67385-10-8Relevant academic research and scientific papers
Photodisulfidation of alkenes with linear disulfides: Reaction scope and kinetics
Kamps, Joshua T.,Soars, Shafer M.,Bongiardina, Nichloas J.,Fairbanks, Benjamin D.,Bowman, Christopher N.
, (2022/03/07)
Thiol-ene and thiol-yne photomediated conjugations have received substantial attention in research and in practice. Herein is presented the photodisulfidation of alkenes based on the radical-mediated 1:1 reaction of a disulfide and a vinyl ether, which provides an additional route for the formation of the types of sulfides seen in thiol-ene and thiol-yne polymers. Although similar linkages are formed, this approach starting with disulfides is expected to have benefits over the thiol-ene and thiol-yne reactions including extended shelf life of disulfides compared to thiols, reduced shrinkage stress, and increased refractive index of the resulting materials. It was determined that vinyl ethers were the only alkenes capable of undergoing photodisulfidation under ambient conditions and in reasonable timescales. The reaction between vinyl ethers and disulfides performed well in a variety of solvents providing modest to excellent yields (100% for bis(1-methylacetate) disulfide (DSMA)/triethyleneglycol divinylether (TEGDVE)) for numerous disulfide substrates evaluated. It was determined that the mechanism of the photodisulfidation reaction involves an auto-propagating cycle of thiyl radicals which add into either end of a vinyl ether to form thio-ether and thio-acetal linkages in the final product. Finally, although the reaction rate is slower than that of the thiol-ene reaction, the photodisulfidation reaction proceeds relatively rapidly under the explored conditions.
Selective, Modular Probes for Thioredoxins Enabled by Rational Tuning of a Unique Disulfide Structure Motif
Becker, Katja,Busker, Sander,Felber, Jan G.,Maier, Martin S.,Poczka, Lena,Scholzen, Karoline,Theisen, Ulrike,Thorn-Seshold, Julia,Thorn-Seshold, Oliver,Zeisel, Lukas,Arnér, Elias S. J.,Brandst?dter, Christina
supporting information, p. 8791 - 8803 (2021/06/27)
Specialized cellular networks of oxidoreductases coordinate the dithiol/disulfide-exchange reactions that control metabolism, protein regulation, and redox homeostasis. For probes to be selective for redox enzymes and effector proteins (nM to μM concentrations), they must also be able to resist non-specific triggering by the ca. 50 mM background of non-catalytic cellular monothiols. However, no such selective reduction-sensing systems have yet been established. Here, we used rational structural design to independently vary thermodynamic and kinetic aspects of disulfide stability, creating a series of unusual disulfide reduction trigger units designed for stability to monothiols. We integrated the motifs into modular series of fluorogenic probes that release and activate an arbitrary chemical cargo upon reduction, and compared their performance to that of the literature-known disulfides. The probes were comprehensively screened for biological stability and selectivity against a range of redox effector proteins and enzymes. This design process delivered the first disulfide probes with excellent stability to monothiols yet high selectivity for the key redox-Active protein effector, thioredoxin. We anticipate that further applications of these novel disulfide triggers will deliver unique probes targeting cellular thioredoxins. We also anticipate that further tuning following this design paradigm will enable redox probes for other important dithiol-manifold redox proteins, that will be useful in revealing the hitherto hidden dynamics of endogenous cellular redox systems.
Photochemical metal-free aerobic oxidation of thiols to disulfides
Spiliopoulou, Nikoleta,Kokotos, Christoforos G.
supporting information, p. 546 - 551 (2021/01/28)
Thiol oxidation to disulfides is an area of great importance in organic synthesis, both for synthetic and biological purposes. Herein, we report a mild, inexpensive and green photochemical approach for the synthesis of both symmetrical and non-symmetrical disulfides, using metal-free and environmentally friendly conditions. Utilizing phenylglyoxylic acid as the photoinitiator, common household bulbs as the light source and a simple inorganic salt as the additive, a versatile oxidation of thiols leading to products in excellent yields is described. This journal is
Synthesis of a new disulfide Fmoc monomer for creating biologically susceptible linkages in peptide nucleic acid oligomers
Campbell, Brandon,Hood, Taylor,Shank, Nathaniel
, p. 394 - 398 (2018/12/13)
Peptide nucleic acids (PNA) are one of many synthetic mimics of DNA and RNA that have found applications as biological probes, as nano-scaffold components, and in diagnostics. In an effort to use PNA as constructs for cellular delivery we investigated the possibility of installing a biologically susceptible disulfide bond in the backbone of a PNA oligomer. Here we report the synthesis of a new abasic Fmoc monomer containing a disulfide bond that can be incorporated into a PNA oligomer (DS-PNA) using standard solid phase peptide synthesis. The disulfide bond survives cleavage from the resin and DS-PNA forms duplexes with complementary PNA oligomers. Initial studies aimed at determining if the disulfide bond is cleavable to reducing agents while in a duplex are explored using UV thermal analysis and HPLC.
