ABSTRACT
Plasmodium falciparum subtilisin-like serine protease 1 (PfSUB1) is essential for egress of invasive merozoite forms of the parasite, rendering PfSUB1 an attractive antimalarial target. Here, we report studies aimed to improve drug-like properties of peptidic boronic acid PfSUB1 inhibitors including increased lipophilicity and selectivity over human proteasome (H20S). Structure-activity relationship investigations revealed that lipophilic P3 amino acid side chains as well as N-capping groups were well tolerated in retaining PfSUB1 inhibitory potency. At the P1 position, replacing the methyl group with a carboxyethyl substituent led to boralactone PfSUB1 inhibitors with remarkably improved selectivity over H20S. Combining lipophilic end-capping groups with the boralactone reduced the selectivity over H20S. However, compound 4c still showed >60-fold selectivity versus H20S and low nanomolar PfSUB1 inhibitory potency. Importantly, this compound inhibited the growth of a genetically modified P. falciparum line expressing reduced levels of PfSUB1 13-fold more efficiently compared to a wild-type parasite line.
Subject(s)
Antimalarials , Boronic Acids , Plasmodium falciparum , Proteasome Endopeptidase Complex , Protozoan Proteins , Plasmodium falciparum/drug effects , Plasmodium falciparum/enzymology , Humans , Structure-Activity Relationship , Boronic Acids/chemistry , Boronic Acids/pharmacology , Boronic Acids/chemical synthesis , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/metabolism , Proteasome Endopeptidase Complex/metabolism , Antimalarials/pharmacology , Antimalarials/chemistry , Antimalarials/chemical synthesis , Peptides/chemistry , Peptides/pharmacology , Peptides/chemical synthesis , SubtilisinsABSTRACT
Leveraging the elevated hydrogen peroxide (H2O2) levels in cancer cells, H2O2-activated prodrugs have emerged as promising candidates for anticancer therapy. Notably, the efficacy of these prodrugs is influenced by the varying H2O2 levels across different cancer cell types. In this context, we have developed a novel H2O2-activated prodrug, PBE-AMF, which incorporates a phenylboronic ester (PBE) motif. Upon H2O2 exposure, PBE-AMF liberates the fluorescent and cytotoxic molecule amonafide (AMF), functioning as a theranostic agent. Our studies with PBE-AMF have demonstrated a positive correlation between intracellular H2O2 concentration and anticancer activity. The breast cancer cell line MDA-MB-231, characterized by high H2O2 content, showed the greatest susceptibility to this prodrug. Subsequently, we replaced the PBE structure with phenylboronic acid (PBA) to obtain the prodrug PBA-AMF, which exhibited enhanced stability, aqueous solubility, and tumor cell selectivity. This selectivity is attributed to its affinity for sialic acid, which is overexpressed on the surfaces of cancer cells. In vitro assays confirmed that PBA-AMF potently and selectively inhibited the proliferation of MDA-MB-231 cells, while sparing non-cancerous MCF-10A cells. Mechanistic investigations indicated that PBA-AMF impedes tumor proliferation by inhibiting DNA synthesis, reducing ATP levels, inducing apoptosis, and arresting the cell cycle. Our work broadens the range of small molecule H2O2-activated anticancer theranostic prodrugs, which are currently limited in number. We anticipate that the applications of PBA-AMF will extend to a wider spectrum of tumors and other diseases associated with increased H2O2 levels, thereby offering new horizons in cancer diagnostics and treatment.
Subject(s)
Antineoplastic Agents , Cell Proliferation , Drug Screening Assays, Antitumor , Hydrogen Peroxide , Prodrugs , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/chemical synthesis , Humans , Hydrogen Peroxide/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Cell Proliferation/drug effects , Molecular Structure , Structure-Activity Relationship , Apoptosis/drug effects , Dose-Response Relationship, Drug , Theranostic Nanomedicine , Cell Line, Tumor , Cell Survival/drug effects , Boronic Acids/chemistry , Boronic Acids/pharmacology , Boronic Acids/chemical synthesis , Adenine , OrganophosphonatesABSTRACT
The immunoproteasome subunit LMP7 (ß5i)/LMP2 (ß1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit ß5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over ß5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of α-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor 19. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with 19 explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that 19 is orally bioavailable and shows promise as potential treatment for autoimmune diseases.
