Mild deprotection of the <i>N-tert</i>-butyloxycarbonyl (<i>N</i>-Boc) group using oxalyl chloride

George, Nathaniel; Ofori, Samuel; Parkin, Sean; Awuah, Samuel G.

doi:10.1039/d0ra04110f

Cited by 15 publications

(13 citation statements)

References 64 publications

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“…Literature reports EDA-mediated cationization of polymers; however, it requires a large molar excess of EDA to produce the required levels of cationization and protonation indices. Dendron is a wedge-shaped structure comprising a reactive functional group at the focal point and multiple terminal groups. − Strategically, the presence of a tert -butyloxycarbonyl (Boc)-protected amine functional group at the focal point will enable its conjugation with the carboxy group of the polymeric backbone following simple deprotection-conjugation chemistry. , However, no such dendron has been reported in the literature or is devoid commercially. The synthesized dendron can be strategically used for the cationizing of HA to formulate RNAi-therapeutic-loaded nanoparticles using the strategy as patented by our group (Indian Patent application no.…”

Section: Resultsmentioning

confidence: 60%

Dendronized Polymeric Biomaterial for Loading, Stabilization, and Targeted Cytosolic Delivery of microRNA in Cancer Cells

Tambe

Patel

Shard

et al. 2022

ACS Appl. Bio Mater.

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MicroRNAs (miRNAs) are small non-coding RNAs involved in the fine-tuning of gene regulation. Anti-miRNA is a promising RNA-interference (RNAi) agent that potently regulates post-transcriptional expression of an abnormal gene by inhibiting its target mRNAs. To date, ONPATTRO and Leqvio are the only firstin-class USFDA-approved RNAi-therapeutics available in clinic. The deficiency of a fitting delivery carrier remains a primary hindrance to their clinical translation. To address this issue, this investigation reports the development of a dendronized polymeric nanobiomaterial involving a USFDA-approved biopolymer (hyaluronic acid, also called hyaluronan; HA) for the selective delivery of anti-miRNA into the cytosolic compartment of cancer cells. Dendrons are synthesized for focal cationization of HA to produce a cationic dendronized HA polymer (dCHA) using a ligated dendron motif approach. The synthesized dCHA is inert toward blood cells, as observed in the hemolysis assay. It also depicts a strong binding affinity for the CD44-receptor protein and is found to be neutral toward macrophages and albumin proteins (human origin; molecular simulation and docking tool: GROMACS). The developed approach is simple in application, offers high anti-miR21 loading, and avoids RNase enzymatic degradation of loaded anti-miRNA. The dCHA could efficiently escape the lysoendosomal compartment to mediate cytosolic delivery of the loaded anti-miRNA, ascribed to the proton sponge effect offered by weak basic groups of ligated dendron motifs in the dCHA architecture. The dCHA-loaded anti-miR21 upregulates the mRNA levels of Bax and CASP3 and downregulates the levels of Bcl2, accompanied by significant miR21 gene downregulation. Furthermore, under the influence of CD44-receptor blockade, a reduction in the cellular uptake of FAM-labeled anti-miR21 is observed compared to the control, inferring receptor-mediated uptake of dCHA. The conclusive outcome of this research advocates the use of dCHA to be a fit-to-purpose modality to load, preserve, and selectively deliver anti-miRNA-therapeutics to the cytosolic compartment of cancer cells. The developed approach has been tested using anti-miR21 as a model RNAi-therapeutic; however, the knowledge developed in this fundamental research can also be extended to other gene therapeutics, including DNA, siRNA, miRNA mimics, plasmid oligonucleotides, and so forth.

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Section: Resultsmentioning

confidence: 60%

Dendronized Polymeric Biomaterial for Loading, Stabilization, and Targeted Cytosolic Delivery of microRNA in Cancer Cells

Tambe

Patel

Shard

et al. 2022

ACS Appl. Bio Mater.

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“…It rather seems that the presence of methanol is a pivotal factor� which is consistent with the authors' observations. 47 Moreover, we proposed a convenient and straightforward method for the purification and isolation of 2 in a crystalline form; from the post-reaction mixture, concentrated on a rotary evaporator, the pure product can be obtained by recrystallization from water. This methodology is sufficient because 2 is insoluble in water, whereas dimethyl oxalate (byproduct) dissolves in water (Figure S33 and Table S2).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Unprecedented Route to Amide-Functionalized Double-Decker Silsesquioxanes Using Carboxylic Acid Derivatives and a Hydrochloride Salt of Aminopropyl-DDSQ

Władyczyn

John

2023

Inorg. Chem.

