Chemoselective Functionalization Research Articles

Tunable drug delivery using chemoselective functionalization of hydrogels

In the last decades interests on cleavable linkers are growing due to the need to develop controlled drug delivery systems in biochemical and therapeutic applications. The synthesis of hydrogels as devices capable to maintain the drug level within a desired range for a long and sustained period of time is a leading strategy for this aim. However with respect to the good results obtained with antibodies and peptides there are a lot of problems related to the quick and uncontrolled diffusion of small molecules through hydrogel pores. In this work, we propose the functionalization of polyethylene glycol (PEG) chains with two different pH-sensitive linkers, ester and hydrazone, and their application as building blocks of microwave-assisted hydrogels for controlled delivery of small hydrophilic drugs. As drug mimetic we used Rhodamine B, a harmless fluorophore with steric hindrance and reactive groups similar to many small hydrophilic drugs. At physiological and low basic conditions, the cleavability of ester and hydrazone spacer evidenced the possibility to delay the release of drugs from the scaffold compared to hydrogels where drug was entrapped within the network only due to its steric hindrance. The obtained release profiles were compared, underlining the opportunity to tune the release rate using the synthesized hydrogels.

Tunable drug delivery using chemoselective functionalization of hydrogels

Tunable drug delivery using chemoselective functionalization of hydrogels

Surface-Functionalized Nanoparticles by Olefin Metathesis: A Chemoselective Approach for In Vivo Characterization of Atherosclerosis Plaque.

The use of click chemistry reactions for the functionalization of nanoparticles is particularly useful to modify the surface in a well-defined manner and to enhance the targeting properties, thus facilitating clinical translation. Here it is demonstrated that olefin metathesis can be used for the chemoselective functionalization of iron oxide nanoparticles with three different examples. This approach enables, in one step, the synthesis and functionalization of different water-stable magnetite-based particles from oleic acid-coated counterparts. The surface of the nanoparticles was completely characterized showing how the metathesis approach introduces a large number of hydrophilic molecules on their coating layer. As an example of the possible applications of these new nanocomposites, a focus was taken on atherosclerosis plaques. It is also demonstrated how the in vitro properties of one of the probes, particularly its Ca(2+) -binding properties, mediate their final in vivo use; that is, the selective accumulation in atherosclerotic plaques. This opens promising new applications to detect possible microcalcifications associated with plaque vulnerability. The accumulation of the new imaging tracers is demonstrated by in vivo magnetic resonance imaging of carotids and aorta in the ApoE(-/-) mouse model and the results were confirmed by histology.

Chemoselective intramolecular functionalization of methyl groups in nonconstrained molecules promoted by N-iodosulfonamides.

Mechanistic evidence observed in Hofmann-Löffler-Freytag-type reactions has been crucial to achieve the chemoselective functionalization of methyl groups under mild conditions. Radical-mediated methyl iodination and subsequent oxidative deiodination are the key steps in this functionalization, where iodine chemistry has a pivotal role on the formation of the C-N bond. The concepts of single hydrogen atom transfer (SHAT) and multiple hydrogen atom transfer (MHAT) are introduced to describe the observed chemoselectivity.

Chemoselective peptide functionalization of starPEG-GAG hydrogels.

Glycosaminoglycan (GAG)-based hydrogels gain increasing interest in regenerative therapies. To support specific applications, the biomolecular functionality of gel matrices needs to be customized via conjugation of peptide sequences that mediate cell adhesion, expansion and differentiation. Herein, we present an orthogonal strategy for the formation and chemoselective functionalization of starPEG-GAG hydrogels, utilizing the uniform and specific conjugation of peptides and GAGs for customizing the resulting materials. The introduced approach was applied for the incorporation of three different types of RGD peptides to analyze the influence of peptide sequence and conformation on adhesion and morphogenesis of endothelial cells (ECs) grown on the peptide-containing starPEG-GAG hydrogels. The strongest cellular response was observed for hydrogels functionalized with cycloRGD followed by linear forms of RGDSP and RGD, showing that morphogenesis and growth rate of ECs is controlled by both type and quantity of the conjugated peptides.

The effect of substituent, degree of acetylation and positioning of the cationic charge on the antibacterial activity of quaternary chitosan derivatives.

A series of water-soluble cationic chitosan derivatives were prepared by chemoselective functionalization at the amino group of five different parent chitosans having varying degrees of acetylation and molecular weight. The quaternary moieties were introduced at different alkyl spacer lengths from the polymer backbone (C-0, C-2 and C-6) with the aid of 3,6-di-O-tert-butyldimethylsilyl protection of the chitosan backbone, thus allowing full (100%) substitution of the free amino groups. All of the derivatives were characterized using 1H-NMR, 1H-1H COSY and FT-IR spectroscopy, while molecular weight was determined by GPC. Antibacterial activity was investigated against Gram positive S. aureus and Gram negative E. coli. The relationship between structure and activity/toxicity was defined, considering the effect of the cationic group’s structure and its distance from the polymer backbone, as well as the degree of acetylation within a molecular weight range of 7–23 kDa for the final compounds. The N,N,N-trimethyl chitosan with 100% quaternization showed the highest antibacterial activity with moderate cytotoxicity, while increasing the spacer length reduced the activity. Trimethylammoniumyl quaternary ammonium moieties contributed more to activity than 1-pyridiniumyl moieties. In general, no trend in the antibacterial activity of the compounds with increasing molecular weight or degree of acetylation up to 34% was observed.

