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Journal of Medicinal Chemistry Jan 2021Drug conjugates are chemotherapeutic or cytotoxic agents covalently linked to targeting ligands such as an antibody or a peptide via a linker. While antibody-drug... (Review)
Review
Drug conjugates are chemotherapeutic or cytotoxic agents covalently linked to targeting ligands such as an antibody or a peptide via a linker. While antibody-drug conjugates (ADCs) are now clinically established for cancer therapy, peptide-drug conjugates (PDCs) are gaining recognition as a new modality for targeted drug delivery with improved efficacy and reduced side effects for cancer treatment. The linker in a drug conjugate plays a key role in the circulation time of the conjugate and release of the drug for full activity at the target site. Herein, we highlight the main linker chemistries utilized in the design of PDCs and discuss representative examples of PDCs with different linker chemistries with the related outcome in cell and animal studies.
Topics: Amino Acid Sequence; Animals; Antineoplastic Agents; Cell Line, Tumor; Humans; Neoplasms; Oximes; Peptides; Pharmaceutical Preparations; Triazoles; Xenograft Model Antitumor Assays
PubMed: 33382619
DOI: 10.1021/acs.jmedchem.0c01530 -
Molecules (Basel, Switzerland) Oct 2022A series of the eight novel organoantimony(V) cyanoximates of Sb(CH)L composition was synthesized using the high-yield heterogeneous metathesis reaction between solid...
A series of the eight novel organoantimony(V) cyanoximates of Sb(CH)L composition was synthesized using the high-yield heterogeneous metathesis reaction between solid AgL (or TlL) and Sb(CH)Br in CHCN at room temperature. Cyanoximes L were specially selected from a large group of 48 known compounds of this subclass of oximes on the basis of their water solubility and history of prior biological activity. The synthesized compounds are well soluble in organic solvents and were studied using a variety of conventional spectroscopic and physical methods. The crystal structures of all reported organometallic compounds were determined and revealed the formation of the distorted trigonal bipyramidal environment of the Sb atom and monodentate axial binding of acido-ligands via the O atom of the oxime group. The compounds are thermally stable in the solid state and in solution molecular compounds. For the first time, this specially designed series of organoantimony(V) compounds is investigated as potential non-antibiotic antimicrobial agents against three bacterial and two fungal human pathogens known for their increasing antimicrobial resistance. Bacterial pathogens included Gram-negative Escherichia coli and Pseudomonas aeruginosa, and Gram-positive Staphylococcus aureus. Fungal pathogens included Cryptococcus neoformans and Candida albicans. The cyanoximates alone showed no antimicrobial impact, and the incorporation of the SbPh group enabled the antimicrobial effect. Overall, the new antimony compounds showed a strong potential as both broad- and narrow-spectrum antimicrobials against selected bacterial and fundal pathogens and provide insights for further synthetic modifications of the compounds to increase their activities.
Topics: Humans; Anti-Bacterial Agents; Antimony; Anti-Infective Agents; Staphylococcus aureus; Candida albicans; Bacteria; Oximes; Microbial Sensitivity Tests; Antifungal Agents
PubMed: 36363997
DOI: 10.3390/molecules27217171 -
Trends in Pharmacological Sciences Jul 2022High lethality, fast action, and simple synthesis make nerve agents (NAs) the most dreaded chemical weapons (CWs) of mass destruction in the world. Disturbances of the... (Review)
Review
High lethality, fast action, and simple synthesis make nerve agents (NAs) the most dreaded chemical weapons (CWs) of mass destruction in the world. Disturbances of the autonomic nervous system and neuromuscular junction (NMJ) by NAs and organophosphorus (OP) insecticides lead to cholinergic crisis and skeletal muscle paralysis. Current medical intervention has remained mostly unchanged since their first discovery in the 1950s. Within this overview, we have followed their development, clinical successes, and failures and discuss the major demerits of available antidotes. In current times, with precision medicine becoming increasingly relevant in various fields of medicine, the antidotal approach should be broadened to better cope with individual cases of NA intoxication. When possible, countermeasures could be targeted directly to achieve a better patient prognosis. As the threat of NA misuse and accidental cases of OP insecticide intoxication are still omnipresent, advancement of intervention expertise and further research in this field should be supported.
Topics: Antidotes; Cholinesterase Reactivators; Humans; Organophosphate Poisoning; Oximes
PubMed: 35643835
DOI: 10.1016/j.tips.2022.04.008 -
Archives of Toxicology Jul 2020Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical... (Review)
Review
Organophosphorus (OP) pesticides and nerve agents still pose a threat to the population. Treatment of OP poisoning is an ongoing challenge and burden for medical services. Standard drug treatment consists of atropine and an oxime as reactivator of OP-inhibited acetylcholinesterase and is virtually unchanged since more than six decades. Established oximes, i.e. pralidoxime, obidoxime, TMB-4, HI-6 and MMB-4, are of insufficient effectiveness in some poisonings and often cover only a limited spectrum of the different nerve agents and pesticides. Moreover, the value of oximes in human OP pesticide poisoning is still disputed. Long-lasting research efforts resulted in the preparation of countless experimental oximes, and more recently non-oxime reactivators, intended to replace or supplement the established and licensed oximes. The progress of this development is slow and none of the novel compounds appears to be suitable for transfer into advanced development or into clinical use. This situation calls for a critical analysis of the value of oximes as mainstay of treatment as well as the potential and limitations of established and novel reactivators. Requirements for a straightforward identification of superior reactivators and their development to licensed drugs need to be addressed as well as options for interim solutions as a chance to improve the therapy of OP poisoning in a foreseeable time frame.