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An easy, efficient, and scalable synthetic procedure is described to obtain novel amide-functionalized double-decker silsesquioxanes (DDSQs). The use of mild conditions of deprotection of the BOC group, which does not result to the cleavage of the cage-like silsesquioxane structure, is reported. This method leads to the so far undescribed hydrochloride salt of aminoalkyl-DDSQ. Interestingly, the cis/trans-isomerization of DDSQ molecules was observed during the reaction. The resulting compounds are characterized using multinuclear NMR (1H, 13C, and 29Si), MALDI-TOF, FT-IR, and elemental analysis. Moreover, crystal structures are reported for three trans DDSQs. The chloride salt of aminoalkyl derivative, obtained in one of the steps of the synthetic pathway, shows an intriguing structure of the crystal lattice in which large channels are present, caused by ionic interactions in the lattice. The described approach opens the way to synthesizing new DDSQ derivatives and materials using BOC-blocked amines. We believe our findings would advance investigations about new materials based on little known organic–inorganic DDSQ-based hybrids.

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“…Although several protocols avoiding the use of TFA were reported [29][30][31][32], such synthetic approaches were barely used for compounds with several guanidino functions on an aliphatic skeleton. As an example, preparation of the antimicrobial polyhexamethylene guanidine (PHMG) polymer involved the use of non-protected guanylating agents, yielding the guanidinium hydrochloride without additional reactions involving strong acids [33].…”

Section: Resultsmentioning

confidence: 99%

The impact of counterions in biological activity: case study of antibacterial alkylguanidino ureas

et al. 2022

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Trifluoroacetic acid (TFA), due to its strong acidity and low boiling point, is extensively used in protecting groups-based synthetic strategies. Indeed, synthetic compounds bearing basic functions, such as amines or guanidines (commonly found in peptido or peptidomimetic derivatives), developed in the frame of drug discovery programmes, are often isolated as trifluoroacetate (TF-Acetate) salts and their biological activity is assessed as such in in vitro, ex vivo , or in vivo experiments. However, the presence of residual amounts of TFA was reported to potentially affect the accuracy and reproducibility of a broad range of cellular assays (e. g. antimicrobial susceptibility testing, and cytotoxicity assays) limiting the further development of these derivatives. Furthermore, the impact of the counterion on biological activity, including TF-Acetate, is still controversial. Herein, we present a focused case study aiming to evaluate the activity of an antibacterial AlkylGuanidino Urea (AGU) compound obtained as TF-Acetate ( 1a ) and hydrochloride ( 1b ) salt forms to highlight the role of counterions in affecting the biological activity. We also prepared and tested the corresponding free base ( 1c ). The exchange of the counterions applied to polyguanidino compounds represents an unexplored and challenging field, which required significant efforts for the successful optimization of reliable methods of preparation, also reported in this work. In the end, the biological evaluation revealed a quite similar biological profile for the salt derivatives 1a and 1b and a lower potency was found for the free base 1c . Graphical abstract Supplementary Information The online version contains supplementary material available at 10.1007/s11030-022-10505-6.

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Mild deprotection of the N-tert-butyloxycarbonyl (N-Boc) group using oxalyl chloride

Abstract: We report a mild method for the selective deprotection of the N-Boc group from a structurally diverse set of compounds, encompassing aliphatic, aromatic, and heterocyclic substrates by using oxalyl chloride in methanol.

Cited by 15 publications

References 64 publications

Dendronized Polymeric Biomaterial for Loading, Stabilization, and Targeted Cytosolic Delivery of microRNA in Cancer Cells

Dendronized Polymeric Biomaterial for Loading, Stabilization, and Targeted Cytosolic Delivery of microRNA in Cancer Cells

Unprecedented Route to Amide-Functionalized Double-Decker Silsesquioxanes Using Carboxylic Acid Derivatives and a Hydrochloride Salt of Aminopropyl-DDSQ

The impact of counterions in biological activity: case study of antibacterial alkylguanidino ureas

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