29022-11-5Relevant articles and documents
Large molecular assembly of amphotericin B formed in ergosterol-containing membrane evidenced by solid-state NMR of intramolecular bridged derivative
Matsumori, Nobuaki,Sawada, Yuri,Murata, Michio
, p. 11977 - 11984 (2006)
Amphotericin B (AmB 1) is known to assemble and form an ion channel across biomembranes. We have recently reported that conformation-restricted derivatives of AmB 2-4 show different ergosterol preferences in ion-channel assays, which suggested that the orientation of the mycosamine strongly affects the sterol selectivity of AmB. The data allowed us to assume that compound 3 showing the highest selectivity would reflect the active conformation of AmB in the channel assembly. In this study, to gain further insight into the active conformation of AmB, we prepared a new intramolecular-bridged derivative 5, where the linker encompassed a hydrophilic glycine moiety. The derivative has almost equivalent ion-channel activity to those of AmB and 3. The antifungal activity of 5 compared with 3 improves significantly, possibly because the increasing hydrophilicity in the linker enhances the penetrability through the fungal cell wall. Conformation of 5 was well converged and very similar to that of 3, thus further supporting the notion that the conformations of these derivatives reproduce the active structure of AmB in the channel complex. Then we used the derivative to probe the mobility of AmB in the membrane by solid-state NMR. To measure dipolar couplings and chemical shift anisotropies, we incorporated [1-13C,15N]glycine into the linker. The results indicate that 5 is mostly immobilized in ergosterol-containing DMPC bilayers, implying formation of large aggregates of 5. Meanwhile some fraction of 5 remains mobile in sterol-free DMPC bilayers, suggesting promotion of Amb aggregation by ergosterol.
Fmoc-Amox, A Suitable Reagent for the Introduction of Fmoc
Kumar, Ashish,Sharma, Anamika,Haimov, Elvira,El-Faham, Ayman,De La Torre, Beatriz G.,Albericio, Fernando
, p. 1533 - 1541 (2017)
Synthesis of most peptides is achieved using solid-phase peptide synthesis employing the Fmoc/tert-butyl strategy. However, the introduction of Fmoc in N-unprotected amino acids seems to be challenging due to the formation of dipeptides and sometimes tripeptides as impurities and β-alanyl impurities when Fmoc-OSu is used as well. Herein, we report an efficient and successful method using Fmoc-Amox, which is an oxime based derivative, toward the synthesis of Fmoc-glycine with no traces of side reactions. Fmoc-Amox is inexpensive, and Amox can be easily removed after the reaction, thus affording pure Fmoc-Gly-OH devoid of any detrimental impurities or contamination, mainly dipeptide or Amox itself, as shown by high-performance liquid chromatography and NMR, respectively.
Synthesis and characterization of a photocleavable collagen-like peptide
Li, Chunqiang,Ornelas, Alfredo,Williams, Kaitlyn N.,Hatch, Kevin A.,Paez, Aurelio,Aguilar, Angela C.,Ellis, Cameron C.,Tasnim, Nishat,Ray, Supriyo,Dirk, Carl W.,Boland, Thomas,Joddar, Binata,Michael, Katja
, p. 1000 - 1013 (2018)
A 34-amino acid long collagen-like peptide rich in proline, hydroxyproline, and glycine, and with four photoreactive N-acyl-7-nitroindoline units incorporated into the peptide backbone was synthesized by on-resin fragment condensation. Its circular dichroism supports a stable triple helix structure. The built-in photochemical function enables the decomposition of the peptide into small peptide fragments by illumination with UV light of 350 nm in aqueous solution. Illumination of a thin film of the peptide, or a thin film of a photoreactive amino acid model compound containing a 5-bromo-7-nitroindoline moiety, with femtosecond laser light at 710 nm allows for the creation of well-resolved micropatterns. The cytocompatibility of the peptide was demonstrated using human mesenchymal stem cells and mouse embryonic fibroblasts. Our data show that the full-length peptide is cytocompatible as it can support cell growth and maintain cell viability. In contrast, the small peptide fragments created by photolysis are somewhat cytotoxic and therefore less cytocompatible. These data suggest that biomimetic collagen-like photoreactive peptides could potentially be used for growing cells in 2D micropatterns based on patterns generated by photolysis prior to cell growth.