Subject(s)
Boronic Acids , Cryoelectron Microscopy , Proteasome Endopeptidase Complex , Proteasome Inhibitors , Proteasome Endopeptidase Complex/metabolism , Proteasome Endopeptidase Complex/chemistry , Animals , Proteasome Inhibitors/pharmacology , Proteasome Inhibitors/chemistry , Proteasome Inhibitors/chemical synthesis , Mice , Boronic Acids/chemistry , Boronic Acids/pharmacology , Boronic Acids/chemical synthesis , Humans , Structure-Activity Relationship , Cysteine Endopeptidases/metabolism , Molecular Structure , Molecular Dynamics Simulation , Drug DiscoveryABSTRACT
Timely lysosome escape is of paramount importance for endocytosed nanomedicines to avoid premature degradation under the acidic and hydrolytic conditions in lysosomes. Herein, we report an exciting finding that phenylboronic acid (PBA) modification can greatly facilitate the lysosome escape of cylindrical polymer brushes (CPBs). On the basis of our experimental results, we speculate that the mechanism is associated with the specific interactions of the PBA groups with lysosomal membrane proteins and hot shock proteins. The featured advantage of the PBA modification over the known lysosome escape strategies is that it does not cause significant adverse effects on the properties of the CPBs; on the contrary, it enhances remarkably their tumor accumulation and penetration. Furthermore, doxorubicin was conjugated to the PBA-modified CPBs with a drug loading content larger than 20%. This CPBs-based prodrug could eradicate the tumors established in mice by multiple intravenous administrations. This work provides a novel strategy for facilitating the lysosome escape of nanomaterials and demonstrates that PBA modification is an effective way to improve the overall properties of nanomedicines including the tumor therapeutic efficacy.
Subject(s)
Antineoplastic Agents/therapeutic use , Boronic Acids/chemistry , Drug Carriers/chemistry , Lysosomes/metabolism , Neoplasms/drug therapy , Polymethacrylic Acids/chemistry , Animals , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Boronic Acids/chemical synthesis , Boronic Acids/metabolism , Cell Line, Tumor , Doxorubicin/chemistry , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Drug Carriers/chemical synthesis , Drug Carriers/metabolism , Drug Liberation , Drug Screening Assays, Antitumor , Humans , Male , Mice, Inbred ICR , Polymethacrylic Acids/chemical synthesis , Polymethacrylic Acids/metabolism , Prodrugs/chemistry , Prodrugs/pharmacology , Prodrugs/therapeutic useABSTRACT
Peptides inherently feature the favorable properties of being easily synthesized, water-soluble, biocompatible, and typically non-toxic. Thus, boronic acid has been widely integrated with peptides with the goal of discovering peptide ligands with novel biological activities, and this effort has led to broad applications. Taking the integration between boronic acid and peptide as a starting point, we provide an overview of the latest research advances and highlight the versatile and robust functionalities of boronic acid. In this review, we summarize the diverse applications of peptide boronic acids in medicinal chemistry and chemical biology, including the identification of covalent reversible enzyme inhibitors, recognition, and detection of glycans on proteins or cancer cell surface, delivery of siRNAs, development of pH responsive devices, and recognition of RNA or bacterial surfaces. Additionally, we discuss boronic acid-mediated peptide cyclization and peptide modifications, as well as the facile chemical synthesis of peptide boronic acids, which paved the way for developing a growing number of peptide boronic acids.