Total syntheses of lycoposerramine-V and 5-epi-lycoposerramine-V.

Enantioselective total syntheses of lycopodium alkaloids lycoposerramine-V and 5-epi-lycoposerramine-V have been accomplished. Features of the newly established total synthesis include: 1) introduction of the first chiral center with a scalable desymmetrization reaction of an meso-anhydride; 2) chemoselective functionalization of a bis-Weinreb-amide with Grignard addition; and 3) construction of the multifunctionalized cyclohexanone with a stereoselective intramolecular Michael addition.

Wettability adjustment of PVDF surfaces by combining radiation-induced grafting of (2,3,4,5,6)-pentafluorostyrene and subsequent chemoselective “click-type” reaction

A novel strategy combining (2,3,4,5,6)-pentafluorostyrene (PFS) grafting and subsequent thiol/para-fluorine “click” type post-grafting modification is presented to impart specific surface properties to bulky PVDF samples. First, PFS was radiation-induced grafted on the surface of PVDF using γ-rays as the radiation source, and both pre-irradiation and simultaneous irradiation techniques were attempted. The extent of modification was higher with the latter strategy, as determined by semi-quantitative ATR-FTIR analyses. Subsequent coupling was then undertaken using 3-mercapto-1,2-propanediol (MPD). The chemoselective functionalization was qualitatively and semi-quantitatively evidenced by ATR-FTIR, and led to PVDF-g-PPFS decorated with hydroxyl groups. The resulting surface properties were investigated by wettability measurements, and hysteresis with water and contact angle with acetonitrile both evidenced the successful and appropriate modification. This strategy opens the scope of a new means to modify both swelling and surface properties of PVDF samples, as required for specific applications (such as separator in electrochemical devices or in pipe systems for handling specific chemicals).

Iron‐Catalyzed Generation of α‐Amino Nitriles from Tertiary Amines

AbstractThe use of iron(II) chloride as catalyst, trimethylsilyl cyanide as source of cyanide ions, and tert‐butyl hydroperoxide as oxidant enabled the conversion of aromatic, benzylic, and aliphatic tertiary amines into α‐amino nitriles under mild conditions. Chemoselective functionalization of NCH3 to NCH2CN was achieved in the presence of N‐benzyl and N‐alkyl groups. N,N‐Dialkylanilines, PhNR2, with R=Et, Bu, Bn furnished the alkyl(aryl)aminoacetonitriles PhN(R)CH2CN as the main products accompanied by α‐amino nitriles generated by ordinary α‐cyanation of the aniline PhNR2. Formation of PhN(R)CH2CN was rationalized by oxidative degradation of N,N‐dialkylanilines to N‐alkylanilines, their condensation with formaldehyde, generated by oxidation of the solvent methanol, and final trapping of the thus formed iminium ions by cyanide.magnified image

Chemoselective sp2-sp3 Cross-Couplings: Iron-Catalyzed Alkyl Transfer to Dihaloaromatics

The chemoselective functionalization of a range of dihaloaromatics with methyl, cyclopropyl, and higher alkyl Grignard reagents via iron-catalyzed cross-coupling is described. The site selectivity of C-X (X = halogen) activation is determined by factors such as the position of the halogen on the ring, the solvent, and the nucleophile. A one-pot protocol for the chemoselective synthesis of mixed dialkyl heterocycles is achieved solely employing iron catalysis.

New Preparation of TMPZnCl·LiCl by Zn Insertion into TMPCl. Application to the Functionalization of Dibromodiazines

A practical zinc insertion starting from cheap commercial zinc powder and TMPCl (1-chloro-2,2,6,6-tetramethylpiperidine) allows a fast and efficient synthesis of the zinc base TMPZnCl·LiCl under mild conditions in high yields. This base is kinetically highly active and was used for the regio- and chemoselective functionalization of dibromodiazines (pyridazines and pyrazines).

Transition‐Metal‐Free Atropo‐Selective Synthesis of Biaryl Compounds Based on Arynes

A modular way towards biaryls: Highly enantioenriched biphenyls can be prepared based on a transition-metal-free aryl-aryl coupling followed by efficient desymmetrization or deracemization and chemoselective functionalization (see scheme).

A photocleavable linker for the chemoselective functionalization of biomaterials

The functionalization of matrices with “caged” functional groups and their subsequent selective uncaging is a promising approach for generating patterns of bioactive molecules to guide cell growth or recreate in vivo microarchitectures. To date, this has been limited to caged carboxylic acids, amines and thiols, functional groups found within biological systems. We present a bifunctional caged carbonyl linker as an alternative approach for the chemoselective functionalization of biomaterials. This linker was readily coupled to collagen, employed as a model biomaterial, and underwent rapid uncaging in aqueous media upon irradiation with ultraviolet light to yield free carbonyl groups. Modified surfaces proved to be non-adhesive to cells until the chemoselective reintroduction of adhesion following incubation of uncaged carbonyls with gelatin hydrazide, with native gelatin failing to elicit a cellular response.

