Protection-deprotection Strategy Research Articles

Unleashing the potential of vanillic acid: A new twist on nature's recipe to fight inflammation and circumvent azole-resistant fungal infections

Vanillic acid (VA) — a naturally occurring phenolic compound in plants — is not only used as a flavoring agent but also a prominent metabolite post tea consumption. VA and its associated compounds are believed to play a significant role in preventing diseases, underscoring the need for a systematic investigation. Herein, we report a 4-step synthesis employing the classical organic reactions, such as Willamson’s alkylation, Fischer-Spier reaction, and Steglich esterification, complemented with a protection-deprotection strategy to prepare 46 VA derivatives across the five series (1a–1i, 2a–2i, 3, 3a–3i, 4a–4i, 5a–5i) in high yields. The synthesized compounds were investigated for their antifungal, anti-inflammatory, and toxic effects. Notably, compound 1a demonstrated remarkable ROS inhibition with an IC50 value of 5.1 ± 0.7 µg/mL, which is more than twice as effective as the standard ibuprofen drug. A subset of the synthesized derivatives (2b, 2c, 2e, 3b–3d, 4a–4c, 5a, and 5e) manifested their antifungal effect against drug-resistant Candida strains. Compound 5g, in particular, revealed synergism with the established antifungal drugs amphotericin B (AMB) and fluconazole (FLZ), doubling FLZ's potency against azole resistant Candida albican ATCC 36082. Furthermore, 5g improved the potency of these antifungals against FLZ-sensitive strains, including C. glabrata ATCC 2001 and C. parapsilosis ATCC 22019, as well as various multidrug-resistant (MDR) Candida strains, namely C. albicans ATCC 14053, C. albicans CL1, and C. krusei SH2L OM341600. Additionally, pharmacodynamics of compound 5g was examined using time-kill assay, and a benign safety profile was observed with no hemolytic activity in whole blood, and no cytotoxicity towards the normal BJ human cell line. The synergistic potential of 5g was further investigated through both experimental methods and docking simulations.These findings highlight the therapeutic potential of VA derivatives, particularly in addressing inflammation and circumventing FLZ resistance in Candida albicans.

Enhancing the Crystallinity of Keto-enamine-Linked Covalent Organic Frameworks through an in situ Protection-Deprotection Strategy.

β-Keto-enamine-linked 2D covalent organic frameworks (COFs) have emerged as highly robust materials, showing significant potential for practical applications. However, the exclusive reliance on 1,3,5-triformylphloroglucinol (Tp aldehyde) in the design of such COFs often results in the production of non-porous amorphous polymers when combined with certain amine building blocks. Attempts to adjust the crystallinity and porosity by a modulator approach are inefficient because Tp aldehyde readily forms stable β-keto-enamine-linked monomers/oligomers with various aromatic amines through an irreversible keto-enol tautomerization process. Our research employed a unique protection-deprotection strategy to enhance the crystallinity and porosity of β-keto-enamine-linked squaramide-based 2D COFs. Advanced solid-state NMR studies, including 1D 13 C CPMAS, 1 H fast MAS, 15 N CPMAS, 2D 13 C-1 H correlation, 1 H-1 H DQ-SQ, and 14 N-1 H HMQC NMR were used to establish the atomic-level connectivity within the resultant COFs. The TpOMe -Sqm COFs synthesized utilizing this strategy have a surface area of 487 m2 g-1 , significantly higher than similar COFs synthesized using Tp aldehyde. Furthermore, detailed time-dependent PXRD, solid-state 13 C CPMAS NMR, and theoretical DFT studies shed more light on the crystallization and linkage conversion processes in these 2D COFs. Ultimately, we applied this protection-deprotection method to construct novel keto-enamine-linked highly porous organic polymers with a surface area of 1018 m2 g-1 .