Subject(s)
Boronic Acids/chemistry , Boronic Acids/pharmacology , Peptides/chemistry , Peptides/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Boron Compounds/chemistry , Boron Compounds/pharmacology , Boronic Acids/chemical synthesis , Bortezomib/chemistry , Bortezomib/pharmacology , Drug Design , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Glycine/analogs & derivatives , Glycine/chemistry , Glycine/pharmacology , Humans , Peptides/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/pharmacologyABSTRACT
Bicyclic hydrocarbons, and bicyclo[1.1.1]pentanes (BCPs) in particular, are playing an emerging role as saturated bioisosteres in pharmaceutical, agrochemical and materials chemistry. Taking advantage of strain-release strategies, prior synthetic studies have featured the synthesis of bridgehead-substituted (C1, C3) BCPs from [1.1.1]propellane. Here, we describe an approach to access multisubstituted BCPs via intramolecular cyclization. In addition to C1,C3-disubstituted BCPs, this method also enables the construction of underexplored multisubstituted (C1, C2 and C3) BCPs from readily accessible cyclobutanones. The broad generality of this method has also been examined through the synthesis of a variety of other caged bicyclic molecules, ranging from [2.1.1] to [3.2.1] scaffolds. The modularity afforded by the pendant bridgehead boron pinacol esters generated during the cyclization reaction has been demonstrated through several downstream functionalizations, highlighting the ability of this approach to enable the programmed and divergent synthesis of multisubstituted bicyclic hydrocarbons.
Subject(s)
Boronic Acids/chemical synthesis , Boronic Acids/chemistry , Bridged Bicyclo Compounds/chemistry , Cyclization , Molecular StructureABSTRACT
Pathogenic biofilms formed on the surfaces of implantable medical devices and materials pose an urgent global healthcare problem. Although conventional antibacterial surfaces based on bacteria-repelling or bacteria-killing strategies can delay biofilm formation to some extent, they usually fail in long-term applications, and it remains challenging to eradicate recalcitrant biofilms once they are established and mature. From the viewpoint of microbiology, a promising strategy may be to target the middle stage of biofilm formation including the main biological processes involved in biofilm development. In this work, a dual-functional antibiofilm surface is developed based on copolymer brushes of 2-hydroxyethyl methacrylate (HEMA) and 3-(acrylamido)phenylboronic acid (APBA), with quercetin (Qe, a natural antibiofilm molecule) incorporated via acid-responsive boronate ester bonds. Due to the antifouling properties of the hydrophilic poly(HEMA) component, the resulting surface is able to suppress bacterial adhesion and aggregation in the early stages of contact. A few bacteria are eventually able to break through the protection of the anti-adhesion layer leading to bacterial colonization. In response to the resulting decrease in the pH of the microenvironment, the surface could then release Qe to interfere with the microbiological processes related to biofilm formation. Compared to bactericidal and anti-adhesive surfaces, this dual-functional surface showed significantly improved antibiofilm performance to prevent biofilm formation involving both Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus for up to 3 days. In addition, both the copolymer and Qe are negligibly cytotoxic, thereby avoiding possible harmful effects on adjacent normal cells and the risk of bacterial resistance. This dual-functional design approach addresses the different stages of biofilm formation, and (in accordance with the growth process of the biofilm) allows sequential activation of the functions without compromising the viability of adjacent normal cells. A simple and reliable solution may thus be provided to the problems associated with biofilms on surfaces in various biomedical applications.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Biofouling/prevention & control , Boronic Acids/chemistry , Polyhydroxyethyl Methacrylate/chemistry , Quercetin/pharmacology , Anti-Bacterial Agents/chemistry , Bacterial Adhesion/drug effects , Boronic Acids/chemical synthesis , Polyhydroxyethyl Methacrylate/chemical synthesis , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/physiology , Quercetin/chemistry , Staphylococcus aureus/drug effects , Staphylococcus aureus/physiology , Surface PropertiesABSTRACT
Boron-homologation reactions represent an efficient and programmable approach to prepare alkylboronates, which are valuable and versatile synthetic intermediates. The typical boron-homologation reaction, also known as the Matteson reaction, involves formal carbenoid insertions into C-B bonds. Here we report the development of aza-Matteson reactions via carbenoid insertions into the N-B bonds of aminoboranes. By changing the leaving groups of the carbenoids and altering Lewis acid activators, selective mono- and double-methylene insertions can be realized to access various α- and ß-boron-substituted tertiary amines, respectively, from common secondary amines. The derivatization of complex amine-containing bioactive molecules, diverse functionalization of the boronate products, and sequential insertions of different carbenoids have also been achieved.
