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General Description

2,5-Pyrrolidinedione, 1-[(6-azido-1-oxohexyl)oxy]- is a chemical compound with the molecular formula C11H15N3O4. It is a derivative of pyrrolidinedione and contains an azido group and a hexyl oxo substituent. 2,5-Pyrrolidinedione, 1-[(6-azido-1-oxohexyl)oxy]- may have potential applications in the fields of medicinal chemistry and organic synthesis, as azido groups are often used in bioconjugation and click chemistry reactions. Its properties and reactivity make it a valuable building block for the synthesis of complex organic molecules. Further research and exploration of its potential uses are warranted to fully understand its utility and practical applications.

Upstream product

• 6066-82-6 1-hydroxy-pyrrolidine-2,5-dione 
• 79598-53-1 6-azidohexanoic acid 
• 4224-70-8 6-bromohexanoic acid 

Downstream Products

• 1346434-20-5 O-(9-(2-((N-(6-azidohexanoyl)-N-methylamino)methyl)fluorenyl)methyl) N-phenylcarbamate 

Relevant academic research and scientific papers

SiO2 nanoparticles as platform for delivery of nucleoside triphosphate analogues into cells

A system for delivery of analogues of 2′-deoxyribonucleoside triphosphate (dNTP) based on SiO2 nanoparticles was proposed. A simple and versatile method was developed for the preparation of SiO 2-dNTP conjugates using the 'click'-reaction between premodified nanoparticles containing the azido groups and dNTP containing the alkyne-modified γ-phosphate group. The substrate properties of SiO 2-dNTP were tested using Klenow fragment and HIV reverse transcriptase. Nucleoside triphosphates being a part of the SiO2-dNTP nanocomposites were shown to be incorporated into the growing DNA chain. The rate of polymerization with the use of SiO2-dNTP or common dNTP in case of HIV reverse transcriptase differed insignificantly. It was shown by confocal microscopy that the proposed SiO2-dNTP nanocomposites bearing the fluorescent label penetrate into cells and even into cellular nuclei.

Comb-like dextran copolymers: A versatile strategy to coat highly porous MOF nanoparticles with a PEG shell

Nanoparticles made of metal-organic frameworks (nanoMOFs) are becoming of increasing interest as drug carriers. However, engineered coatings such as poly(ethylene glycol) (PEG) based ones are required to prevent nanoMOFs recognition and clearance by the innate immune system, a prerequisite for biomedical applications. This still presents an important challenge due to the highly porous structure and degradability of nanoMOFs. We provide here a proof of concept that the surface of iron-based nanoMOFs can be functionalized in a rapid, organic solvent-free and non-covalent manner using a novel family of comb-like copolymers made of dextran (DEX) grafted with both PEG and alendronate (ALN) moieties, which are iron complexing groups to anchor to the nanoMOFs surface. We describe the synthesis of DEX-ALN-PEG copolymers by click chemistry, with control of both the amount of PEG and ALN moieties. Stable DEX-ALN-PEG coatings substantially decreased their internalization by macrophages in vitro, providing new perspectives for biomedical applications.

Intracellular Delivery of Functional Native Antibodies under Hypoxic Conditions by Using a Biodegradable Silica Nanoquencher

Antibodies are important biopharmaceuticals, but almost all existing antibody-based drugs are limited to targeting antigens located at the cell exterior because of the inability of antibodies to enter the cell interior. Available methods for intracellular

Finding a human telomere DNA-RNA hybrid G-quadruplex formed by human telomeric 6-mer RNA and 16-mer DNA using click chemistry: A protective structure for telomere end

Telomeric repeat-containing RNA is a non-coding RNA molecule newly found in mammalian cells. The telomere RNA has been found to localize to the telomere DNA, but how the newly discovered RNA molecule interacts with telomere DNA is less known. In this study, using the click chemistry we successfully found that a 6-mer human telomere RNA and 16-mer human telomere DNA sequence can form a DNA-RNA hybrid type G-quadruplex structure. Detection of the click-reaction products directly probes DNA-RNA G-quadruplex structures in a complicated solution, whereas traditional methods such as NMR and crystallography may not be suitable. Importantly, we found that formation of DNA-RNA G-quadruplex induced an exonuclease resistance for telomere DNA, indicating that such structures might be important for protecting telomeric DNA from enzyme digestion to avoid telomere DNA shortening. These results provide the direct evidence for formation of DNA-RNA hybrid G-quadruplex structure by human telomere DNA and RNA sequence, suggesting DNA-RNA hybrid G-quadruplex structure associated between telomere DNA and RNA may respond to chromosome end protection and/or present a valuable target for drug design.

Simultaneous Imaging of Endogenous Survivin mRNA and On-Demand Drug Release in Live Cells by Using a Mesoporous Silica Nanoquencher

The design of multifunctional drug delivery systems capable of simultaneous target detection, imaging, and therapeutics in live mammalian cells is critical for biomedical research. In this study, by using mesoporous silica nanoparticles (MSNs) chemically modified with a small-molecule dark quencher, followed by sequential drug encapsulation, MSN capping with a dye-labeled antisense oligonucleotide, and bioorthogonal surface modification with cell-penetrating poly(disulfide)s, the authors have successfully developed the first mesoporous silica nanoquencher (qMSN), characterized by high drug-loading and endocytosis-independent cell uptake, which is able to quantitatively image endogenous survivin mRNA and release the loaded drug in a manner that depends on the survivin expression level in tumor cells. The authors further show that this novel drug delivery system may be used to minimize potential cytotoxicity encountered by many existing small-molecule drugs in cancer therapy.

