28170-07-2Relevant articles and documents
Platform to Discover Protease-Activated Antibiotics and Application to Siderophore-Antibiotic Conjugates
Boyce, Jonathan H.,Dang, Bobo,Ary, Beatrice,Edmondson, Quinn,Craik, Charles S.,Degrado, William F.,Seiple, Ian B.
, p. 21310 - 21321 (2020)
Here we present a platform for discovery of protease-activated prodrugs and apply it to antibiotics that target Gram-negative bacteria. Because cleavable linkers for prodrugs had not been developed for bacterial proteases, we used substrate phage to discover substrates for proteases found in the bacterial periplasm. Rather than focusing on a single protease, we used a periplasmic extract of E. coli to find sequences with the greatest susceptibility to the endogenous mixture of periplasmic proteases. Using a fluorescence assay, candidate sequences were evaluated to identify substrates that release native amine-containing payloads. We next designed conjugates consisting of (1) an N-terminal siderophore to facilitate uptake, (2) a protease-cleavable linker, and (3) an amine-containing antibiotic. Using this strategy, we converted daptomycin - which by itself is active only against Gram-positive bacteria - into an antibiotic capable of targeting Gram-negative Acinetobacter species. We similarly demonstrated siderophore-facilitated delivery of oxazolidinone and macrolide antibiotics into a number of Gram-negative species. These results illustrate this platform's utility for development of protease-activated prodrugs, including Trojan horse antibiotics.
Folic acid targeting porphin photosensitizer coupled by different connecting chains and synthesis and application of folic acid targeting porphin photosensitizer
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Paragraph 0131-0133, (2020/12/15)
The invention relates to a folic acid targeting porphin photosensitizer coupled by different connecting chains and synthesis and application thereof, and discloses a photosensitizer as shown in a general formula (I), a preparation method of the photosensitizer and an application of the photosensitizer in tumor photodynamic therapy and tumor imaging diagnosis. In the photosensitizer, folic acid, which is a tumor-targeting ligand, is linked to a porphin-type photosensitive moiety via different chain lengths of linking moieties optionally having an acidic amino acid fragment. A-Lys-(L)m-(B)o-C(I)is shown in the specification.
Cationic lipid molecule, and application thereof in nucleic acid delivery
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Paragraph 0162-0165, (2019/10/08)
The present invention discloses a cationic lipid molecule, and an application thereof in nucleic acid delivery. The structural formula of the cationic lipid molecule is represented by formula i. The invention further provides a cationic liposome, a lipid compound, a reagent, a kit, a preparation and a medicinal composition based on the cationic lipid molecule. The cationic lipid molecule has the advantages of simple synthesis process and good stability, and the cationic liposome has a high efficiency (characterized by high transfection efficiency) and a low toxicity, is stable and uniform, is easy to prepare, and can be used for transferring various cell lines. The cationic lipid molecule has excellent transitivity, and can efficiently deliver active substances (such as exemplary siRNA) omto cells (such as exemplary lung cancer cells), tissues and organs to achieve efficient regulation of the active substances. The problem that the toxicity and the transfer efficiency of cationic liposome existing in the prior art are low is solved.
Palladium-Catalyzed Decarboxylative Carbonylative Transformation of Benzyl Aryl Carbonates: Direct Synthesis of Aryl 2-Arylacetates
Xu, Jian-Xing,Wu, Xiao-Feng
supporting information, p. 5938 - 5941 (2018/09/21)
A procedure on palladium-catalyzed decarboxylative alkoxycarbonylation of carbonates for the synthesis of aryl 2-arylacetates has been developed. A broad range of aryl 2-arylacetates were obtained in good yields under mild conditions under a carbon monoxide atmosphere. Interestingly, other alcohols can be added as nucleophiles as well, and the corresponding esters were also obtained in good yields.
Investigations into the carbonic anhydrase inhibition of COS-releasing donor core motifs
Steiger, Andrea K.,Zhao, Yu,Choi, Won Jin,Crammond, Alder,Tillotson, McKinna R.,Pluth, Michael D.
, p. 124 - 130 (2017/12/04)
Carbonyl sulfide (COS) releasing scaffolds are gaining popularity as hydrogen sulfide (H2S) donors through exploitation of the carbonic anhydrase (CA)-mediated hydrolysis of COS to H2S. The majority of compounds in this emerging class of donors undergo triggerable decomposition (often referred to as self-immolation) to release COS, and a handful of different COS-releasing structures have been reported. One benefit of this donation strategy is that numerous caged COS-containing core motifs are possible and are poised for development into self-immolative COS/H2S donors. Because the intermediate release of COS en route to H2S donation requires CA, it is important that the COS donor motifs do not inhibit CA directly. In this work, we investigate the cytotoxicity and CA inhibition properties of different caged COS donor cores, as well as caged CO2 and CS2 motifs and non-self-immolative control compounds. None of the compounds investigated exhibited significant cytotoxicity or enhanced cell proliferation at concentrations up to 100 μM in A549 cells, but we identified four core structures that function as CA inhibitors, thus providing a roadmap for the future development of self-immolative COS/H2S donor motifs.