Subject(s)
Boronic Acids/chemical synthesis , Amines/chemistry , Boranes/chemistry , Models, Chemical , Molecular StructureABSTRACT
We prepared the magnetic chitosan carbon quantum dot nanoparticles (Fe3O4@CQD NPs) via the hydrothermal treatment of chitosan biopolymer and then its magnetization with Fe3O4 nanoparticles. (4-Acetylphenyl)boronic acid compound was utilized for the modification of surface of Fe3O4@CQD nanoparticles via the covalent imine bond formation between NH2 groups of chitosan quantum dot with carbonyl functional of acetyl-substituted arylboronic acid. The synthesized Fe3O4@CQD@AP-B(OH)2 was characterized by FE-SEM, EDS, XRD, VSM and ICP-OES analysis and its fluorescence property was studied. This magnetic multifunctional nanoplatform sensor has shown high potential sensitivity for Cu2+ ions (in the range of 1.0-30.0 µM with limit of detection 0.3 µM) through interaction of cupric ions with the boronic-acid moiety.
Subject(s)
Boronic Acids/chemistry , Chitosan/chemistry , Copper/analysis , Magnetic Phenomena , Nanocomposites/chemistry , Quantum Dots/chemistry , Boronic Acids/chemical synthesis , Cations , Chitosan/chemical synthesis , Fluorescence , Ions , Nanocomposites/ultrastructure , Quantum Dots/ultrastructure , Spectroscopy, Fourier Transform Infrared , X-Ray DiffractionABSTRACT
Over the past decade, several different metal-free bioorthogonal reactions have been developed to enable simultaneous double-click labeling with minimal-to-no competing cross-reactivities; such transformations are termed 'mutually orthogonal'. More recently, several examples of successful triple ligation strategies have also been described. In this minireview, we discuss selected aspects of the development of orthogonal bioorthogonal reactions over the past decade, including general strategies to drive future innovations to achieve simultaneous, mutually orthogonal click reactions in one pot.
Subject(s)
Alkynes/chemical synthesis , Boronic Acids/chemical synthesis , Phosphines/chemical synthesis , Alkynes/chemistry , Boronic Acids/chemistry , Cycloaddition Reaction , Molecular Structure , Phosphines/chemistryABSTRACT
We synthesized phenylboronic acid pinacol ester (PBPE)-conjugated hyaluronic acid (HA) via thiobis(ethylamine) (TbEA) linkage (abbreviated as HAsPBPE conjugates) to fabricate the radiosensitive delivery of caffeic acid phenetyl ester (CAPE) and for application in radioprotection. PBPE was primarily conjugated with TbEA and then PBPE-TbEA conjugates were conjugated again with hyaluronic acid using carbodiimide chemistry. CAPE-incorporated nanoparticles of HAsPBPE were fabricated by the nanoprecipitation method and then the organic solvent was removed by dialysis. CAPE-incorporated HAsPBPE nanoparticles have a small particle size of about 80 or 100 nm and they have a spherical shape. When CAPE-incorporated HAsPBPE nanoparticles were irradiated, nanoparticles became swelled or disintegrated and their morphologies were changed. Furthermore, the CAPE release rate from HAsPBPE nanoparticles were increased according to the radiation dose, indicating that CAPE-incorporated HAsPBPE nanoparticles have radio-sensitivity. CAPE and CAPE-incorporated HAsPBPE nanoparticles appropriately prevented radiation-induced cell death and suppressed intracellular accumulation of reactive oxygen species (ROS). CAPE and CAPE-incorporated HAsPBPE nanoparticles efficiently improved survivability of mice from radiation-induced death and reduced apoptotic cell death. We suggest that HAsPBPE nanoparticles are promising candidates for the radio-sensitive delivery of CAPE.