Stable and highly efficient HMDS terminated m-Cresol inhibitor for inhibiting coal spontaneous combustion

A stable and highly efficient 1, 1, 3, 3, 3-hexamethyldisilazane (HMDS) terminated m-Cresol inhibitor was synthesized based on the protection-deprotection strategy. The inhibitory effect of HMDS terminated m-Cresol inhibitor on spontaneous combustion of lignite was explored through temperature-programmed oxidation tests, in-situ infrared analysis and thermogravimetric analysis. Results show that, the oxidation of active phenolic hydroxyl groups in the m-Cresol inhibitor can be hindered by the protection of HMDS. After encountering coal, the HMDS terminated inhibitor can be gradually deprotected to regenerate the m-Cresol inhibitor that contains massive active phenolic hydroxyl groups, thus improving the chemical inhibition efficiency of coal spontaneous combustion. For the coal sample inhibited with HMDS terminated m-Cresol inhibitor, the initial contents of the active functional groups are lower and more stable during heating, and the inhibition rate reaches 70% at 130 °C. Moreover, the crossing-point temperature rises by 32.4 °C–181.2 °C. The activation energy increases by 11 kJ/mol and 18 kJ/mol at below and above 130 °C respectively. The peak temperature at maximum weight loss rate rises by 65 °C–431.2 °C, and the corresponding residual carbon rate increased by 31.3%–61.6%. The inhibition mechanism of the HMDS terminated m-Cresol inhibitor on coal spontaneous combustion was deduced.

Practical Strategy to 1,1'-Dideoxygossypol Derivatives from Gossypol and Its Antitumor Activities.

A practical and scalable route for the synthesis of 1,1′-dideoxygossypol from natural polyphenol product gossypol is described. The key step is the successful regioselective deacetylation of hexaacetyl apogossypol 9 and the following reductive removal of hydroxyl groups. The two steps of deacetylation occurred on the different sites under different conditions. The synthetic route follows a simple protection–deprotection strategy, and the yields of each step are over 85%. The total yield of this 9-step synthesis is over 40%, which is much better than the reported total synthesis method. The antitumor results illustrate that 1,1′-hydroxyl groups are not necessary for antitumor activities. In addition, 1,1′-dideoxygossypol has superior aqueous solubility (215 mg/L) compared to gossypol (64 mg/L).

A Simple and Feasible Synthetic Strategy towards Poly(4‐thiostyrene)

AbstractPoly(4‐thiostyrene), a historically challenging to synthesize polymer, is synthesized herein via a feasible three‐step protocol. Based on the newly developed protection–deprotection strategy, the precursor polymer containing thiomethyl groups is deprotected using Li/naphthalene to yield poly(4‐thiostyrene) after acidification. This newly developed procedure is crucial for preventing crosslinking of the thiol groups and therefore the resulting polymer is soluble in common organic solvents (e.g., chloroform, tetrahydrofuran) and can be stored long‐term, which has been challenging to accomplish over the past 60 years. The successful synthesis is confirmed by various characterization techniques including NMR, Fourier‐transform infrared spectroscopy (FTIR), and Raman analysis, which collectively are new and useful data that have generally been unavailable in previous reports. This work provides a robust approach for synthesizing this promising polymer and offers a new route to investigate thiol‐containing polymers.

Synthesis of Dithiocatechol-Pendant Polymers.

Although the synthesis of thiophenol-pendant polymers was reported in the 1950s, the polymers generally suffered from oxidation and became insoluble in organic solvents, hampering detailed characterization and further applications. Dithiocatechol-pendant polymers, which have one additional ortho-thiol group than thiophenol-pendant polymers, have never been synthesized, despite their promise in various applications due to their analogous molecular structure with catechol-pendant polymers. Herein, we report the first synthesis of dithiocatechol-pendant polymers using a novel protection-deprotection strategy. We carefully examined the synthetic routes and identified the deprotection conditions that do not cause cross-linking of the dithiocatechol moieties. Because the resulting dithiocatechol-pendant polymers were soluble in common organic solvents (e.g., tetrahydrofuran and N,N-dimethylformamide), the polymers can be fully characterized by standard spectroscopic methods, providing valuable data for future researchers. We also showed that besides free-radical polymerization, reversible addition-fragmentation chain-transfer polymerization can also be adopted to synthesize dithiocatechol-pendant polymers. This work paves the way for the exploitation of dithiocatechol-containing polymers for the fabrication of novel functional materials.

