- Novel amphiphilic PEG-hydroxycamptothecin conjugates as glutathione-responsive prodrug nanocapsules for cancer chemotherapy
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A series of novel hydroxycamptothecin (HCPT) conjugates (13a–14d), which contained a polyethylene glycol moiety and disulfide bond, were designed and synthesized in five to six steps, with overall yields of 20–39%. The anticancer activities and toxicities of these new conjugates were evaluated using an in vitro MTT assay in K562, HepG2, and HT-29 cell lines and HUVECs. The conjugates displayed enhanced antitumor activity and reduced toxicity in comparison with their parent molecule, HCPT. Among these conjugates, compound 13a exhibited 100-fold better selectivity to the tumor cells than to HUVECs. TEM and DLS experiments demonstrated that 13a formed nanosized micelles with a diameter of approximately 200?nm in aqueous solution and that the conjugate could undergo glutathione-responsive degradation to release HCPT at the tumor site. The improved potency and reduced toxicity of these conjugates may be caused by the enhanced permeation and retention (EPR) effect of nanoparticles.
- Guo, Na,Hao, Tiantian,Shang, Xiuzhuan,Zhang, Tianle,Liu, Huan,Zhang, Qian,Wang, Jing,Jiang, Du,Rong, Yao,Teng, Yuou,Yu, Peng
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- Design and development of stable, water-soluble, human toll-like receptor 2 specific monoacyl lipopeptides as candidate vaccine adjuvants
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Antigens in modern subunit vaccines are largely soluble and poorly immunogenic proteins inducing relatively short-lived immune responses. Appropriate adjuvants initiate early innate immune responses, amplifying subsequent adaptive immune responses. Agonists of Toll-like receptor 2 (TLR2) are devoid of significant proinflammatory activity in ex vivo human blood models and yet are potently adjuvantic, suggesting that this chemotype may be a safe and effective adjuvant. Our earlier work on the monoacyl lipopeptide class of TLR2 agonists led to the design of a highly potent lead but with negligible aqueous solubility, necessitating the reintroduction of aqueous solubility. We explored several strategies of introducing ionizable groups on the lipopeptide, as well as the systematic evaluation of chemically stable bioisosteres of the ester-linked palmitoyl group. These studies have led to a fully optimized, chemically stable, and highly water-soluble human TLR2-specific agonist, which was found to have an excellent safety profile and displayed prominent adjuvantic activities in rabbit models.
- Salunke, Deepak B.,Connelly, Seth W.,Shukla, Nikunj M.,Hermanson, Alec R.,Fox, Lauren M.,David, Sunil A.
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- Zinc-acetic acid reductive cyclisation in a two-step synthesis of the S1-N10 nine-membered lactone core of ent-griseoviridin
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The synthesis of the S1-N10 nine-membered lactone core 28 of enf-griseoviridin is reported. Starting from cystine derivative 25, encompassing a terminal ynoate, treatment under Zn/AcOH conditions led to the formation of lactone 28 in 12% yield. Therefore, the lactone moiety of enf-griseoviridin is obtained in 10.7% overall yield for two steps. An access to the corresponding 5-epi-griseoviridin lactone 29 is also described.
- Chaume, Gregory,Kuligowski, Carine,Bezzenine-Laffolee, Sophie,Ricard, Louis,Pancrazi, Ange,Ardisson, Janick
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- Gd-DTPA L-cystine bisamide copolymers as novel biodegradable macromolecular contrast agents for MR blood pool imaging
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Purpose. The purpose of this study was to synthesize biodegradable Gd-DTPA l-cystine bisamide copolymers (GCAC) as safe and effective, macromolecular contrast agents for magnetic resonance imaging (MRI) and to evaluate their biodegradability and efficacy in MR blood pool imaging in an animal model. Methods. Three new biodegradable GCAC with different substituents at the cystine bisamide [R = H (GCAC), CH2CH2CH3 (Gd-DTPA l-cystine bispropyl amide copolymers, GCPC), and CH(CH3)2 (Gd-DTPA cystine bisisopropyl copolymers, GCIC)] were prepared by the condensation copolymerization of diethylenetriamine pentaacetic acid (DTPA) dianhydride with cystine bisamide or bisalkyl amides, followed by complexation with gadolinium triacetate. The degradability of the agents was studied in vitro by incubation in 15 μM cysteine and in vivo with Sprague-Dawley rats. The kinetics of in vivo contrast enhancement was investigated in Sprague-Dawley rats on a Siemens Trio 3 T scanner. Results. The apparent molecular weight of the polydisulfide Gd(III) chelates ranged from 22 to 25 kDa. The longitudinal (T 1) relaxivities of GCAC, GCPC, and GCIC were 4.37, 5.28, and 5.56 mM-1 s-1 at 3 T, respectively. The polymeric ligands and polymeric Gd(III) chelates readily degraded into smaller molecules in incubation with 15 μM cysteine via disulfide-thiol exchange reactions. The in vitro degradation rates of both the polymeric ligands and macromolecular Gd(III) chelates decreased as the steric effect around the disulfide bonds increased. The agents readily degraded in vivo, and the catabolic degradation products were detected in rat urine samples collected after intravenous injection. The agents showed strong contrast enhancement in the blood pool, major organs, and tissues at a dose of 0.1 mmol Gd/kg. The difference of their in vitro degradability did not significantly alter the kinetics of in vivo contrast enhancement of the agents. Conclusion. These novel GCAC are promising contrast agents for cardiovascular and tumor MRI, which are later cleaved into low molecular weight Gd(III) chelates and rapidly cleared from the body.