Subject(s)
Boronic Acids/chemistry , Caffeic Acids/pharmacology , Glycols/chemistry , Hyaluronic Acid/chemistry , Nanoparticles/chemistry , Phenylethyl Alcohol/analogs & derivatives , Radiation Protection , Animals , Boronic Acids/chemical synthesis , Caffeic Acids/chemical synthesis , Cell Line , Cell Survival/drug effects , Drug Liberation , Hydrogen Peroxide/toxicity , Liver/metabolism , Mice, Inbred BALB C , Nanoparticles/ultrastructure , Particle Size , Phenylethyl Alcohol/chemical synthesis , Phenylethyl Alcohol/pharmacology , Proton Magnetic Resonance Spectroscopy , Spectroscopy, Fourier Transform InfraredABSTRACT
Phenylboronic acid (PBA) forms neutral tetrahedral N,O-coordinated 6-membered cyclic complexes with stability constants reaching the values as large as 1.3 × 104 M-1 at pH 7.4 in water with amino phenolic compounds including 2-(2'-hydroxyphenyl)-1H-benzimidazole (HPBI) often used for protein probing and labeling. The crystal structures of isolated complexes demonstrate unusually high for boronate adducts degree of the tetrahedral character of the boron atom with short B-N bonds in agreement with their high solution stability. The complexation of PBA with HPBI, causes a strong enhancement of the fluorescence of the "enol" form of the ligand, increases the affinity of the dye to a protein (bovine serum albumin) and makes more pronounced the shift in emission maximum induced by the protein binding. Similar, but larger effects are observed with an amino HPBI derivative and with a stronger boronic acid benzoxaborole. Thus, the binding constant to the protein about 2 × 104 M-1 for free HPBI increases to 1.2 × 106 M-1 for the complex of 5-amino-HPBI with benzoxaborole making it suitable for an efficient non-covalent protein labeling or bioconjugation.
Subject(s)
Boronic Acids/chemistry , Fluorescence , Phenols/chemistry , Serum Albumin, Bovine/chemistry , Animals , Boronic Acids/chemical synthesis , Cattle , Ligands , Molecular StructureABSTRACT
Malaria is a devastating infectious disease, which causes over 400,000 deaths per annum and impacts the lives of nearly half the world's population. The causative agent, a protozoan parasite, replicates within red blood cells (RBCs), eventually destroying the cells in a lytic process called egress to release a new generation of parasites. These invade fresh RBCs to repeat the cycle. Egress is regulated by an essential parasite subtilisin-like serine protease called SUB1. Here, we describe the development and optimization of substrate-based peptidic boronic acids that inhibit Plasmodium falciparum SUB1 with low nanomolar potency. Structural optimization generated membrane-permeable, slow off-rate inhibitors that prevent Pfalciparum egress through direct inhibition of SUB1 activity and block parasite replication in vitro at submicromolar concentrations. Our results validate SUB1 as a potential target for a new class of antimalarial drugs designed to prevent parasite replication and disease progression.