Polyamine–Oligonucleotide Conjugates: 2′-OMe-Triazole-Linked 1,4,7,10-Tetraazacyclododecane and Intercalating Dyes and Their Effect on the Thermal Stability of DNA Duplexes

Oligonucleotides with the sequences 5′-GTG AUPA TGC, 5′-GCA TAUP CAC and 5′-GUPG ATA UPGC, where UP is 2′-O-propargyl uridine, were subjected to post-synthetic Cu(I)-catalyzed azide–alkyne cycloaddition to attach 1,4,7,10-tetraazacyclododecane (cyclen) and two well-known DNA intercalating dyes: thioxanthone and 1,8-naphthalimide. We propose a convenient cyclen protection–deprotection strategy that allows efficient separation of the resulting polyamine–oligonucleotide conjugates from the starting materials by RP-HPLC to obtain high-purity products. In this paper, we present hitherto unknown macrocyclic polyamine–oligonucleotide conjugates and their hybridization properties reflected in the thermal stability of thirty-two DNA duplexes containing combinations of labeled strands, their unmodified complementary strands, and strands with single base pair mismatches. Circular dichroism measurements showed that the B-conformation is retained for all dsDNAs consisting of unmodified and modified oligonucleotides. An additive and destabilizing effect of cyclen moieties attached to dsDNAs was observed. Tm measurements indicate that placing the hydrophobic dye opposite to the cyclen moiety can reduce its destabilizing effect and increase the thermal stability of the duplex. Interestingly, the cyclen-modified U showed significant selectivity for TT mismatch, which resulted in stabilization of the duplex. We conclude the paper with a brief review and discussion in which we compare our results with several examples of oligonucleotides labeled with polyamines at internal strand positions known in the literature.

Designed Synthesis of Diversely Substituted Hydantoins and Hydantoin-Based Hybrid Molecules: A Personal Account

AbstractHydantoin and its analogues such as thiohydantoin and iminohydantoin have received substantial attention from both a chemical and a biological point of view. Several compounds of this class have shown useful pharmacological activities such as anticonvulsant, antitumor, antiarrhythmic, and herbicidal properties that have led, in some cases, to clinical applications. Because of these broad-spectrum activities, intensive research efforts have been dedicated in industry and academia to the synthesis and structural modifications of hydantoin and its derivatives. Realizing the importance of hydantoin in organic and medicinal chemistry, we also initiated a research program that successfully designed and developed new routes and methods for the formation of hydantoin, thiohydantoin, and iminohydantoin substituted at various positions, particularly at the N-1 position without following a protection–deprotection strategy. Because combinations of two or more pharmacophoric groups can lead to hybrid molecules that display a mixed mechanism of action on biological targets, we extended our developed strategy to the syntheses of new types of hydantoin-based hybrid molecules by combining hydantoin with a triazole, isoxazoline, or phosphate scaffold as a second pharmacophore to exploit their diverse biological functions.1 Introduction2 Chemistry and Properties2.1 Physical Properties2.2 Chemical Properties2.3 Biological Properties3 General Synthetic Methods4 Synthesis of Diversely Substituted Hydantoins5 Synthesis of Diversely Substituted Thiohydantoins6 Synthesis of Diversely Substituted Iminohydantoins7 Fused or Bicyclic (Thio)hydantoins8 Di- or Multivalent (Thio)hydantoins9 Hydantoin-Based Hybrid Molecules9.1 Hydantoin–Isooxazoline Hybrids9.2 Hydantoin–Triazole Hybrids9.3 Hydantoin–Phosphate Hybrids: Phosphorylated Hydantoins10 Summary and Outlook

A non-peptide probe for detecting chymotrypsin activity based on protection-deprotection strategy in living systems.

Chymotrypsin (CHT) plays a vital role in the metabolism of organisms and affects cell proliferation and apoptosis. Abnormal levels of CHT will lead to a variety of diseases, such as inflammatory arthritis, diabetes, pharyngitis, indigestion, and pancreatic cancer. Therefore, it is significant to design an effective method for the detection of CHT in living systems. Here, we synthesized a specific deep-red non-peptide probe DT by effectively combining isophorone and p-hydroxybenzaldehyde for the detection of CHT using 3-phenylpropionate chloride as the recognition group based on a protection-deprotection strategy. The DT probe exhibited an emission range of 525-700 nm and showed excellent photostability, high sensitivity (LOD = 0.071 U mL-1), and selectivity for CHT detection. The cellular experiments demonstrated that DT could sensitively recognize CHT activity in three cell lines and the content of CHT was much higher in P815 cells than in MCF-7 and 3T3 cells. Also, DT was successfully used to visualize the endogenous CHT in zebrafish. Notably, the DT probe provided an intuitive way to visualize endogenous CHT in mouse pancreas for the first time, demonstrating the potential for application in the future clinical diagnosis of pancreatic diseases. Therefore, the small-molecule probe DT is expected to be a useful molecular tool for CHT-related disease diagnosis and drug discovery.

