1 from the parasite Toxoplasma gondii, have distinct specificities that depend on amino acid residues distal to the palmitoyl cysteine. This information informs the design of optimal and non-optimal substrates as well as isoform-selective substrates to detect the activity of a specific depalmitoylase in complex proteomes. In addition to providing tools for studying depalmitoylases, our findings identify a previously unrecognized mechanism for regulating steady-state levels of distinct palmitoylation sites by sequence-dependent control of depalmitoylation rates. Amara et al. describe a method for preparing positional scanning libraries of fluorogenic palmitoylated peptide substrates. This allowed identification of residues that are distal to the palmitoylation site that impact turnover. This information allowed the design of substrates that are selective for a specific depalmitoylating enzyme.
- Amara, Neri,Foe, Ian T.,Onguka, Ouma,Garland, Megan,Bogyo, Matthew
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p. 35 - 7,47
(2018/10/24)
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- Efficient synthesis of unsaturated 1-monoacyl glycerols for in meso crystallization of membrane proteins
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A highly efficient synthesis of unsaturated 1-monoacyl glycerols was established to fulfill the pressing need for materials that form lipidic mesophases utilized in membrane protein crystallization. Georg Thieme Verlag Stuttgart.
- Fu, Yu,Weng, Yue,Hong, Wen-Xu,Zhang, Qinghai
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experimental part
p. 809 - 812
(2011/06/21)
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- Synthesis of aromatic triols and triacids from oleic and erucic acid: separation and characterization of the asymmetric and symmetric isomers
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Hexasubstituted benzene derivatives, aromatic triols 4, 9 and triacids 5, 10 have been synthesized from oleic and erucic acid derivatives followed by a cyclotrimerization step catalyzed by palladium-on-carbon (Pd/C) and chlorotrimethylsilane (TMSCl). The asymmetric isomer, which is the main product, was isolated from its symmetric isomer by flash chromatography. All the products were fully characterized by IR, 1H NMR, 13C NMR and mass spectrometry. The products are suitable monomers for the production of polyurethanes, polyesters and polyamides.
- Yue, Jin,Narine, Suresh S.
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- In vivo studies of dialkynoyl analogues of DOTAP demonstrate improved gene transfer efficiency of cationic liposomes in mouse lung
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A novel set of dialkynoyl analogues of the cationic, gene delivery lipid DOTAP (1) was synthesized. Structure-activity studies demonstrate that replacement of the cis-double bonds of DOTAP with triple bonds in varying positions alters both the physical properties of the resultant cationic liposome-DNA complexes and their biological functionalities, both in vitro and in vivo. Particularly, in vivo studies demonstrate that pDNA transfection of mouse lung endothelial cells with lead analogue DS(14-yne)TAP (4):cholesterol lipoplexes exhibits double the transfection level with less associated toxicity relative to the well-established DOTAP:cholesterol system. In fact, 4:cholesterol delivers up to 3 times the dose of pDNA in mice than can be tolerated by DOTAP, leading to nearly 3 times greater marker-gene expression. X-ray diffraction studies suggest that lipoplexes containing analogue 4 display increased stability at physiological temperatures. Our results thus suggest that analogue 4 is a potentially strong candidate for the gene therapy of lung tumors.
- Fletcher, Steven,Ahmad, Ayesha,Perouzel, Eric,Heron, Andrew,Miller, Andrew D.,Jorgensen, Michael R.
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p. 349 - 357
(2007/10/03)
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- A dialkynoyl analogue of DOPE improves gene transfer of lower-charged, cationic lipoplexes
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Positively-charged gene delivery agents, such as cationic liposomes, typically prepared by mixing a cationic lipid and a neutral lipid in a 1: 1 molar ratio, exhibit a fundamental flaw: on the one hand, the charge encourages cell uptake; on the other hand, the charge leads to aggregation in vivo with anionic serum components. We herein report a more phase-stable analogue of the zwitterionic and fusogenic lipid DOPE that allows for the reduction of the cationic lipid component of the liposome from 50 to 9 mol% with almost no apparent loss in transfection activity. This reduction in charge may induce important in vivo stability whilst still imparting high cell uptake and transgene expression. The Royal Society of Chemistry 2006.
- Fletcher, Steven,Ahmad, Ayesha,Perouzel, Eric,Jorgensen, Michael R.,Miller, Andrew D.
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p. 196 - 199
(2007/10/03)
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- Useful Direct Conversion of Tetrahydropyranyl Ethers of Fatty Alcohols into Fatty Acids
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Tetrahydro-2-pyranyl ethers from fatty primary alcohols can be converted in a one-step procedure into the corresponding carboxylic acids in high yields.This process avoids the synthesis of symmetrical esters, particularly for long-chain compounds.This reaction proved to be useful, for instance, to produce polyunsaturated fatty acids immediately before their biological testing. - Key words: Oxidation; polyunsaturated fatty acids; tetrahydropyranyl ethers
- Gruiec, Regine,Noiret, Nicolas,Patin, Henri
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p. 1083 - 1085
(2007/10/03)
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- Quantitative Treatment of the Rotational Dynamics of Flexible-Chain Molecules. 13C NMR Relaxation Study of Hydrocarbon Chains Attached to the Fluorene Anchor
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13C spin-lattice relaxation times (T1) and nuclear Overhauser enhancements (NOEs) were measured for individual carbons in flexible-chain molecules consisting of a hydrocarbon chain attached to fluorene moiety at position 3 through an ester bond.Quantitative treatment of the relaxation data of the ring carbons revealed an anisotropic motion for all the molecules studied.The relaxation times of the chain carbons were analysed in terms of a correlation function describing multiple internal rotations about successive C-C bonds.The results (rotational diffusion constants) were used to discuss features of the chain mobility as a function of chain length and chain unsaturation.The assumptions involved in the quantitative treatment were examined and the values were compared with those of n-alkanes and lipid bilayers. - Keywords: 13C NMR spin-lattice relaxation times Rotational diffusion constants Rotational dynamics Overall and internal motions Hydrocarbon-chain esters of fluorene-3-carboxylic acid
- Pissas, D.,Dais, Photis,Mikros, E.
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p. 263 - 275
(2007/10/02)
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