Subject(s)
Antimalarials/pharmacology , Boronic Acids/pharmacology , Peptides/pharmacology , Plasmodium falciparum/drug effects , Protozoan Proteins/chemistry , Subtilisins/chemistry , Antimalarials/chemical synthesis , Binding Sites , Boronic Acids/chemical synthesis , Drug Design , Erythrocytes/drug effects , Erythrocytes/parasitology , Gene Expression , Humans , Kinetics , Life Cycle Stages/drug effects , Life Cycle Stages/physiology , Models, Molecular , Molecular Docking Simulation , Peptides/chemical synthesis , Plasmodium falciparum/enzymology , Plasmodium falciparum/genetics , Plasmodium falciparum/growth & development , Protein Binding , Protein Conformation , Protein Interaction Domains and Motifs , Protozoan Proteins/antagonists & inhibitors , Protozoan Proteins/genetics , Protozoan Proteins/metabolism , Structure-Activity Relationship , Substrate Specificity , Subtilisins/antagonists & inhibitors , Subtilisins/genetics , Subtilisins/metabolism , ThermodynamicsABSTRACT
Eye-drop formulations as conventional regimens to tackle ocular diseases are far from efficient due to the rapid clearance by eye tears and the blockage of the corneal epithelium barrier. Here, we describe a bioadhesive glycosylated nanoplatform with boric acid pendants as a drug carrier for noninvasive trans-corneal delivery of drugs to treat corneal neovascularization (CNV), a serious corneal disease resulting in significant vision impairment. This biocompatible nanoplatform is formulated from a synthetic amphiphilic boric acid-based copolymer self-assembling to form highly stable micelles with a high loading capacity for dexamethasone (DEX). The nanoplatform is demonstrated to be in contact with the corneal epithelium for a long period under the bioadhesive function of boric acid modules and releases the drug over 96 h in a controlled manner. Our results also suggest that the nanoplatform can be efficiently internalized by corneal epithelial cells in vitro and realize transcytosis in vivo to greatly enhance the transcorneal penetration of the loaded drugs into the pathological corneal stroma. On topical application against rat corneal alkali burn, the nanoformulation presents more robust efficacy on neovascularization suppression and inflammation elimination than free DEX with a negligible effect on normal tissues. This bioadhesive strategy which focuses on extending ocular drug retention and improving trans-corneal drug delivery not only highlights an approach for alternative noninvasive therapy of CNV but also provides a versatile paradigm for other biomedical applications by overcoming protective barriers.
Subject(s)
Biocompatible Materials/chemistry , Boronic Acids/chemistry , Corneal Neovascularization/drug therapy , Dexamethasone/pharmacology , Drug Delivery Systems , Animals , Biocompatible Materials/chemical synthesis , Boronic Acids/chemical synthesis , Cell Survival/drug effects , Cornea/drug effects , Dexamethasone/chemistry , Drug Carriers/chemistry , Drug Compounding , Glycosylation , Humans , Male , Nanoparticles/chemistry , Rats , Rats, Sprague-DawleyABSTRACT
It is known that phenylboronic acid (PBA) can target tumor tissues by binding to sialic acid, a substrate overexpressed by cancer cells. This capability has previously been explored in the design of targeting diagnostic probes such as Gd- and 68Ga-DOTA-EN-PBA, two contrast agents for magnetic resonance imaging (MRI) and positron emission tomography (PET), respectively, whose potential has already been demonstrated through in vivo experiments. In addition to its high resolution, the intrinsic low sensitivity of MRI stimulates the search for more effective contrast agents, which, in the case of small-molecular probes, basically narrows down to either increased tumbling time of the entire molecule or elevated local concentration of the paramagnetic ions, both strategies resulting in enhanced relaxivity, and consequently, a higher MRI contrast. The latter strategy can be achieved by the design of multimeric GdIII complexes. Based on the monomeric PBA-containing probes described recently, herein, we report the synthesis and characterization of the dimeric analogues (GdIII-DOTA-EN)2-PBA and (GdIII-DOTA-EN)2F2PBA. The presence of two Gd ions in one molecule clearly contributes to the improved biological performance, as demonstrated by the relaxometric study and cell-binding investigations.