- Kaneshiro, Todd L.,Ke, Tianyi,Jeong, Eun-Kee,Parker, Dennis L.,Lu, Zheng-Rong
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- Structure-activity relationships in toll-like receptor 2-agonists leading to simplified monoacyl lipopeptides
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Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. In continuation of previously reported structure-activity relationships on this chemotype, we have determined that at least one acyl group of optimal length (C16) and an appropriately oriented ester carbonyl group is essential for TLR2-agonistic activity. The spacing between one of the palmitoyl ester carbonyl and the thioether is crucial to allow for an important H-bond, which observed in the crystal structure of the lipopeptide:TLR2 complex; consequently, activity is lost in homologated compounds. Penicillamine-derived analogues are also inactive, likely due to unfavorable steric interactions with the carbonyl of Ser 12 in TLR2. The thioether in this chemotype can be replaced with a selenoether. Importantly, the thioglycerol motif can be dispensed with altogether and can be replaced with a thioethanol bridge. These results have led to a structurally simpler, synthetically more accessible, and water-soluble analogue possessing strong TLR2-agonistic activities in human blood.
- Agnihotri, Geetanjali,Crall, Breanna M.,Lewis, Tyler C.,Day, Timothy P.,Balakrishna, Rajalakshmi,Warshakoon, Hemamali J.,Malladi, Subbalakshmi S.,David, Sunil A.
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- Effect of disulphide loop length on mechanochemical structural stability of macromolecules
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In Nature, numerous proteins have evolved to perform similar roles, such as mechanical energy dispersion in different tissues. These biological macromolecules obtain their function from their tertiary structure, but proteins with similar roles can be quite different from each other, making it hard to define what structural features could be mimicked in synthetic materials in order to improve their performance. Here, we introduce an important protein feature-disulphide loops-into synthetic polymers and study the role of the loop size on mechanical energy dispersion. By stressing these polymers in solution, we were able to show, experimentally, that the loop size, up to a certain level, has a significant effect on the chain mechanochemical fragmentation rate, indicating it is affecting the polymer unfolding in solution prior to mechanochemical scission of the polymer backbone. Importantly, this experimental study uses homopolymers, providing information on an individual parameter-loop size-which cannot be obtained from comparing different proteins. This research emphasises the use of tailor-designed polymer-peptide hybrids to study fundamental questions on protein tertiary structures.
- Wang, Feng,Diesendruck, Charles E.
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- Cationic gemini lipids with cyclen headgroups: Interaction with DNA and gene delivery abilities
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A series of novel 1,4,7,10-tetraazacyclododecane (cyclen)-based gemini cationic lipids were synthesized, and l-cystine was used as backbone between the two amphiphilic units. The liposomes formed from the lipids and DOPE could efficiently condense plasmid DNA into nanoparticles with suitable size and zeta-potentials, which might be suitable for gene transfection. These lipids were applied as non-viral gene delivery vectors, and their structure-activity relationship was studied. It was found that both the hydrophobic tails and the linking group could largely influence the transfection efficiency, and the oleylamine derived lipid gave the best transfection results, which were close to the commercially available transfection reagent lipofectamine 2000. The gemini structure would favor the gene transfection, and the transfection efficiency of the gemini lipid was much higher than the mono counterpart. Besides, these lipids have very low cytotoxicity, suggesting their good biocompatibility. Results indicate that such gemini lipids might be promising non-viral gene delivery vectors. This journal is
- Zhang, Yi-Mei,Liu, Yan-Hong,Zhang, Ji,Liu, Qiang,Huang, Zheng,Yu, Xiao-Qi
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- An efficient and scalable synthesis of potent TLR2 agonistic PAM2CSK4
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Diacylated PAM2CSK4, a highly expensive lipopeptide with desirable aqueous solubility and a broad spectrum of cytokine/chemokine induction is a most potent dual (human and murine) Toll-Like Receptor-2 (TLR2) agonist. Besides such thrilling characteristics, its synthetic process is not reported in the literature. The present report describes an efficient and scalable 20 step synthesis of PAM2CSK4 in good yield (all steps > 60%) along with a clear description of the hindrances and easy solutions adopted in each step. Overall, a convergent synthetic approach was adopted involving synthesis of appropriately protected starting materials, synthesis of a key backbone skeleton PAM2CS, synthesis of a tetralysine fragment and the final coupling to yield PAM2CSK4. Tedious column chromatography was avoided on a large scale in many steps.
- Kaur, Arshpreet,Poonam,Patil, Madhuri T.,Mehta, Surinder K.,Salunke, Deepak B.
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- t-BUTYL 2-PYRIDYL CARBONATE. A USEFUL REAGENT FOR t-BUTOXYLATION OF AMINO ACIDS
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t-Butyl 2-pyridyl carbonate, a stable crystalline compound, is found to be very efficient in the t-butoxycarbonylation of amino acids.
