Cytotoxicity of Amino-BODIPY Modulated via Conjugation with 2-Phenyl-3-Hydroxy-4(1H)-Quinolinones

The combination of cytotoxic amino-BODIPY dye and 2-phenyl-3-hydroxy-4(1H)-quinolinone (3-HQ) derivatives into one molecule gave rise to selective activity against lymphoblastic or myeloid leukemia and the simultaneous disappearance of the cytotoxicity against normal cells. Both species′ conjugation can be realized via a disulfide linker cleavable in the presence of glutathione characteristic for cancer cells. The cleavage liberating the free amino-BODIPY dye and 3-HQ derivative can be monitored by ratiometric fluorescence or by the OFF-ON effect of the amino-BODIPY dye. A similar cytotoxic activity is observed when the amino-BODIPY dye and 3-HQ derivative are connected through a non-cleavable maleimide linker. The work reports the synthesis of several conjugates, the study of their cleavage inside cells, and cytotoxic screening.     

An Aldehyde Responsive,Cleavable Linker for Glucose Responsive Insulins

A glucose responsive insulin (GRI) that responds to changes in blood glucose concentrations has remained an elusive goal. Here we describe the development of glucose cleavable linkers based on hydrazone and thiazolidine structures. We developed linkers with low levels of spontaneous hydrolysis but increased level of hydrolysis with rising concentrations of glucose, which demonstrated their glucose responsiveness in vitro. Lipidated hydrazones and thiazolidines were conjugated to the LysB29 side-chain of HI by pH-controlled acylations providing GRIs with glucose responsiveness confirmed in vitro for thiazolidines. Clamp studies showed increased glucose infusion at hyperglycemic conditions for one GRI indicative of a true glucose response. The glucose responsive cleavable linker in these GRIs allow changes in glucose levels to drive the release of active insulin from a circulating depot. We have demonstrated an unprecedented, chemically responsive linker concept for biopharmaceuticals.     

Theoretical investigation of nonlinear optical behavior for rod and T-Shaped phenothiazine based D-π-A organic compounds and their derivatives

The exploration of novel materials with excellent nonlinear optical (NLO) features is an area of frontline investigation for scientific community from technological point of view. This study reports the novel phenothiazine-based rod-shaped and T-shaped NLO molecules which are quantum chemically designed from synthesized compounds: rod-shaped (CFA and CBA) and T-shaped (CTA, CCA and CPA). Structural tailoring was performed on D-π-π-A centered CPA chromophore and the effect of various π-spacers, as well as solvents on NLO response properties is investigated. Density functional theory (DFT) along with time dependent DFT (TDDFT) calculations have been executed at B3LYP/6-311G(d,p) functional to examine entire analysis. Results showed a smaller energy gap in structurally modified compounds as compared to reference CPA. Global reactivity parameters analysis revealed smaller hardness and larger softness values in T-shaped compounds. UV–Vis analysis of investigated molecules displayed a red shift in absorption maximum value as compared to CPA. Natural bond orbital (NBO) and frontier molecular orbital (FMO) analysis revealed the stability and intra-molecular electron transferring (ICT) process in investigated molecules. ICT showed the effective charge shift from donor to acceptor via π-spacers. Overall, promising NLO response exists in gas phase and different solvents (acetonitrile, ethyl alcohol and water). Interestingly, proposed molecule CPP presented a maximum value of linear polarizability < α > as 1518.23 a.u and first hyperpolarizability (β_tot) as 755322.39 a.u in acetonitrile solvent. In short, entitled chromophores exhibited excellent NLO properties due to their lower charge transport resistance. This NLO study may open a new topic for researchers to discover novel NLO for hi-tech submissions of modern era.     

A Combined Experimental and Computational Study on the Adsorption Sites of Zinc-Based MOFs for Efficient Ammonia Capture

Ammonia (NH₃) is a common pollutant mostly derived from pig manure composting under humid conditions, and it is absolutely necessary to develop materials for ammonia removal with high stability and efficiency. To this end, metal–organic frameworks (MOFs) have received special attention because of their high selectivity of harmful gases in the air, resulting from their large surface area and high density of active sites, which can be tailored by appropriate modifications. Herein, two synthetic metal–organic frameworks (MOFs), 2-methylimidazole zinc salt (ZIF-8) and zinc-trimesic acid (ZnBTC), were selected for ammonia removal under humid conditions during composting. The two MOFs, with different organic linkers, exhibit fairly distinctive ammonia absorption behaviors under the same conditions. For the ZnBTC framework, the ammonia intake is 11.37 mmol/g at 298 K, nine times higher than that of the ZIF-8 framework (1.26 mmol/g). In combination with theoretical calculations, powder XRD patterns, FTIR, and BET surface area tests were conducted to reveal the absorption mechanisms of ammonia for the two materials. The adsorption of ammonia on the ZnBTC framework can be attributed to both physical and chemical adsorption. A strong coordination interaction exists between the nitrogen atom from the ammonia molecule and the zinc atom in the ZnBTC framework. In contrast, the absorption of ammonia in the ZIF-8 framework is mainly physical. The weak interaction between the ammonia molecule and the ZIF-8 framework mainly results from the inherent severely steric hindrance, which is related to the coordination mode of the imidazole ligands and the zinc atom of this framework. Therefore, this study provides a method for designing promising MOFs with appropriate organic linkers for the selective capture of ammonia during manure composting.     