Carbon Dioxide Utilisation for the Synthesis of Unsymmetrical Dialkyl and Cyclic Carbonates Promoted by Basic Ionic Liquids
Goodrich, Peter,Gunaratne, H. Q. Nimal,Jin, Lili,Lei, Yuntao,Seddon, Kenneth R.
, p. 181 - 185 (2018/03/09)
An efficient and greener synthesis of unsymmetrical organic carbonates mediated by Hünig's base-appended basic ionic liquids, via carbon dioxide conversion, is described here. These ionic liquids were found to be effective bases for the fixation of carbon dioxide by various alcohols and benzyl bromide, at room temperature. When the alcohol and the halide functionalities are present within the same substrate, the reaction cleanly produces a cyclic carbonate. These functionalised basic ionic liquids were fully recyclable with no loss product yields.
Activation of Benzyl Aryl Carbonates: The Role of Cation-π Interactions
Reddy, Golipalli Ramana,Avadhani, Anusha S.,Rajaram, Sridhar
, p. 4134 - 4141 (2016/06/09)
Benzyl aryl carbonates can react with a nucleophile to yield an activated electrophile and an aryloxide anion. Previously, we had utilized this in the synthesis of α-nitro esters from nitroalkanes. To further understand the process of activation of these carbonates by nucleophiles, we have performed kinetic studies on the hydrolysis of carbonates using nucleophiles. Rate constants for the hydrolysis were obtained under pseudo-first-order conditions with DABCO as the nucleophile. A comparison of rate constant for hydrolysis of isobutyl phenyl carbonate with benzyl phenyl carbonate shows that the presence of benzyl group results in a 16-fold acceleration of hydrolysis rate. This indicates that the transition state for activation of carbonate is stabilized by cation-π interactions. A comparison of the rate constant for various aromatic rings indicates that electron-donating substituents on the benzyl groups accelerate the rate of hydrolysis. Studies were also carried out with DMAP as nucleophile and the results are presented. Our studies show that stable carbonates can be activated using nucleophiles. Activated acyl groups generated from acid anhydrides have been used in several enantioselective reactions. Our studies show that carbonates can be stable alternatives to acid anhydrides.
ANTIBACTERIAL SIDEROMYCINS
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Page/Page column 61; 62, (2016/03/13)
A compound, comprising: an Fe(III)-binding and/or Fe(III)-bound siderophore; one or more optional linker covalently bound to the siderophore; and daptomycin covalently bound to the linker, or, if no linker is present, then to the siderophore; or pharmaceu
Unusual reactivity of nitronates with an aryl alkyl carbonate: Synthesis of α-amino esters
Reddy, Golipalli Ramana,Mukherjee, Debopreeti,Chittoory, Arjun Kumar,Rajaram, Sridhar
supporting information, p. 5874 - 5877 (2015/01/08)
The monoanions of nitroalkanes are ambident nucleophiles that react with carbonate electrophiles through the oxygen atom. Products arising from reactivity at the carbon atom will yield α-nitro esters, which are precursors for α-amino esters. We demonstrate this in the reactions of nitroalkanes with benzyl phenyl carbonate and DABCO where α-nitro esters are obtained instead of nitrile oxides. The products are readily reduced to α-amino esters. This pathway could be a safe alternative to the Strecker reaction.
Comparison of alternative nucleophiles for Sortase A-mediated bioconjugation and application in neuronal cell labelling
Baer, Samuel,Nigro, Julie,Madej, Mariusz P.,Nisbet, Rebecca M.,Suryadinata, Randy,Coia, Gregory,Hong, Lisa P. T.,Adams, Timothy E.,Williams, Charlotte C.,Nuttall, Stewart D.
, p. 2675 - 2685 (2014/05/06)
The Sortase A (SrtA) enzyme from Staphylococcus aureus catalyses covalent attachment of protein substrates to pentaglycine cross-bridges in the Gram positive bacterial cell wall. In vitro SrtA-mediated protein ligation is now an important protein engineering tool for conjugation of substrates containing the LPXTGX peptide recognition sequence to oligo-glycine nucleophiles. In order to explore the use of alternative nucleophiles in this system, five different rhodamine-labelled compounds, with N-terminal nucleophilic amino acids, triglycine, glycine, and lysine, or N-terminal non-amino acid nucleophiles ethylenediamine and cadaverine, were synthesized. These compounds were tested for their relative abilities to function as nucleophiles in SrtA-mediated bioconjugation reactions. N-Terminal triglycine, glycine and ethylenediamine were all efficient in labelling a range of LPETGG containing recombinant antibody and scaffold proteins and peptides, while reduced activity was observed for the other nucleophiles across the range of proteins and peptides studied. Expansion of the range of available nucleophiles which can be utilised in SrtA-mediated bioconjugation expands the range of potential applications for this technology. As a demonstration of the utility of this system, SrtA coupling was used to conjugate the triglycine rhodamine-labelled nucleophile to the C-terminus of an Im7 scaffold protein displaying Aβ, a neurologically important peptide implicated in Alzheimer's disease. Purified, labelled protein showed Aβ-specific targeting to mammalian neuronal cells. Demonstration of targeting neuronal cells with a chimeric protein illustrates the power of this system, and suggests that SrtA-mediated direct cell-surface labelling and visualisation is an achievable goal. This journal is the Partner Organisations 2014.