- Kim, Sunggak,Lee, Jae In
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- The role of disulfide-bridge on the activities of H-shape gemini-like cationic lipid based siRNA delivery
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In our previous study, a H-shape gemini-like cationic lipid (ssGLCL, formerly named as CLD), composed of two hydrophilic lysine heads and two hydrophobic oleyl alcohol tails with a bridge of the redox-active disulfide-bond, had been synthesized and used as a nanocarrier for delivering small interfering RNAs (siRNAs) into cells. In order to further elucidate the role of disulfide ( - S - S - ) bridge on the activity of ssGLCL based siRNA delivery, a comparable ccGLCL bridged with a non-reducible carbon-carbon bond was synthesized and used as control in this study. Both two H-shape GLCL molecules could individually self-assemble into cationic nanoparticles in water phase and complex with negatively-charged siRNA into nanoplexes with particle size of ~ 200 nm and zeta potential of ~ + 30 mV, and exhibit effective siRNA delivery both in vitro and in vivo. Investigation of internalization pathway displayed that both ssGLCL/siRNA and ccGLCL/siRNA nanoplexes were predominantly internalized into MCF-7 cells by the clathrin-mediated endocytosis pattern. Although a lower cellular uptake of siRNA was found in the human breast cancer MCF-7 cells, the ssGLCL/siRNA nanoplexes could exhibit similar or even stronger down-regulation effects on the targeted EGFR mRNA and protein in MCF-7 cells when compared to the ccGLCL/siRNA nanoplexes. Furthermore, mechanistic study showed that the enhanced down-regulation effects of ssGLCL/siRNA nanoplexes on targeted mRNA and protein were probably attributed to the increased release of siRNA from lysosomes to cytoplasm following the cleavage of redox-active disulfide-bridge in ssGLCL. Therefore, we believed that the redox-active H-shape ssGLCL could be a potential nanocarrier towards improving siRNA delivery.
- Ma, Xiao-Fei,Sun, Jing,Qiu, Chong,Wu, Yi-Fan,Zheng, Yi,Yu, Min-Zhi,Pei, Xi-Wei,Wei, Lin,Niu, Yu-Jie,Pang, Wen-Hao,Yang, Zhen-Jun,Wang, Jian-Cheng,Zhang, Qiang
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- Reactions of 1,3-Diketones with a Dipeptide Isothiazolidin-3-one: Toward Agents That Covalently Capture Oxidized Protein Tyrosine Phosphatase 1B
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Protein tyrosine phosphatase 1B (PTP1B) is a validated therapeutic target for the treatment of type 2 diabetes; however, the enzyme has been classified by some as an "undruggable target". Here we describe studies directed toward the development of agents that covalently capture the sulfenyl amide "oxoform" of PTP1B generated during insulin signaling events. The sulfenyl amide residue found in oxidized PTP1B presents a unique electrophilic sulfur center that may be exploited in drug and probe design. Covalent capture of oxidized PTP1B could permanently disable the intracellular pool of enzyme involved in regulation of insulin signaling. Here, we employed a dipeptide model of oxidized PTP1B to investigate the nucleophilic capture of the sulfenyl amide residue by structurally diverse 1,3-diketones. All of the 1,3-diketones examined here reacted readily with the electrophilic sulfur center in the sulfenyl amide residue to generate stable covalent attachments. Several different types of products were observed, depending upon the substituents present on the 1,3-diketone. The results provide a chemical foundation for the development of agents that covalently capture the oxidized form of PTP1B generated in cells during insulin signaling events.
- Ruddraraju, Kasi Viswanatharaju,Parsons, Zachary D.,Llufrio, Elizabeth M.,Frost, Natasha L.,Gates, Kent S.
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- Synthesis and gene transfer activities of novel serum compatible reducible tocopherol-based cationic lipids
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The molecular structure of the cationic lipids greatly influences their transfection efficiency. High transfection efficiencies of tocopherol-based simple monocationic transfection lipids with hydroxylethyl headgroups were recently reported by us (Kedika, B., et al. J. Med. Chem.2011, 54 (2), 548-561). Toward enhancing the transfection efficiency of tocopherol-based lipids, we have synthesized two tocopherol-based dicationic lipids (1 and 2) using simple cystine in the headgroup region. The efficiency of tocopherol-based lipids (1 and 2) were compared with nontocopherol-based lipids (3 and 4) with cystine in the headgroup region. We report also a comprehensive structure-activity relationship study that identified tocopherol-based gemini cationic lipid 1 is a better transfecting agent than its monomeric lipid counterpart 2 and two other nontocopherol-based gemini cationic lipids (3 and 4). The transfection efficiency of lipid 1 was also greater than that of commercial formulation in HepG2 cell lines. A major characteristic feature of this investigation is that serum does not inhibit the transfection activity of tocopherol-based lipids (1 and 2) in general and in particular lipid 1 which is found to be highly serum-compatible even at higher concentrations of serum when compared to its monomeric counterpart lipid 2 and the other two control lipid analogues 3 and 4.
- Kedika, Bhavani,Patri, Srilakshmi V.
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- Cystine cholesterol gel factor and preparation method thereof
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The cystine cholesterol gel factor is obtained by taking natural product cholesterol and cystine as a raw material and carrying out chemical reaction. The invention also discloses a supramolecular gel which is prepared from the gel factors in benzene solvents. The micro-morphology is a regular nanobelt or nano fiber network structure in a solvent such as n-propanol or cyclohexane. Raw materials used in the preparation process of the gel factor and the supramolecular gel belong to natural small molecule compounds, and have the advantages of wide sources, good biocompatibility, unique structure and the like, and exhibit better ion selective recognition and reduction response characteristics. The gel system has good biocompatibility and environmental friendliness, provides a new idea for construction of the intelligent response gel material, and provides a new reference for expanding the application of the cystine and the cholesterol natural small molecule compound in the supermolecule field.