Staudinger-Phosphonite Reactions for the Chemoselective Transformation of Azido-Containing Peptides and Proteins

Site-specific functionalization of proteins by bioorthogonal modification offers a convenient pathway to create, modify, and study biologically active biopolymers. In this paper the Staudinger reaction of aryl-phosphonites for the chemoselective functionalization of azido-peptides and proteins was probed. Different water-soluble phosphonites with oligoethylene substituents were synthesized and reacted with unprotected azido-containing peptides in aqueous systems at room temperature in high conversions. Finally, the Staudinger-phosphonite reaction was successfully applied to the site-specific modification of the protein calmodulin.

Synthesis, cytotoxicity, and structure–activity relationship (SAR) studies of andrographolide analogues as anti-cancer agent

A series of analogues of andrographolide, prepared through chemo-selective functionalization at C14 hydroxy, have been evaluated for in vitro cytotoxicities against human leukemic cell lines. Two of the analogues (6a, 9b) exhibited significant potency. Preliminary studies on structure-activity relationship (SAR) revealed that the α-alkylidene-γ-butyrolactone moiety of andrographolide played a major role in the activity profile. The structures of the analogues were established through spectroscopic and analytical data.

Chemo- and regio-selective functionalization of Morita–Baylis–Hillman bromides with anthranilic acid

Nucleophilic substitution products of Morita–Baylis–Hillman adducts and their derivatives are valuable synthons. In an attempt to ameliorate the functionality of these functionalized motifs, we report the regio- and chemo-selective functionalization of Morita–Baylis–Hillman bromides with anthranilic acid.

ChemInform Abstract: Chemoselective Functionalization of α‐Carbolines at the C‐2, C‐3, C‐4, and C‐6 Positions Using Suzuki—Miyaura Reactions.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Efficient, chemoselective synthesis of immunomicelles using single-domain antibodies with a C-terminal thioester

BackgroundClassical bioconjugation strategies for generating antibody-functionalized nanoparticles are non-specific and typically result in heterogeneous compounds that can be compromised in activity. Expression systems based on self-cleavable intein domains allow the generation of recombinant proteins with a C-terminal thioester, providing a unique handle for site-specific conjugation using native chemical ligation (NCL). However, current methods to generate antibody fragments with C-terminal thioesters require cumbersome refolding procedures, effectively preventing application of NCL for antibody-mediated targeting and molecular imaging.ResultsTargeting to the periplasm of E. coli allowed efficient production of correctly-folded single-domain antibody (sdAb)-intein fusions proteins. On column purification and 2-mercapthoethanesulfonic acid (MESNA)-induced cleavage yielded single-domain antibodies with a reactive C-terminal MESNA thioester in good yields. These thioester-functionalized single-domain antibodies allowed synthesis of immunomicelles via native chemical ligation in a single step.ConclusionA novel procedure was developed to obtain soluble, well-folded single-domain antibodies with reactive C-terminal thioesters in good yields. These proteins are promising building blocks for the chemoselective functionalization via NCL of a broad range of nanoparticle scaffolds, including micelles, liposomes and dendrimers.

A Chemical Approach to Immunoprotein Engineering: Chemoselective Functionalization of Thioester Proteins in Their Native State

Less than 6 feet under: Serum proteins C3, C4, and alpha(2)M each contain a thioester domain buried within a hydrophobic pocket, which is thought to shield the labile thioester from hydrolysis. Herein, we make use of the inherent reactivity of the hydrazide for thioester moieties to chemoselectively label these crucial serum regulators in their native conformation; this demonstrates that access to the thioester site is much greater than previously supposed.

Cover Picture: A Chemical Approach to Immunoprotein Engineering: Chemoselective Functionalization of Thioester Proteins in Their Native State (ChemBioChem 8/2009)

AbstractThe cover picture shows chemoselective labeling of the “buried” macrocyclic thiolactone‐containing component of complement protein C3 with a variety of hydrazide probes. C3, C4, and α2‐macroglobulin play crucial roles within the complement system and as blood homeostasis regulators. Given their role in the immune system and disease, these proteins and their resulting processed fragments are highly studied, and the generation of chemically defined conjugates of these proteins offers the potential for significant advances in vaccine design and applied immunological studies. The hydrazide functionalities shown in the lower portion of this image have been used to chemoselectively label the thioester site with molecular tags, thus providing a new bioconjugation approach for thioester proteins and insight into the chemical accessibility of the thioester site. In the background of this cover image is a haystack landscape by Claude Monet representing the ability of these probes to reach these thioester “needles” within their protein scaffold and selectively label them within the complex plasma “haystack”. For further details, see the article by P. Wentworth et al. on p. 1340 ff.magnified image