Charge-Switchable Nanozymes for Bioorthogonal Imaging of Biofilm-Associated Infections.

Early detection of biofilms is crucial for limiting infection-based damage. Imaging these biofilms is challenging: conventional imaging agents are unable to penetrate the dense matrix of the biofilm, and many imaging agents are susceptible to false positive/negative responses due to phenotypical mutations of the constituent microbes. We report the creation of pH-responsive nanoparticles with embedded transition metal catalysts (nanozymes) that effectively target the acidic microenvironment of biofilms.

Using the Power of Organic Synthesis for Engineering the Interactions of Nanoparticles with Biological Systems.

The surface properties of nanoparticles (NPs) dictate their interaction with the outside world. The use of precisely designed molecular ligands to control NP surface properties provides an important toolkit for modulating their interaction with biological systems, facilitating their use in biomedicine. In this review we will discuss the application of the atom-by-atom control provided by organic synthesis to the generation of engineered nanoparticles, with emphasis on how the functionalization of NPs with these "small" organic molecules (Mw < 1,000) can be used to engineer NPs for a wide range of applications.

The Interplay of Size and Surface Functionality on the Cellular Uptake of Sub-10 nm Gold Nanoparticles.

Correlation of the surface physicochemical properties of nanoparticles with their interactions with biosystems provides key foundational data for nanomedicine. We report here the systematic synthesis of 2, 4, and 6 nm core gold nanoparticles (AuNP) featuring neutral (zwitterionic), anionic, and cationic headgroups. The cellular internalization of these AuNPs was quantified, providing a parametric evaluation of charge and size effects.

Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts.

Bioorthogonal catalysis broadens the functional possibilities of intracellular chemistry. Effective delivery and regulation of synthetic catalytic systems in cells are challenging due to the complex intracellular environment and catalyst instability. Here, we report the fabrication of protein-sized bioorthogonal nanozymes through the encapsulation of hydrophobic transition metal catalysts into the monolayer of water-soluble gold nanoparticles.

Binding Studies of Cucurbit[7]uril with Gold Nanoparticles Bearing Different Surface Functionalities.

Host-guest interactions between a synthetic receptor, cucurbit[7]uril (CB[7]), and gold nanoparticles (AuNPs) have been quantified using isothermal titration calorimetry. AuNPs were functionalized with ligands containing tertiary or quaternary benzylamine derivatives, with electron donating or withdrawing groups at the position of the benzene ring. Analysis of binding interactions reveals that functional groups at the position have no significant effect on binding constant.

Acylsulfonamide-Functionalized Zwitterionic Gold Nanoparticles for Enhanced Cellular Uptake at Tumor pH.

A nanoparticle design featuring pH-responsive alkoxyphenyl acylsulfonamide ligands is reported herein. As a result of ligand structure, this nanoparticle is neutral at pH 7.4, becoming positively charged at tumor pH (<6.

Investigations of possible prodrug structures for 2-(2-mercaptophenyl)tetrahydropyrimidines: reductive conversion from anti-HIV agents with pyrimidobenzothiazine and isothiazolopyrimidine scaffolds.

3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) and 3,4-dihydro-2H-benzo[4,5]isothiazolo[2,3-a]pyrimidine are the heterocyclic antiretroviral agents against human immunodeficiency virus type 1 (HIV-1) infection. On the basis of similar structure-activity relationships of anti-HIV activities toward the early-stage of viral infection between these unique scaffolds, the transformations under the bioassay conditions were investigated. The distinctive S-N bond in the isothiazolopyrimidine scaffold was immediately cleaved under reductive conditions in the presence of GSH to generate a thiophenol derivative.

Identification of anti-HIV agents with a novel benzo[4,5]isothiazolo[2,3-a]pyrimidine scaffold.

3,4-Dihydro-2H-benzo[4,5]isothiazolo[2,3-a]pyrimidine is a newly identified antiviral agent against human immunodeficiency virus type 1 (HIV-1) infection, derived from 3,4-dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182). The introduction of the hydrophobic 8-aryl substituent on the benzene substructure improved its anti-HIV activity, resulting in the identification of 6-fold more potent analogs. In addition, it was demonstrated that these isothiazolopyrimidine derivatives exert anti-HIV effects at an early stage of viral infection.