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Paragraph 0040; 0041; 0043
(2021/09/21)
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- Carnosine dipeptidase II (CNDP2) protects cells under cysteine insufficiency by hydrolyzing glutathione-related peptides
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The knockout (KO) of the cystine transporter xCT causes ferroptosis, a type of iron-dependent necrotic cell death, in mouse embryonic fibroblasts, but this does not occur in macrophages. In this study, we explored the gene that supports cell survival under a xCT deficiency using a proteomics approach. Analysis of macrophage-derived peptides that were tagged with iTRAQ by liquid chromatography-mass spectrometry revealed a robust elevation in the levels of carnosine dipeptidase II (CNDP2) in xCT KO macrophages. The elevation in the CNDP2 protein levels was confirmed by immunoblot analyses and this elevation was accompanied by an increase in hydrolytic activity towards cysteinylglycine, the intermediate degradation product of glutathione after the removal of the γ-glutamyl group, in xCT KO macrophages. Supplementation of the cystine-free media of Hepa1-6 cells with glutathione or cysteinylglycine extended their survival, whereas the inclusion of bestatin, an inhibitor of CNDP2, counteracted the effects of these compounds. We established CNDP2 KO mice by means of the CRISPR/Cas9 system and found a decrease in dipeptidase activity in the liver, kidney, and brain. An acetaminophen overdose (350 mg/kg) showed not only aggravated hepatic damage but also renal injury in the CNDP2 KO mice, which was not evident in the wild-type mice that were receiving the same dose. The aggravated renal damage in the CNDP2 KO mice was consistent with the presence of abundant levels of CNDP2 in the kidney, the organ prone to developing ferroptosis. These collective data imply that cytosolic CNDP2, in conjugation with the removal of the γ-glutamyl group, recruits Cys from extracellular GSH and supports redox homeostasis of cells, particularly in epithelial cells of proximal tubules that are continuously exposed to oxidative insult from metabolic wastes that are produced in the body.
- Fujii, Junichi,Han, Jia,Homma, Takujiro,Kobayashi, Sho,Konno, Hiroyuki,Nagaoka, Keita,Okumura, Nobuaki,Sato, Hideyo,Takao, Toshifumi,Yamada, Sohsuke
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- COMPOUNDS AND COMPOSITIONS COMPRISING THE SAME FOR TREATING HYPERTENSION OR HEART FAILURE
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The present invention relates to compounds, to compositions comprising the same, to methods for preparing the compounds, and the use of these compounds in therapy. In particular, the present invention relates to a compound that is useful in the treatment and prevention of primary and secondary arterial hypertension, ictus, myocardial ischaemia, cardiac and renal insufficiency, myocardial infarction, peripheral vascular disease, diabetic proteinuria, Syndrome X and glaucoma.
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(2020/09/30)
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- Highly Selective Sub-Nanomolar Cathepsin S Inhibitors by Merging Fragment Binders with Nitrile Inhibitors
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Pharmacological inhibition of cathepsin S (CatS) allows for a specific modulation of the adaptive immune system and many major diseases. Here, we used NMR fragment screening and crystal structure-aided merging to synthesize novel, highly selective CatS inhibitors with picomolar enzymatic Ki values and nanomolar functional activity in human Raji cells. Noncovalent fragment hits revealed binding hotspots, while the covalent inhibitor structure-activity relationship enabled efficient potency optimization.
- Schade, Markus,Merla, Beatrix,Lesch, Bernhard,Wagener, Markus,Timmermanns, Simone,Pletinckx, Katrien,Hertrampf, Torsten
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supporting information
p. 11801 - 11808
(2020/11/26)
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- Scalable synthesis of orthogonally protected β-methyllanthionines by indium(III)-mediated ring opening of aziridines
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Lantibiotics are a class of peptide antibiotics with activity against most Gram-positive bacteria. Lanthionine (Lan) and β-MeLan are unusual thioether-bridged, non-proteinogenic amino acids, which are characteristic features of lantibiotics. In this paper, we report the facile stereoselective synthesis of β-methyllanthionines with orthogonal protection by nucleophilic ring opening of aziridines. This method leads to an expedient access to β-methyllanthionines and allows production of over 30 g of β-methyllanthionine in a single batch.
- Li, Ziran,Gentry, Zachary,Murphy, Brennan,Vannieuwenhze, Michael S.
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supporting information
p. 2200 - 2203
(2019/03/26)
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- Identification and immunological evaluation of novel TLR2 agonists through structure optimization of Pam3CSK4
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Toll-like receptor 2 (TLR2) is a bridge between innate immunity and adaptive immunity. TLR2 agonists have been exploited as potential vaccine adjuvants and antitumor agents. However, no TLR2 agonists have been approved by FDA up to now. To discover drug-like TLR2 selective agonists, a novel series of Pam3CSK4 derivatives were designed based on the crystal structure of hTLR2-hTLR1-Pam3CSK4 complex, synthesized and evaluated for their immune-stimulatory activities. Among them, 35c was identified as a murine-specific TLR2 agonist, while 35f was a human-specific TLR2 agonist. Besides, 35d (human and murine TLR2 agonist) showed TLR2 agonistic activity comparable to Pam3CSK4, which included: elevated IL-6 expression level (EC50 = 83.08 ± 5.94 nM), up-regulated TNF-α and IL-6 mRNA expression and promoted maturation of DCs through activating the NF-κB signaling pathway. TLRs antibodies test showed that 35a and 35d were TLR2/1 agonists, while 35f was a TLR2/6 agonist.
- Du, Xinming,Qian, Jiawen,Wang, Yujie,Zhang, Mingming,Chu, Yiwei,Li, Yingxia
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p. 2784 - 2800
(2019/05/17)
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- Palladium-Catalyzed Enantioselective Thiocarbonylation of Styrenes
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A highly enantioselective thiocarbonylation of styrenes with CO and thiols has been achieved by Pd catalysis, providing highly enantioenriched thioesters in good to excellent yields. Key to the successful execution of this reaction is the use of a chiral sulfoxide-(P-dialkyl)-phosphine (SOP) ligands. This thiocarbonylation proceeds smoothly under mild reaction conditions (1 atm CO and 0 °C) and displays broad substrate scope. Also demonstrated is that this transformation can be conducted using surrogates of CO, greatly increasing the safety aspects of running the reaction. The generality and utility of the method is manifested by its application to the synthetic transformations of thioester products and the direct acylation of cysteine-containing dipeptides. A primary mechanism was investigated and a plausible catalytic cycle was proposed.