Oxime carbonates: Novel reagents for the introduction of fmoc and alloc protecting groups, free of side reactions
Khattab, Sherine N.,Subiros-Funosas, Ramon,El-Faham, Ayman,Albericio, Fernando
, p. 3275 - 3280 (2010)
Fmoc and Alloc protecting groups represent a consistent alternative to classical Boc protection in peptide chemistry. The former was established in the last decades as the α-amino protecting group of choice, whereas the latter allows a fully orthogonal protection strategy with Fmoc and Boc. Usually, the introduction of the Fmoc and Alloc moieties takes place through their halogenoformates, azides, or activated carbonates. This rather simple reaction is accompanied by several side reactions, specially the formation of Fmoc/Alloc dipeptides and even tripeptides. The present work describes new promising Fmoc/Alloc-oxime reagents, which are easy to prepare, stable, and highly reactive crystalline materials that afford almost: contaminant-free Fmoc/Alloc-amino acids in high yields by following a conventional procedure. Amongst the Fmoc-oxime derivatives, the N-hydroxypicolimmidoyl cyanide derivative (N-([(9H-fluoren-9-yl)methoxy]carbonyloxy}picolinimidoyl cyanide) gave the best results for the preparation of Fmoc-Gly-OH, which is the most predisposed to give side reactions. The same Alloc-oxime analogue afforded the preparation of Alloc-Gly-OH in good yield, purity, and extremely low dipeptide formation, as analyzed by reverse-phase HPLC and NMR spectroscopy.
Fungal Dioxygenase AsqJ Is Promiscuous and Bimodal: Substrate-Directed Formation of Quinolones versus Quinazolinones
Einsiedler, Manuel,Jamieson, Cooper S.,Maskeri, Mark A.,Houk, Kendall N.,Gulder, Tobias A. M.
supporting information, p. 8297 - 8302 (2021/03/01)
Previous studies showed that the FeII/α-ketoglutarate dependent dioxygenase AsqJ induces a skeletal rearrangement in viridicatin biosynthesis in Aspergillus nidulans, generating a quinolone scaffold from benzo[1,4]diazepine-2,5-dione substrates. We report that AsqJ catalyzes an additional, entirely different reaction, simply by a change in substituent in the benzodiazepinedione substrate. This new mechanism is established by substrate screening, application of functional probes, and computational analysis. AsqJ excises H2CO from the heterocyclic ring structure of suitable benzo[1,4]diazepine-2,5-dione substrates to generate quinazolinones. This novel AsqJ catalysis pathway is governed by a single substituent within the complex substrate. This unique substrate-directed reactivity of AsqJ enables the targeted biocatalytic generation of either quinolones or quinazolinones, two alkaloid frameworks of exceptional biomedical relevance.
Dihydroartemisinin and steroid conjugates, and preparation method and application thereof
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Paragraph 0098-0102, (2019/11/20)
The present invention discloses conjugates, having a general formula (I), obtained by condensation of dihydroartemisinin and steroids, or isomers or pharmaceutically acceptable salts or prodrug molecules thereof. The 10-position hydroxyl group of artemisinin and the 3-position hydroxyl group of the steroid compounds are condensed and linked by an ether bond. The invention discloses a preparation method of the compounds, and an application of the compounds in the treatment of autoimmune diseases. The dihydroartemisinin and steroid conjugates of the present invention are novel immunosuppressants, and can be used alone or in combination with other drugs to treat the human autoimmune diseases. The conjugates have the advantages of high curative effect, small toxicity and very broad applicationprospect.
Unwanted hydrolysis or α/β-peptide bond formation: How long should the rate-limiting coupling step take?