Subject(s)
Boronic Acids , Contrast Media , Magnetic Resonance Imaging , Melanoma, Experimental , Animals , Boronic Acids/chemical synthesis , Boronic Acids/chemistry , Boronic Acids/pharmacology , Cell Line, Tumor , Contrast Media/chemical synthesis , Contrast Media/chemistry , Contrast Media/pharmacology , Melanoma, Experimental/diagnostic imaging , Melanoma, Experimental/metabolism , MiceABSTRACT
N-aryl-oxazolidinones is a prominent family of antimicrobials used for treating infections caused by clinically prevalent Gram-positive bacteria. Recently, boron-containing compounds have displayed intriguing potential in the antibiotic discovery setting. Herein, we report the unprecedented introduction of a boron-containing moiety such as an aryl boronic acid in the external region of the oxazolidinone structure via a chemoselective acyl coupling reaction. As a result, we accessed a series of analogues with a distal aryl boronic pharmacophore on the oxazolidinone scaffold. We identified that a peripheric linear conformation coupled with freedom of rotation and no further substitution on the external aryl boronic ring, an amido linkage with hydrogen bonding character, in addition to a para-relative disposition between boronic group and linker, are the optimal combination of structural features in this series for antimicrobial activity. In comparison to linezolid, the analogue comprising all those features, compound 20b, displayed levels of antimicrobial activity augmented by an eight-fold to a thirty-two-fold against a panel of Gram-positive strains, and a near one hundred-fold against Escherichia coli JW5503, a Gram-negative mutant strain with a defective efflux capability.
Subject(s)
Anti-Bacterial Agents/pharmacology , Boronic Acids/pharmacology , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Oxazolidinones/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Boronic Acids/chemical synthesis , Boronic Acids/chemistry , Dose-Response Relationship, Drug , Microbial Sensitivity Tests , Molecular Structure , Oxazolidinones/chemical synthesis , Oxazolidinones/chemistry , Structure-Activity RelationshipABSTRACT
Boron containing compounds have not been widely studied in Medicinal Chemistry, mainly due to the idea that this group could confer some toxicity. Nowadays, this concept has been demystified and, especially after the discovery of the drug bortezomib, the interest for these compounds, mainly boronic acids, has been growing. In this review, several activities of boronic acids, such as anticancer, antibacterial, antiviral activity, and even their application as sensors and delivery systems are addressed. The synthetic processes used to obtain these active compounds are also referred. Noteworthy, the molecular modification by the introduction of boronic acid group to bioactive molecules has shown to modify selectivity, physicochemical, and pharmacokinetic characteristics, with the improvement of the already existing activities. Besides, the preparation of compounds with this chemical group is relatively simple and well known. Taking into consideration these findings, this review reinforces the relevance of extending the studies with boronic acids in Medicinal Chemistry, in order to obtain new promising drugs shortly.
Subject(s)
Boronic Acids/chemical synthesis , Boronic Acids/pharmacology , Animals , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Antiviral Agents/chemical synthesis , Antiviral Agents/chemistry , Antiviral Agents/pharmacology , Boronic Acids/chemistry , Chemistry Techniques, Synthetic , HumansABSTRACT
Bioorthogonal click reactions yielding stable and irreversible adducts are in high demand for in vivo applications, including in biomolecular labeling, diagnostic imaging, and drug delivery. Previously, we reported a novel bioorthogonal "click" reaction based on the coupling of ortho-acetyl arylboronates and thiosemicarbazide-functionalized nopoldiol. We now report that a detailed structural analysis of the arylboronate/nopoldiol adduct by X-ray crystallography and 11B NMR reveals that the bioorthogonal reactants form, unexpectedly, a tetracyclic adduct through the cyclization of the distal nitrogen into the semithiocarbazone leading to a strong B-N dative bond and two new 5-membered rings. The cyclization adduct, which protects the boronate unit against hydrolytic breakdown, sheds light on the irreversible nature of this polycondensation. The potential of this reaction to work in a live animal setting was studied through in vivo capture of fluorescently labeled molecules in vivo. Arylboronates were introduced into tissues through intradermal injection of their activated NHS esters, which react with amines in the extracellular matrix. Fluorescently labeled nopoldiol molecules were administered systemically and were efficiently captured by the arylboronic acids in a location-specific manner. Taken together, these in vivo proof-of-concept studies establish arylboronate/nopoldiol bioorthogonal chemistry as a candidate for wide array of applications in chemical biology and drug delivery.