- Wang, Xihong,Wang, Bing,Yin, Xuemei,Yu, Wangzhi,Liao, Yang,Ye, Jialin,Wang, Min,Hu, Lianrui,Liao, Jian
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supporting information
p. 12264 - 12270
(2019/08/01)
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- Elongation of the Hydrophobic Chain as a Molecular Switch: Discovery of Capsaicin Derivatives and Endogenous Lipids as Potent Transient Receptor Potential Vanilloid Channel 2 Antagonists
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The transient receptor potential vanilloid type-2 (TRPV2) protein is a nonselective Ca2+ permeable channel member of the TRPV subfamily, still considered an orphan TRP channel due to the scarcity of available selective and potent pharmacological tools and endogenous modulators. Here we describe the discovery of novel synthetic long-chain capsaicin derivatives as potent TRPV2 antagonists in comparison to the totally inactive capsaicin, the role of their hydrophobic chain, and how the structure-activity relationships of such derivatives led, through a ligand-based approach, to the identification of endogenous long-chain fatty acid ethanolamides or primary amides acting as TRPV2 antagonists. Both synthetic and endogenous antagonists exhibited differential inhibition against known TRPV2 agonists characterized by distinct kinetic profiles. These findings represent the first example of both synthetic and naturally occurring TRPV2 modulators with efficacy in the submicromolar/low-micromolar range, which will be useful for clarifying the physiopathological roles of this receptor, its regulation, and its targeting in pathological conditions.
- Schiano Moriello, Aniello,López Chinarro, Silvia,Novo Fernández, Olalla,Eras, Jordi,Amodeo, Pietro,Canela-Garayoa, Ramon,Vitale, Rosa Maria,Di Marzo, Vincenzo,De Petrocellis, Luciano
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p. 8255 - 8281
(2018/09/25)
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- Highly Cytotoxic Bioconjugated Gold(I) Complexes with Cysteine-Containing Dipeptides
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Several gold(I) complexes with cysteine-containing dipeptides have been prepared starting from cystine by coupling different amino acids and using several orthogonal protections. The first step is the reaction of cystine, where the sulfur centre is protected as disulfide, with Boc2O in order to protect the amino group, followed by coupling of an amino acid ester; finally the disulfide bridge is broken with mercaptoethanol to afford the dipeptide derivative. Further reaction with [AuCl(PPh3)] gives the gold-dipeptide-phosphine species. Starting from these formally gold(I) thiolate-dipeptide phosphine complexes with the general formula [Au(SR)(PR3)] different structural modifications, such as change in the type of the amino protecting group, the type of phosphine, the number of gold(I) atoms per molecule, or the use of a non-proteinogenic conformationally restricted amino acid ester, were introduced in order to evaluate their influence in the biological activity of the final complexes. The cytotoxic activity, in vitro, of these complexes was evaluated against different tumour human cell lines (A549, MiaPaca2 and Jurkat). The complexes show an outstanding cytotoxic activity with IC50 values in the very low micromolar range. Structure-activity relationship studies from the complexes open the possibility of designing more potent and promising gold(I) anticancer agents. Striking with gold: Gold(I) complexes with cysteine-containing dipeptides were prepared starting from cystine by coupling different amino acids, and using several orthogonal protections. The complexes show excellent cytotoxic activity with IC50 values in the very low micromolar range. The structural changes in the parent compound led to the synthesis of the most effective compound in the cell lines tested, which is the complex with two AuPPh3+ fragments coordinated to the Boc-Cys-Gly-OMe peptide (see scheme).
- Gutiérrez, Alejandro,Marzo, Isabel,Cativiela, Carlos,Laguna, Antonio,Gimeno, M. Concepci?n
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supporting information
p. 11088 - 11095
(2015/11/10)
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- TOLL-LIKE RECEPTOR 2-AGONISTIC LIPOPEPTIDES, AND METHOD OF MAKING THE SAME
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The present disclosure is directed to a novel class of toll-like receptor 2-agnonistic (TLR2) lipopeptide compounds having specific structures, and synthetic methods of making the compounds. These compounds provide high potency of agonistic activities with human, other than murine, TLR2, and are useful as vaccine adjuvants. Vaccines are perhaps one of the most successful medical interventions against infectious disease.
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Paragraph 0107-0108; 0256-0257
(2014/08/06)
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- A comprehensive one-pot synthesis of protected cysteine and selenocysteine SPPS derivatives
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A proof-of-principle methodology is presented in which all commercially-available cysteine (Cys) and selenocysteine (Sec) solid phase peptide synthesis (SPPS) derivatives are synthesized in high yield from easily prepared protected dichalcogenide precursors. A Zn-mediated biphasic reduction process applied to a series of four bis-Nα-protected dichalcogenide compounds allows facile conversion to their corresponding thiol and selenol intermediates followed by insitu S- or Se-alkylation with various electrophiles to directly access twenty one known Cys and Sec SPPS derivatives. Most of these derivatives were able to be precipitated in crude form out of petroleum ether in sufficient purity for direct use as peptide building blocks. Subsequent incorporation of these derivatives into peptide models nicely illustrates their viability and applicability toward SPPS.