Goldschmidt G?z, Viktória,Nagy, Adrienn,Farkas, Viktor,Keszei, Ern?,Perczel, András
, p. 30720 - 30728 (2019/10/28)
Nowadays, in Solid Phase Peptide Synthesis (SPPS), being either manual, automated, continuous flow or microwave-assisted, the reaction with various coupling reagents takes place via in situ active ester formation. In this study, the formation and stability of these key active esters were investigated with time-resolved 1H NMR by using the common PyBOP/DIEA and HOBt/DIC coupling reagents for both α- and β-amino acids. Parallel to the amide bond formation, the hydrolysis of the α/β-active esters, a side reaction that is a considerable efficacy limiting factor, was studied. Based on the chemical nature/constitution of the active esters, three amino acid categories were determined: (i) the rapidly hydrolyzing ones (t 24 h) in solution. The current insight into the kinetics of this key hydrolysis side reaction serves as a guide to optimize the coupling conditions of α- and β-amino acids, thereby saving time and minimizing the amounts of reagents and amino acids to be used-all key factors of more environmentally friendly chemistry.
A 4-OTBS benzyl-based protective group for carboxylic acids
Fang, Zhijun,Li, Yuyao,Xie, Hexin
supporting information, p. 1658 - 1662 (2019/05/29)
Reported herein is a novel 4-OTBS benzyl-based protective group for carboxylic acids. This protective group can be removed in the presence of TBAF or TFA with high efficiency, which makes it compatible with base-sensitive or acid-sensitive substrates. With this protective group, a near-infrared fluorogenic probe for the detection of γ-glutamyltranspeptidase activities was readily prepared.
PHOTOREACTIVE COLLAGEN-LIKE PEPTIDES
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Paragraph 0092, (2019/04/30)
A novel 34 amino acid long collagen-like peptide rich in proline, hydroxyproline, and glycine, and with several photoreactive N-acyl-7-nitroindoline units incorporated into the peptide backbone was synthesized by on-resin fragment condensation. The circular dichroism measurement of this peptide supports a stable triple helix structure. This peptide has potential as a new biomimetic material with built-in latent photochemical functions that enable the decomposition into small peptide fragments by illumination with UV light of 350 nm. Using a photoreactive glycine derivative as a model compound for the collagen-like peptide, we demonstrate that its photolysis can also be triggered by a two-photon absorption process using a femtosecond laser at 710 nm. When a thin film of this compound is irradiated with femtosecond laser light at 710 nm the photochemistry occurs only at locations of irradiation. In addition, the collagen-like peptide is able to support mesenchymal stem cell growth, indicating its non-toxicity to these cells and its potential in tissue engineering applications.
A colourful azulene-based protecting group for carboxylic acids
Bevan, Thomas W.,Francis-Taylor, James,Wong, Helena,Northcote, Peter T.,Harvey, Joanne E.
supporting information, p. 2942 - 2955 (2018/05/16)
An intensely blue-coloured protecting group for carboxylic acids has been developed. The protecting group is introduced through a Steglich esterification that couples 6-(2-hydroxyethyl)azulene (AzulE) and the carboxylic acid substrate. Deprotection is effected under basic conditions by the addition of the amidine base DBU, whereupon cleavage occurs, accompanied by a colour change. A two-step deprotection methodology comprising activation with oxalyl chloride and deprotection with a very mild base was developed for use with base-sensitive substrates. The AzulE esters were found to be compatible with other commonly employed protecting groups – silyl ethers, MOM acetals – by studying their orthogonal and concomitant deprotections. The stability of the new protecting group towards various synthetic processes – oxidation, reduction, cross-coupling, olefination and treatment with base – provided the basis of a versatility profile. This indicated that AzulE esters are sensitive to strongly oxidising and basic agents while being compatible with reducing conditions and selected other reactions. The convenience of a highly coloured protecting group for tracking material (and avoiding loss of compound) through laboratory processes warrants further investigation of this and/or related species.