Mass spectrometric detection of nanoparticle host-guest interactions in cells.

Synthetic host-guest chemistry is a versatile tool for biomedical applications. Characterization and detection of host-guest complexes in biological systems, however, is challenging due to the complexity of the biological milieu. Here, we describe and apply a mass spectrometric method to monitor the association and dissociation of nanoparticle (NP)-based host-guest interactions that integrates NP-assisted laser desorption/ionization (LDI) and matrix assisted laser desoption/ionization (MALDI) mass spectrometry.

Structure-activity relationship study of phenylpyrazole derivatives as a novel class of anti-HIV agents.

The structure-activity relationship of phenylpyrazole derivative 1 was investigated for the development of novel anti-HIV agents. Initial efforts revealed that the diazenyl group can be replaced by an aminomethylene group. In addition, we synthesized various derivatives by the reductive amination of benzaldehydes with 5-aminopyrazoles and carried out parallel structural optimization on the benzyl group and the pyrazole ring.

Design and synthesis of biotin- or alkyne-conjugated photoaffinity probes for studying the target molecules of PD 404182.

To investigate the mechanism of action of the potent antiviral compound PD 404182, three novel photoaffinity probes equipped with a biotin or alkyne indicator were designed and synthesized based on previous structure-activity relationship studies. These probes retained the potent anti-HIV activity of the original pyrimidobenzothiazine derivatives. In photoaffinity labeling studies using HIV-1-infected H9 cells (H9IIIB), eight potential proteins were observed to bind PD 404182.

Structure-activity relationship study of pyrimido[1,2-c][1,3]benzothiazin-6-imine derivatives for potent anti-HIV agents.

3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is an antiretroviral agent with submicromolar inhibitory activity against human immunodeficiency virus-1 (HIV-1) and HIV-2 infection. In the current study, the structure-activity relationships of accessory groups at the 3- and 9-positions of pyrimido[1,2-c][1,3]benzothiazin-6-imine were investigated for the development of more potent anti-HIV agents. Several different derivatives containing a 9-aryl group were designed and synthesized using Suzuki-Miyaura cross-coupling and Ullmann coupling reactions.

Concise synthesis and anti-HIV activity of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles.

3,4-Dihydro-2H,6H-pyrimido[1,2-c][1,3]benzothiazin-6-imine (PD 404182) is a virucidal heterocyclic compound active against various viruses, including HCV, HIV, and simian immunodeficiency virus. Using facile synthetic approaches that we developed for the synthesis of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic derivatives, the parallel structural optimizations of the central 1,3-thiazin-2-imine core, the benzene part, and the cyclic amidine part of PD 404182 were investigated. Replacement of the 6-6-6 pyrimido[1,2-c][1,3]benzothiazin-6-imine framework with 5-6-6 or 6-6-5 derivatives led to a significant loss of anti-HIV activity, and introduction of a hydrophobic group at the 9- or 10-positions improved the potency.

Efficient synthesis of pyrimido[1,2-c] [1,3]benzothiazin-6-imines and related tricyclic heterocycles by S(N)Ar-type C-S, C-N, or C-O bond formation with heterocumulenes.

A simple and practical synthetic method of pyrimido[1,2-c][1,3]benzothiazin-6-imines and related tricyclic heterocycles has been developed. Treatment of 2-(2-haloaryl)tetrahydropyrimidines with NaH and a heterocumulene such as carbon disulfide, isothiocyanates, and isocyanates in DMF provides the desired cyclization products through a regioselective S(N)Ar-type reaction. This method provides direct access to PD 404182 and related compounds.

Cu(II)-mediated oxidative intermolecular ortho C-H functionalisation using tetrahydropyrimidine as the directing group.

Tetrahydropyrimidine works efficiently as a directing group in Cu(ii)-mediated oxidative aromatic C-H functionalisation for the selective introduction of oxygen or nitrogen to the ortho-position.