Cyclic telluride reagents with remarkable glutathione peroxidase-like activity for purification-free synthesis of highly pure organodisulfides
Arai, Kenta,Osaka, Yuui,Haneda, Masahiro,Sato, Yuumi
, p. 3647 - 3655 (2019/07/22)
Monoamino cyclic tellurides with a five- or six-membered ring structure and their derivatives were developed as a new class of catalyst for the oxidation of organothiols to organodisulfides in a glutathione peroxidase-like catalytic reaction. Quantitative conversion and high reaction rate were achieved by performing the reaction in an organic-aqueous segmented microflow system. Importantly, the process circumvented product purification, which is a major limitation of current organodisulfide synthetic methods.
Biomimetic pH/redox dual stimuli-responsive zwitterionic polymer block poly(L-histidine) micelles for intracellular delivery of doxorubicin into tumor cells
John, Johnson V.,Uthaman, Saji,Augustine, Rimesh,Manickavasagam Lekshmi, Kamali,Park, In-Kyu,Kim, Il
, p. 2061 - 2070 (2017/05/08)
A series of pH/redox dual stimuli-responsive poly(2-methacryloyloxyethyl phosphorylcholine)25-block-poly(l-histidine)n (p[MPC])25-b-p[His]n, n = 20, 35, 50, and 75) copolymers consisting of a pH-responsive p(His)n block and a biocompatible phospholipid analog p(MPC) block connected by a redox-responsive disulfide linker have been synthesized. The block copolymers are self-assembled into uniform micelles (～100 nm) in which doxorubicin (Dox) is efficiently encapsulated. The in vitro release profile shows an enhanced release of Dox at low pH (5.0) in 10 mM glutathione (GSH). The in vitro cell viability assays performed using various cell lines show that the blank hybrid micelles have no acute or intrinsic toxicity. A pH-dependent cytotoxicity is observed with the Dox-loaded micelles, especially at pH 5.0. Moreover, confocal microscopy images and flow cytometry results show the pH-dependent cellular uptake of Dox-loaded micelles. Therefore, the Dox-loaded micelles can be considered a good candidate for cancer therapy.
METHODS OF CHEMOTYPE EVOLUTION
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Paragraph 0155; 0156, (2015/11/10)
Herein is described a method to rapidly screen a large chemical space for a compound that binds to a target protein through an iterative fragment assembly approach that can be performed at low reagent cost and without requiring purification of the assembled product. The method employs a library of test ligands each of which comprise a ‘bait’ molecule, which is known from prior art or prior screening to have some intrinsic affinity for the target protein, and a test moiety.
Thiolates chemically induce redox activation of BTZ043 and related potent nitroaromatic anti-tuberculosis agents
Tiwari, Rohit,Moraski, Garrett C.,Krchňák, Viktor,Miller, Patricia A.,Colon-Martinez, Mariangelli,Herrero, Eliza,Oliver, Allen G.,Miller, Marvin J.
supporting information, p. 3539 - 3549 (2013/04/23)
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.
Dehydratase-specific probes for fatty acid and polyketide synthases
Ishikawa, Fumihiro,Haushalter, Robert W.,Burkart, Michael D.
supporting information; experimental part, p. 769 - 772 (2012/03/07)
We targeted the development of a dehydratase (DH)-specific reactive probe that can facilitate detection, enrichment, and identification of DH enzymes in fatty acid synthases (FASs) and polyketide synthases (PKSs). The first reported mechanism-based inactivator, 3-decynoyl-N-acetylcysteamine (3-decynoyl-NAC), while active against the Escherichia coli β-hydroxydecanoyl thiol ester DH FabA, translates poorly to an activity-based probe because of nonspecific reactivity of the thioester moiety. Here we describe the design, synthesis, and utility of a DH-specific probe that contains a sulfonyl 3-alkyne reactive warhead engineered to avoid hydrolysis or nonenzymatic inactivation. When coupled with a fluorescent tag, this probe targets DH enzymes from recombinant type I and type II FAS and PKS enzyme systems and in whole proteomes. Activity studies, including FabA inactivation and antibiotic susceptibility, suggest that this sulfonyl 3-alkyne scaffold selectively targets a common DH mechanism. These studies indicate that the DH-specific mechanism-based probe can greatly accelerate both the functional characterization and molecular identification of virtually any type of FAS and PKS in complex proteomes.
CLEAVABLE LIPIDS
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Page/Page column 62-64, (2013/02/27)
Disclosed herein are novel compounds, pharmaceutical compositions comprising such compounds and related methods of their use. The compounds described herein are useful, e.g., as liposomal delivery vehicles to facilitate the delivery of encapsulated polynucleotides to target cells and subsequent iransfection of said target cells, and in certain embodiments are characterized as having one or more properties that afford such compounds advantages relative to other similarly classified lipids.