4 + 2]-Cycloadditions of a thiazol-based tricyclic 1,4-diphosphinine and a new easy 1,4-diphosphinine protection deprotection strategy.

Diels-Alder-reactions of a thiazol-2-thione-based, tricyclic 1,4-di-phosphinine were investigated, showing that the central aromatic π-system can react with various dienophiles. The reaction with 4-phenyl-1,2,4-triazoline-3,5-dione was special as the product revealed a remarkable sensitivity towards light, thus enabling the photochemical deprotection of the tricyclic 1,4-diphosphinine.

Design of fluorescent protein-based sensors through a general protection-deprotection strategy.

Engineered fluorescent proteins have been extensively used in biological research for the study of gene expression, protein function and trafficking, and protein-protein interactions. In addition, fluorescent proteins have also been engineered to act as biosensing agents to detect intracellular signaling molecules and other small-molecule metabolites. Although they have been engineered extensively to achieve novel properties, fluorescent proteins are traditionally modified using the 20 canonical amino acids. This limits the number of functional groups that are available to the design and construction of novel fluorescent proteins. The expansion of the genetic code through the incorporation of noncanonical amino acids presents an opportunity to add new functionalities with the intent of modifying chemical and physical properties of fluorescent proteins. Herein we provide a general procedure for the site-specific incorporation of noncanonical amino acids into fluorescent proteins in live cells. We will also discuss a noncanonical amino acid-containing fluorescent protein sensor that is based on a general protection-deprotection design strategy, for the selective detection and quantification of Hg2+.

Interconversion between nanoribbons and nanospheres mediated by detachable ‘invisibility suit’

Taming the ultrathin nanomaterials with the desired stability and functionality is one of the challenges of chemistry and materials science. Developing a detachable smart ’invisibility suit’ may represent an attractive strategy for coping with this dilemma. Here, a protection-deprotection strategy for ultrathin nanomaterials of hydrogen-bonded organic frameworks (HOFs), by putting on and taking off a detachable ’invisibility suit,’ is reported. Upon wearing the ’invisibility suit,’ the ultrathin nanoribbons with high crystallinity can fold into ’sturdy’ nanospheres, the latter featured with amorphous character, stimuli inertia, and excellent extreme condition resistance, achieving the challenging goal of ’stealth.’ In addition, the superior water affinity, sensitive selectivity, ultrahigh water adsorption capacity, and promising energy-saving activation steps for the ’stealth’ nanospheres have been demonstrated, suggesting a promising candidate for the real-world application as an effective dehydrator. More importantly, taking off the ’invisibility suit’ leads to the release of the initial nanoribbons, which features the promising thermal and NIR light-triggered photoluminescence and photocatalysis. These results have provided an inter-conversion cycle between nanoribbons and nanospheres, which are expected to significantly promote the demand-oriented storage, transportation, and practical application of ultrathin nanomaterials.

Hydroxy-Substituted Azacalix[4]Pyridines: Synthesis, Structure, and Construction of Functional Architectures.

A number of hydroxyl-substituted azacalix[4]pyridines were synthesized using Pd-catalyzed macrocyclic “2+2” and “3+1” coupling methods and the protection–deprotection strategy of hydroxyl group. While the conformation of the these hydroxyl-substituted azacalix[4]pyridines is fluxional in solution, in the solid state, they adopted shape-persistent 1,3-alternate conformations. Besides, X-ray analysis revealed that the existence of hydroxy groups on the para-position of pyridine facilitated the formation of solvent-bridged intermolecular hydrogen bonding for mono-hydroxyl-substituted while partial tautomerization for four-hydroxyl-substituted macrocycles, respectively. Taking the hydroxyl-substituted azacalix[4]pyridines as molecular platforms, multi-macrocycle-containing architectures and functional building blocks were constructed. The self-assembly behavior of the resulting building blocks was investigated in crystalline state.