- Flemer, Stevenson
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p. 1257 - 1264
(2015/04/14)
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- Conjugated TLR7 and/or TLR8 and TLR2 polycationic agonists
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The present invention relates to a conjugated compound of Formula I : Q-Z-R4 wherein Q is a TLR7 and/or TLR8 agonist and Z-R4 is a TLR2 agonist, said conjugated compound being chosen among compounds of Formula II :
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Paragraph 0250
(2014/09/03)
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- Construction of targeting-clickable and tumor-cleavable polyurethane nanomicelles for multifunctional intracellular drug delivery
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New strategies for the construction of versatile nanovehicles to overcome the multiple challenges of targeted delivery are urgently needed for cancer therapy. To address these needs, we developed a novel targeting-clickable and tumor-cleavable polyurethane nanomicelle for multifunctional delivery of antitumor drugs. The polyurethane was synthesized from biodegradable poly(ε-caprolactone) (PCL) and l-lysine ethyl ester diisocyanate (LDI), further extended by a new designed l-cystine-derivatized chain extender bearing a redox-responsive disulfide bond and clickable alkynyl groups (Cys-PA), and finally terminated by a detachable methoxyl-poly(ethylene glycol) with a highly pH-sensitive benzoic-imine linkage (BPEG). The obtained polymers show attractive self-assembly characteristics and stimuli-responsiveness, good cytocompatibility, and high loading capacity for doxorubicin (DOX). Furthermore, folic acid (FA) as a model targeting ligand was conjugated to the polyurethane micelles via an efficient click reaction. The decoration of FA results in an enhanced cellular uptake and improved drug efficacy toward FA-receptor positive HeLa cancer cells in vitro. As a proof-of-concept, this work provides a facile approach to the design of extracellularly activatable nanocarriers for tumor-targeted and programmed intracellular drug delivery.
- Song, Nijia,Ding, Mingming,Pan, Zhicheng,Li, Jiehua,Zhou, Lijuan,Tan, Hong,Fu, Qiang
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p. 4407 - 4419
(2014/01/06)
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- Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents
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The development of multidrug resistant (MDR) and extensively drug resistant (XDR) forms of tuberculosis (TB) has stimulated research efforts globally to expand the new drug pipeline. Nitroaromatic compounds, including 1,3-benzothiazin-4-ones (BTZs) and related agents, are a promising new class for the treatment of TB. Research has shown that the nitroso intermediates of BTZs that are generated in vivo cause suicide inhibition of decaprenylphosphoryl- β-d-ribose 2′ oxidase (DprE1), which is responsible for cell wall arabinogalactan biosynthesis. We have designed and synthesized novel anti-TB agents inspired from BTZs and other nitroaromatic compounds. Computational studies indicated that the unsubstituted aromatic carbons of BTZ043 and related nitroaromatic compounds are the most electron-deficient and might be prone to nucleophilic attack. Our chemical studies on BTZ043 and the additional nitroaromatic compounds synthesized by us and others confirmed the postulated reactivity. The results indicate that nucleophiles such as thiolates, cyanide, and hydride induce nonenzymatic reduction of the nitro groups present in these compounds to the corresponding nitroso intermediates by addition at the unsubstituted electron-deficient aromatic carbon present in these compounds. Furthermore, we demonstrate here that these compounds are good candidates for the classical von Richter reaction. These chemical studies offer an alternate hypothesis for the mechanism of action of nitroaromatic anti-TB agents, in that the cysteine thiol(ate) or a hydride source at the active site of DprE1 may trigger the reduction of the nitro groups in a manner similar to the von Richter reaction to the nitroso intermediates, to initiate the inhibition of DprE1.
- Tiwari, Rohit,Moraski, Garrett C.,Krchňák, Viktor,Miller, Patricia A.,Colon-Martinez, Mariangelli,Herrero, Eliza,Oliver, Allen G.,Miller, Marvin J.
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supporting information
p. 3539 - 3549
(2013/04/23)
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- Structure-activity relationships in human toll-like receptor 2-specific monoacyl lipopeptides
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Toll-like receptor 2-agonistic lipopeptides typified by S-[2,3-bis(palmitoyloxy)-(2RS)-propyl]-R-cysteinyl-S-serine (PAM2CS) compounds are potential vaccine adjuvants. We had previously determined that at least one acyl group of optimal length (C16) and an appropriately orientated ester carbonyl group is essential for TLR2-agonistic activity. We now show that these structurally simpler analogues display agonistic activities with human, but not murine, TLR2. SAR studies on the monoacyl derivatives show that the optimal acyl chain length is C16, and aryl substituents are not tolerated. A variety of alkyl and acyl substituents on the cysteine amine were examined. All N-alkyl derivatives were inactive. In contradistinction, short-chain N-acyl analogues were found to be highly active, with a clear dependence on the chain length. A cysteine N-acetyl analogue was found to be the most potent (EC50: 1 nM), followed by the N-butyryl analogue. The N-acetyl analogue is human TLR2-specific, with its potency comparable to that of PAM2CS.
- Salunke, Deepak B.,Shukla, Nikunj M.,Yoo, Euna,Crall, Breanna M.,Balakrishna, Rajalakshmi,Malladi, Subbalakshmi S.,David, Sunil A.
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scheme or table
p. 3353 - 3363
(2012/06/01)
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- Hydrazine-sensitive thiol protecting group for peptide and protein chemistry
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In the search for a new Cys side-chain protecting group that is compatible to the solid-phase peptide synthesis yet can be removed under mild conditions, the Hqm and Hgm groups that are readily deprotected by using aqueous hydrazine have been developed. The utility of these groups for peptide and protein chemistry is tested by the total synthesis of a peptide antibiotic trifolitoxin and the human neutrophil defensin hNP2.