Subject(s)
Boronic Acids/chemistry , Semicarbazides/chemistry , Animals , Boronic Acids/chemical synthesis , Click Chemistry/methods , Crystallography, X-Ray , Magnetic Resonance Spectroscopy , Mice , Models, Molecular , Semicarbazides/chemical synthesisABSTRACT
Rhomboid intramembrane proteases regulate pathophysiological processes, but their targeting in a disease context has never been achieved. We decoded the atypical substrate specificity of malaria rhomboid PfROM4, but found, unexpectedly, that it results from "steric exclusion": PfROM4 and canonical rhomboid proteases cannot cleave each other's substrates due to reciprocal juxtamembrane steric clashes. Instead, we engineered an optimal sequence that enhanced proteolysis >10-fold, and solved high-resolution structures to discover that boronates enhance inhibition >100-fold. A peptide boronate modeled on our "super-substrate" carrying one "steric-excluding" residue inhibited PfROM4 but not human rhomboid proteolysis. We further screened a library to discover an orthogonal alpha-ketoamide that potently inhibited PfROM4 but not human rhomboid proteolysis. Despite the membrane-immersed target and rapid invasion, ultrastructural analysis revealed that single-dosing blood-stage malaria cultures blocked host-cell invasion and cleared parasitemia. These observations establish a strategy for designing parasite-selective rhomboid inhibitors and expose a druggable dependence on rhomboid proteolysis in non-motile parasites.
Subject(s)
Amides/pharmacology , Antimalarials/pharmacology , Drug Design , Malaria/drug therapy , Protease Inhibitors/pharmacology , Protozoan Proteins/antagonists & inhibitors , Amides/chemical synthesis , Amides/chemistry , Antimalarials/chemical synthesis , Antimalarials/chemistry , Boronic Acids/chemical synthesis , Boronic Acids/chemistry , Boronic Acids/pharmacology , HEK293 Cells , Humans , Malaria/blood , Malaria/metabolism , Molecular Structure , Parasitic Sensitivity Tests , Peptide Hydrolases/blood , Peptide Hydrolases/metabolism , Peptides/chemical synthesis , Peptides/chemistry , Peptides/pharmacology , Plasmodium falciparum/drug effects , Plasmodium falciparum/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/chemistry , Proteolysis/drug effects , Protozoan Proteins/blood , Protozoan Proteins/metabolismABSTRACT
Boronic acids are known reversible covalent inhibitors of serine ß-lactamases. The selectivity and high potency of specific boronates bearing an amide side chain that mimics the ß-lactam's amide side chain have been advanced in several studies. Herein, we describe a new class of boronic acids in which the amide group is replaced by a bioisostere triazole. The boronic acids were obtained in a two-step synthesis that relies on the solid and versatile copper-catalyzed azide-alkyne cycloaddition (CuAAC) followed by boronate deprotection. All of the compounds show very good inhibition of the Klebsiella pneumoniae carbapenemase KPC-2, with Ki values ranging from 1â nM to 1â µM, and most of them are able to restore cefepime activity against K. pneumoniae harboring blaKPC-2 . In particular, compound 1 e, bearing a sulfonamide substituted by a thiophene ring, proved to be an excellent KPC-2 inhibitor (Ki =30â nM); it restored cefepime susceptibility in KPC-Kpn cells (MIC=0.5â µg/mL) with values similar to that of vaborbactam (Ki =20â nM, MIC in KPC-Kpn 0.5â µg/mL). Our findings suggest that α-triazolylboronates might represent an effective scaffold for the treatment of KPC-mediated infections.