CO2‐Breathing Induced Reversible Activation of Mechanophore within Microgels

In this work, CO₂‐breathing induced reversible activation of mechanophore within microgels is reported. The microgels are prepared through soap‐free emulsion polymerization of CO₂‐switchable monomer 2‐(diethylamino)ethyl‐methacrylate, using spiropyran (SP) based mechanophore MA‐SP‐MA as cross‐linker. The microgels can be swollen by CO₂ aeration. The swelling of microgels activates the SP mechanophore into merocyanine, causing distinguished color and fluorescence change. Moreover, these transitions are highly reversible, and the initial states of microgels can be easily recovered by “washing off” CO₂ with N₂. The present contribution represents the first example of CO₂‐breathing activation of mechanophore within microgels.

     

Synthetic approaches to constructing proteolysis targeting chimeras (PROTACs)

The development of various heterobifunctional constructs dubbed PRoteolysis-TArgeting Chimeras (PROTACs) has gained a significant impetus in the last few years. A viable alternative to the traditional occupancy-based inhibition of aberrantly hyperactive proteins, PROTACs operate by an event-based catalytic mechanism bringing together the protein of interest (POI, to be degraded) and E3 ubiquitin ligases. The formation of the ternary complex ‘POI–PROTAC–E3 ubiquitin ligase’ is the critical step which leads to the ubiquitination of the POI and its proteasomal degradation. The current Focused Review aims to highlight the syntheses of selected innovative PROTAC-type degraders of the therapeutically important protein targets as well as some notable chemical aspects of PROTAC construction. The overview is focusing on PROTACs aimed at recruiting Cereblon, the most exploited E3 ligase for targeted protein degradation.     

Secondary Amino Alcohols: Traceless Cleavable Linkers for Use in Affinity Capture and Release

Capture and release of peptides is often a critical operation in the pathway to discovering materials with novel functions. However, the best methods for efficient capture impede facile release. To overcome this challenge, we report linkers based on secondary amino alcohols for the release of peptides after capture. These amino alcohols are based on serine (seramox) or isoserine (isoseramox) and can be incorporated into peptides during solid‐phase peptide synthesis through reductive amination. Both linkers are quantitatively cleaved within minutes under NaIO₄ treatment. Cleavage of isoseramox produced a native peptide N‐terminus. This linker also showed broad substrate compatibility; incorporation into a synthetic peptide library resulted in the identification of all sequences by nanoLC‐MS/MS. The linkers are cell compatible; a cell‐penetrating peptide that contained this linker was efficiently captured and identified after uptake into cells. These findings suggest that such secondary amino alcohol based linkers might be suitable tools for peptide‐discovery platforms.     

A biuret‐derived,MS‐cleavable cross‐linking reagent for protein structural analysis: A proof‐of‐principle study

Chemical cross‐linking combined with mass spectrometry (XL‐MS) and computational modeling has evolved as an alternative method to derive protein 3D structures and to map protein interaction networks. Special focus has been laid recently on the development and application of cross‐linkers that are cleavable by collisional activation as they yield distinct signatures in tandem mass spectra. Building on our experiences with cross‐linkers containing an MS‐labile urea group, we now present the biuret‐based, CID‐MS/MS‐cleavable cross‐linker imidodicarbonyl diimidazole (IDDI) and demonstrate its applicability for protein cross‐linking studies based on the four model peptides angiotensin II, MRFA, substance P, and thymopentin.     

Bioorthogonal Cleavage and Exchange of Major Histocompatibility Complex Ligands by Employing Azobenzene‐Containing Peptides

Bioorthogonal cleavable linkers are attractive building blocks for compounds that can be manipulated to study biological and cellular processes. Sodium dithionite sensitive azobenzene‐containing (Abc) peptides were applied for the temporary stabilization of recombinant MHC complexes, which can then be employed to generate libraries of MHC tetramers after exchange with a novel epitope. This technology represents an important tool for high‐throughput studies of disease‐specific T cell responses.