- Shen, Fei,Zhang, Zhi-Ping,Li, Jia-Bin,Lin, Yun,Liu, Lei
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supporting information; experimental part
p. 568 - 571
(2011/04/24)
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- Synthesis, characterization and antioxidant activity of angiotensin converting enzyme inhibitors
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Angiotensin converting enzyme (ACE) catalyzes the conversion of angiotensin I (Ang I) to angiotensin II (Ang II). ACE also cleaves the terminal dipeptide of vasodilating hormone bradykinin (a nonapeptide) to inactivate this hormone. Therefore, inhibition of ACE is generally used as one of the methods for the treatment of hypertension. 'Oxidative stress' is another disease state caused by an imbalance in the production of oxidants and antioxidants. A number of studies suggest that hypertension and oxidative stress are interdependent. Therefore, ACE inhibitors having antioxidant property are considered beneficial for the treatment of hypertension. As selenium compounds are known to exhibit better antioxidant behavior than their sulfur analogues, we have synthesized a number of selenium analogues of captopril, an ACE inhibitor used as an antihypertensive drug. The selenium analogues of captopril not only inhibit ACE activity but also effectively scavenge peroxynitrite, a strong oxidant found in vivo. The Royal Society of Chemistry 2011.
- Bhuyan, Bhaskar J.,Mugesh, Govindasamy
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scheme or table
p. 1356 - 1365
(2011/04/23)
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- Oxidative transformation of thiols to disulfides promoted by activated carbon-air system
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Efficient oxidative transformation of thiols to disulfides took place in the presence of activated carbon under an oxygen (or air) atmosphere. The present oxidation method is available not only for a variety of thiols such as simple aromatic and aliphatic thiols but also for 3,4-dihydropyrimidin-2(1H)- thiones and N-Boc-l-cysteine.
- Hayashi, Masahiko,Okunaga, Ken-Ichi,Nishida, Shunsuke,Kawamura, Kenjiro,Eda, Kazuo
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supporting information; experimental part
p. 6734 - 6736
(2011/02/25)
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- CYSTEINE AND CYSTINE BIOISOSTERES TO TREAT SCHIZOPHRENIA AND REDUCE DRUG CRAVINGS
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The present invention provides cysteine and cystine bioisosteres for the treatment of schizophrenia and drug addiction. The invention further encompasses pharmaceutical compositions containing such bioisosteres and methods of using the bioisosteres for treatment of schizophrenia and drug addiction.
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Page/Page column 27; 28
(2010/01/29)
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- Cyclic dipeptides and azetidinone compounds and their use in treating CNS injury and neurodegenerative disorders
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The present invention provides 4-substituted-2-azetidinone compounds, bicyclic 2-5-diketopiperazine compounds, and pharmaceutical compositions thereof that are potent, safe and effective neuroprotective agents. Due to their strong central nervous system (CNS) activity, the compounds can be used to enhance memory and to treat a variety of neurological disorders. The compounds are particularly useful for treating neurological disorders caused by, or associated with, CNS trauma.
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Page/Page column 46-47
(2010/11/26)
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- Compound containing a labile disulfide bond
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A labile disulfide-containing compound under physiological conditions containing a labile disulfide bond and a transduction signal.
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- Intravascular delivery of non-viral nucleic acid
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A process is described for the delivery of a therapeutic polynucleotide to a tissue suffering from or potentially suffering from ischemia. The process comprises designing a polynucleotide for transfection. Then the polynucleotide is inserted into a mammalian vessel such as an artery or a vein. Prior to insertion, subsequent to insertion, or concurrent with insertion the volume of the tissue is increased such that the genetic material is delivered to the parenchymal cell.
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- Snm as a photolabile protecting group for the cysteinyl radical - Direct evidence from time-resolved IR and UV/Vis spectroscopies
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The cysteinyl radical and the methyl(phenyl)thiocarbamic acid radical have been generated by laser flash photolysis (266 nm) of BOC-Cys(Snm)-OH in acetonitrile and characterized both by time-resolved (IR and UV/Vis) and standard spectroscopic methods (UV, IR, and NMR). The mode of action of the Snm unit [methyl(phenyl)thiocarbamic acid] is similar to the so-called "caging" technique. Cleavage of the disulfide bridge by irradiation is possible in acceptable quantum yields. Time-resolved IR (TR-IR) spectroscopic experiments using the step-scan FTIR technique allowed the detection of the methyl(phenyl)thiocarbamic acid radical (VC=O = 1607.7 and 1579.3 cm-1), which has a lifetime of about 3 ps. Because of the weak absorptions in the IR spectrum and the tendency for fast recombination to BOC-protected cystine, the cysteinyl radical cannot be monitored by TR-IR spectroscopy. Time-resolved UV/Vis spectroscopy revealed the formation of both of these radicals and permitted the determination of the decay rates of the methyl(phenyl)thiocarbamic acid radical in the presence of several quenchers. NMR spectroscopic studies of the photolysis of BOC-Cys(Snm)-OH allowed us to identify N-methylaniline, carbonyl sulfide, and BOC-protected cystine as the major products. This study clearly demonstrates that the thiol protection group Snm is a suitable photolabile protecting group. ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003).