A facile tandem double-dehydrative-double-Heck olefination strategy for pot-economic synthesis of (E)-distyrylbenzenes as multi-target-directed ligands against Alzheimer's disease employing C. elegans model

A concise, one pot and regioselective access to (E)-distyrylbenzenes (DSBs) from arylhalide and secondary phenylenediethanol, a stable precursor for in situ generation of divinylbenzene (DVB) to avoid its polymerization, is described for construction of double CC bond formation via tandem double-dehydrative-double-Heck (D-D-D-H) reaction using Palladium and ionic liquid [hmim]Br as a cooperative catalyst. It is noteworthy that this pot-economy approach also provides direct synthesis of hydroxylated distyrylbenzenes without requirement of protection-deprotection strategy. Importantly, the synthesized DSBs are tested for their protective activity against β amyloid reduction, acetylcholine esterase inhibition, lipid lowering and reactive oxygen species (ROS) reduction properties in transgenic Caenorhabditis elegans model wherein 1,3-bis((E)-4-(trifluoromethyl)styryl)benzene (5c) is found to be active across all above factors thus presenting lead molecule within multi-target-directed ligands (MTDLs) approach. Molecular docking studies were also performed to understand the interactions of potent DSBs with receptors.

An efficient and facile synthesis of D-cycloserine substantially free from potential impurities

An efficient and facile synthesis of D-cycloserine has been developed from D-serine with 61% overall yield employing protectiondeprotection strategy. Different parameters affecting the impurities content and yield of D-cycloserine have been studied. Mild reaction conditions provided the product with remarkable purity (>99%) and high stability.

Fluorescent Protein-Based Turn-On Probe through a General Protection-Deprotection Design Strategy.

We demonstrated a general protection-deprotection strategy for the design of fluorescent protein biosensors through the construction of a turn-on Hg2+ sensor. A combination of fluorescent protein engineering and unnatural amino acid mutagenesis was used. Unlike previously reported fluorescent protein-based Hg2+ sensors that relied on the binding of Hg2+ to the sulfhydryl group of cysteine residues, a well-established chemical reaction, oxymercuration, was transformed into biological format and incorporated into our sensor design. This novel Hg2+ sensor displayed good sensitivity and selectivity both in vitro and in live bacterial cells. Over 60-fold change in fluorescence signal output was observed in the presence of 10 μM Hg2+, while such a change was undetectable when nine other metal ions were tested. This new design strategy could expand the repertoire of fluorescent protein-based biosensors for the detection of small-molecule analytes.

Synthesis of Mono-O-alkylated Homooxacalix[3]arene and a Protection-Deprotection Strategy for Homooxacalix[3]arene.

The regioselective synthesis of mono-O-alkylated homooxacalix[3]arene is accomplished for the first time. The synthetic route relies on two key steps: (i) a facile protection of two OH groups at the lower rim of the homooxacalix[3]arene and (ii) the deprotection of 9-anthrylmethyl groups via the Pd/C-catalyzed hydrogenation under atmospheric hydrogen. An efficient protection-deprotection strategy for the functionalization of homooxacalix[3]arene is presented.

Particulate polyaryletherketones with amine end functionalisation by a Friedel Crafts dispersion polymerisation

Amine end-capped polyaryletherketones (PAEKs) are available by a dispersion process using a protection-deprotection strategy with an end-capping aminoaromatic derivative which adds no further steps to the dispersion polymerisation method. A model compound approach was employed to demonstrate successful amine attachment to the polymer, together with its compatibility and suitability within the polymer system. This approach was also successful for linear and trifunctional versions. Scale-up of the PAEK dispersion synthesis to 300g batches was achieved. Amine end-capped poly(ether ketone ketone) (PEKK) with 100:0, 80:20, 60:40 terephthaloyl (T):isophthaloyl (I) ratios, along with branched PEKK and PEKK-imide copolymers, were synthesised. Mechanical analysis confirmed a substantial increase in fracture toughness on incorporation of the functionalised PEKK particles in an epoxy resin laminate when compared to non-functionalised PEKK particles.

Synthesis of water soluble quaternary chitosan derivative via protection-deprotection strategy and investigation of its antibacterial effect

New water-soluble trimethyl quaternary derivative of chitosan was synthesized by a multi step processes through protection-deprotection strategy. This derivative was characterized using FTIR and 1H NMR spectroscopy. Finally, the antibacterial effect of this derivative against Gram-negative (Escherichia coli and Salmonella typhimurium) and Gram-positive (Staphylococcus aureus and Staphylococcus epidermidis) bacteria in acidic and nutral medium was invetigated. The results of this study demonstrated that this chitosan derivative did not have antibacterial activity against Gram-negative bacteria; however, it showed a relatively good antibacterical effect against Gram-positive bacteria in both acidic and neutral mediums.

ChemInform Abstract: Development of Fluorescent Probes Based on Protection—Deprotection of the Key Functional Groups for Biological Imaging

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