Development of a new azido-oxazoline monomer for the preparation of amphiphilic graft copolymers by combination of cationic ring-opening polymerization and click chemistry

A new monomer (2-(5-azidopentyl)-2-oxazoline) bearing an azido group was synthesized. The cationic ring-opening copolymerization of this monomer with 2-methyl-2-oxazoline resulted in a well-defined linear polymer backbone with pendant azido groups. Alkynyl-poly(D,L-lactide) was grafted onto the azido groups of poly(oxazoline) via a Huisgen 1,3-dipolar cycloaddition reaction to give a novel amphiphilic graft copolymer [poly(2-methyl-2-oxazoline-co-2-pentyl- 2-oxazoline)-g-poly(D,L-lactide)] (P[(MeOx-co-PentOx)-g-LA]). Different graft copolymers were prepared with PLA of different lengths. Preliminary results of the self-association of this copolymer in water indicated the formation of nanoparticles, which suggests this copolymer may have applications as vehicles for drug delivery.

MULTI-FUNCTIONAL CHIMERIC MOLECULES

The present disclosure relates to multifunctional chemical conjugation molecules, which find utility as modifiers of target substrates. The present disclosure includes multifunctional compounds comprising a localizing moiety, a chemical linker moiety, an activator moiety, a first orienting adaptor interconnecting the chemical linker moiety on one end to the activator moiety, and optionally a second orienting adaptor interconnecting the chemical linker molecule on a different end to the localizing moiety. Molecules according to the present invention find use making post-translational modifications to macromolecules that are not the natural substrate of the activator moiety. Diseases or disorders may be treated or prevented with molecules of the present disclosure.

Antibiotic Conjugates with an Artificial MECAM-Based Siderophore Are Potent Agents against Gram-Positive and Gram-Negative Bacterial Pathogens

The development of novel drugs against Gram-negative bacteria represents an urgent medical need. To overcome their outer cell membrane, we synthesized conjugates of antibiotics and artificial siderophores based on the MECAM core, which are imported by bacterial iron uptake systems. Structures, spin states, and iron binding properties were predicted in silico using density functional theory. The capability of MECAM to function as an effective artificial siderophore in Escherichia coli was proven in microbiological growth recovery and bioanalytical assays. Following a linker optimization focused on transport efficiency, five β-lactam and one daptomycin conjugates were prepared. The most potent conjugate 27 showed growth inhibition of Gram-positive and Gram-negative multidrug-resistant pathogens at nanomolar concentrations. The uptake pathway of MECAMs was deciphered by knockout mutants and highlighted the relevance of FepA, CirA, and Fiu. Resistance against 27 was mediated by a mutation in the gene encoding ExbB, which is involved in siderophore transport.

Phosphorylation-Inducing Chimeric Small Molecules

Small molecules have been classically developed to inhibit enzyme activity; however, new classes of small molecules that endow new functions to enzymes via proximity-mediated effect are emerging. Phosphorylation (native or neo) of any given protein-of-interest can alter its structure and function, and we hypothesized that such modifications can be accomplished by small molecules that bring a kinase in proximity to the protein-of-interest. Herein, we describe phosphorylation-inducing chimeric small molecules (PHICS), which enable two example kinases - AMPK and PKC - to phosphorylate target proteins that are not otherwise substrates for these kinases. PHICS are formed by linking small-molecule binders of the kinase and the target protein, and exhibit several features of a bifunctional molecule, including the hook-effect, turnover, isoform specificity, dose and temporal control of phosphorylation, and activity dependent on proximity (i.e., linker length). Using PHICS, we were able to induce native and neo-phosphorylations of BRD4 by AMPK or PKC. Furthermore, PHICS induced a signaling-relevant phosphorylation of the target protein Bruton's tyrosine kinase in cells. We envision that PHICS-mediated native or neo-phosphorylations will find utility in basic research and medicine.

Quantitative Profiling of Protein Carbonylations in Ferroptosis by an Aniline-Derived Probe

Ferroptosis is a regulated form of necrotic cell death implicated in carcinogenesis and neurodegeneration that is driven by phospholipid peroxidation. Lipid-derived electrophiles (LDEs) generated during this process can covalently modify proteins ("carbonylation") and affect their functions. Here we report the development of a quantitative chemoproteomic method to profile carbonylations in ferroptosis by an aniline-derived probe. Using the method, we established a global portrait of protein carbonylations in ferroptosis with >400 endogenously modified proteins and for the first time, identified >20 residue sites with endogenous LDE modifications in ferroptotic cells. Specifically, we discovered and validated a novel cysteine site of modification on voltage-dependent anion-selective channel protein 2 (VDAC2) that might play an important role in sensitizing LDE signals and mediating ferroptosis. Our results will contribute to the understanding of ferroptotic signaling and pathogenesis and provide potential biomarkers for ferroptosis detection.