- Kolano, Christoph,Sander, Wolfram
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p. 1074 - 1079
(2007/10/03)
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- Protein folding: The synthesis and conformational studies on cystinyl- cystinyl-cystine [-CSSCCSSCCSSC-] a novel cross linking motif
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The cysteine capped, ends protected cross linked motifs 6 and 7, arising from pairs of proximally placed cysteines wherein within a 22 atom framework are inscribed 3 disulphide bridges and 2 peptide linkage, have been prepared and their conformations derived by detailed 1H NMR studies and molecular modeling protocols, where excellent agreement was seen. Both compounds 6 and 7 possess a C2 symmetric hydrogen bonded pair involving the peptide NH and the CO of the proximate N-protecting group (Boc or Z). The nature of the latter profoundly influences the conformation. Thus, in 6 where the unit is Boc a bend conformation was promoted by hydrophobic interactions; alternatively in 7 with a Z-protecting group the conformation was linear. Compounds 6 and 7 have much promise in diverse aspects of protein design.
- Ranganathan, Subramania,Tamilarasu, Natarajan,Roy, Raja
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p. 9823 - 9834
(2007/10/03)
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- New diastereoselective synthesis of protected meso-lanthionine with discrimination of the chiral centers
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A synthesis of meso-lanthionine with discrimination of the chiral centers is reported. Two cysteine residues of opposite configuration and with orthogonal protections are temporarily and reversibly linked in order to promote the formation of an intramolecular disulfide bridge thus avoiding symmetrization reactions during the sulfur extrusion step.
- Cavelier-Frontin,Daunis,Jacquier
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- Synthesis of Peptides Containing S-(N-Alkylcarbamoyl)cysteine Residues, Metabolites of N-Alkylformamides in Rodents and in Humans
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Hydrochloride salts of S-(N-methylcarbamoyl), S-(N-ethylcarbamoyl), and S-(N,N-dimethylcarbamoyl) derivatives of cysteine, N-acetylcysteine, and cysteinylglycine have been prepared.S-(N-Methylcarbamoyl)glutathione hydrochloride has also been synthesized.Protecting groups for amino and carboxylic acid functions were selected for their ability to solubilize the peptides in dichloromethane in which solvent the thiols were treated with alkyl isocyanates and with N,N-dimethylcarbamoyl chloride.Removal of S-(amidomethyl) protecting groups using mercury(II) acetate was found to cause some loss of N-(tert-butoxycarbonyl) groups.Elimination of disulfide was evident during coupling of disulfide derivatives of cysteine using mixed anhydride methods but not with a carbodiimide coupling agent.Mixed disulfide protections were reductively cleaved by propane-1,3-dithiol.Many of the deprotected S-carbamoyl amino acids and peptides are metabolites of the corresponding N-alkylformamides in rodents and in humans.
- Threadgill, Michael D.,Gledhill, Adrian P.
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p. 2940 - 2949
(2007/10/02)
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- New Amino-protective Reagents for t-Butoxycarbonylation and Benzyloxycarbonylation of Amines and Amino Acids
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New amino-protective reagents for t-butoxycarbonylation and benzyloxycarbonylation of amines and amino acids have been developed. t-Butyl 2-pyridyl carbonate and t-butyl S-(2-pyridyl) thiocarbonate react cleanly with various amines and amino acids to afford N-Boc amines and N-Boc amino acids in high yields.Benzyl 2-pyridyl carbonate and O-benzyl S-(2-pyridyl) thiocarbonate are also found to be very effective in the benzyloxycarbonylation of amino acids.
- Kim, Sunggak,Lee, Jae In,Yi, Kyu Yang
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p. 3570 - 3575
(2007/10/02)
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- THE USE OF DIACETOXYPHENYLIODINE FOR THE DIRECT OXIDATIVE CONVERSION OF S-PROTECTED L-CYSTEINE COMPOUNDS TO L-CYSTINE DERIVATIVES
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Diacetoxyphenyliodine was used for the direct oxidative conversion of S-Trt, S-Dpm and S-Acm-L-cysteine derivatives to optically pure L-cystine compounds.
- Kolovos, M. G.,Moutevelis-Minakakis, P.
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p. 4153 - 4156
(2007/10/02)
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- 3-NITRO-2-PYRIDINESULFENYL GROUP FOR PROTECTION AND ACTIVATION OF THE THIOL FUNCTION OF CYSTEINE
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The use of the 3-nitro-2-pyridinesulfenyl (Npys) halide, a versatile reagent in peptide chemistry, for the protection and activation of the thiol function is reported.Boc-Cys(Npys)-OH is prepared starting from bis(N-t-butyloxycarbonyl)-L-cystine.The Npys group is easily removed by treatment with a stoichiometric amount of tri-n-butylphosphine in the presence of water, but it is resistant to acids such as trifluoroacetic acid, HCl, and HF.Importantly, the cysteine residue modified with the Npys group can react selectively with free thiol of cysteine to afford a cystine disulfide bond.
- Matsueda, Rei,Kimura, Takahide,Kaiser, Emil Thomas,Matsueda, Gary R.
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p. 737 - 740
(2007/10/02)
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- Amino-acids and Peptides. Part 45. The Protection of the Thiol Function of Cysteine and the Imidazole-N of Histidine by the Diphenyl-4-pyridylmethyl Group
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S-(Diphenyl-4-pyridylmethyl)-L-cysteine (1) and its derivatives (2)-(7) have been prepared and used in peptide synthesis.In contrast to the analogous S-trityl group, this protection is stable in acid but it is cleaved readily by zinc-acetic acid, by mercury(II) acetate, by iodine, and by electrolytic reduction.N(Im)-Diphenyl-4-pyridylmethyl-L-histidine derivatives (9)-(13) are also reported; the protecting group is again stable to acid but cleaved by hydrogenolysis, by zinc-acetic acid, and by electrolytic reduction, and it has been used in the synthesis of L-histidyl-L-leucine, -L-phenylalanine, and -glycine.
- Coyle, Susan,Hallett, Allan,Munns, Michael S.,Young, Geoffrey T.
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p. 522 - 528
(2007/10/02)
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