Topics: Animals; Antidotes; Atropine; Cholinesterase Reactivators; Humans; Nerve Agents; Organophosphate Poisoning; Organophosphonates; Oximes; Pesticides; Treatment Outcome
PubMed: 32506210
DOI: 10.1007/s00204-020-02797-0 -
Methods in Molecular Biology (Clifton,... 2020Click chemistry has found wide application in bioconjugation, enabling control over the site of modification in biomolecules. Demonstrations of this chemistry to...
Click chemistry has found wide application in bioconjugation, enabling control over the site of modification in biomolecules. Demonstrations of this chemistry to construct chemically defined antibody-drug conjugates (ADCs) have increased in recent years, following studies that support benefits of homogeneity and site-specificity of drug placement on the antibody. In this chapter, a brief history of early applications of this chemistry in ADCs is presented. Examples of click chemistries that are utilized for ADC synthesis, including those currently undergoing clinical investigations, are enumerated. Protocols for two common conjugation methods based on carbonyl-aminooxy coupling and strain-promoted azide-alkyne cycloaddition are described.
Topics: Amino Acids; Antibodies, Monoclonal; Chemistry Techniques, Synthetic; Click Chemistry; Cycloaddition Reaction; Drug Development; Humans; Immunoconjugates; Oximes
PubMed: 31643051
DOI: 10.1007/978-1-4939-9929-3_6 -
Chemical Reviews Jul 2019At the advent of cross-coupling chemistry, carbon electrophiles based on halides or pseudohalides were the only suitable electrophilic coupling partners. Almost two... (Review)
Review
At the advent of cross-coupling chemistry, carbon electrophiles based on halides or pseudohalides were the only suitable electrophilic coupling partners. Almost two decades passed before the first cross-coupling reaction of heteroatom-based electrophiles was reported. Early work by Murai and Tanaka initiated investigations into silicon electrophiles. Narasaka and Johnson pioneered the way in the use of nitrogen electrophiles, while Suginome began the exploration of boron electrophiles. The chemistry reviewed within provides perspective on the use of heteroatomic electrophiles, specifically silicon-, nitrogen-, boron-, oxygen-, and phosphorus-based electrophiles in transition-metal catalyzed cross-coupling. For the purposes of this review, a loose definition of cross-coupling is utilized; all reactions minimally proceed via an oxidative addition event. Although not cross-coupling in a traditional sense, we have also included catalyzed reactions that join a heteroatomic electrophile with an in situ generated nucleophile. However, for brevity, those involving hydroamination or C-H activation as a key step are largely excluded. This work includes primary references published up to and including October 2018.
Topics: Boron Compounds; Chemistry Techniques, Synthetic; Chemistry, Organic; Organophosphorus Compounds; Oxidation-Reduction; Oximes; Silicon
PubMed: 31184483
DOI: 10.1021/acs.chemrev.8b00628 -
Nature Chemistry Aug 2022Chiral hydroxylamines are vital substances in bioscience and versatile subunits in the preparation of a variety of functional molecules. However, asymmetric and...
Chiral hydroxylamines are vital substances in bioscience and versatile subunits in the preparation of a variety of functional molecules. However, asymmetric and non-asymmetric synthetic approaches to these compounds are far from satisfactory. Although atom-economic metal-catalysed asymmetric hydrogenations have been studied for over 50 years, the asymmetric hydrogenation of oximes to the corresponding chiral hydroxylamines remains challenging because of the labile N-O bond and inert C=N bond. Here we report an environmentally friendly, earth-abundant, transition-metal nickel-catalysed asymmetric hydrogenation of oximes, affording the corresponding chiral hydroxylamines with up to 99% yield, 99% e.e. and with a substrate/catalyst ratio of 1,000. Computational results indicate that the weak interactions between the catalyst and substrate play crucial roles not only in the transition states, but also during the approach of the substrate to the catalyst, by selectively reducing the reaction barriers and thus improving the reaction efficiency and securing the generation of chirality.
Topics: Catalysis; Hydrogenation; Nickel; Oximes; Stereoisomerism
PubMed: 35697929
DOI: 10.1038/s41557-022-00971-8 -
Molecules (Basel, Switzerland) Jun 2023Oxime ethers are a class of compounds containing the >C=N-O-R moiety. The presence of this moiety affects the biological activity of the compounds. In this review, the... (Review)
Review
Oxime ethers are a class of compounds containing the >C=N-O-R moiety. The presence of this moiety affects the biological activity of the compounds. In this review, the structures of oxime ethers with specific biological activity have been collected and presented, and bactericidal, fungicidal, antidepressant, anticancer and herbicidal activities, among others, are described. The review includes both those substances that are currently used as drugs (e.g., fluvoxamine, mayzent, ridogrel, oxiconazole), as well as non-drug structures for which various biological activity studies have been conducted. To the best of our knowledge, this is the first review of the biological activity of compounds containing such a moiety. The authors hope that this review will inspire scientists to take a greater interest in this group of compounds, as it constitutes an interesting research area.
Topics: Ethers; Structure-Activity Relationship; Oximes; Fungicides, Industrial; Anti-Bacterial Agents; Anesthetics, General
PubMed: 37446703
DOI: 10.3390/molecules28135041 -
Chembiochem : a European Journal of... Sep 2022Proteolysis targeting chimeras are of keen interest as probe molecules and drug leads. Their activity is highly sensitive to the length and nature of the linker...
Proteolysis targeting chimeras are of keen interest as probe molecules and drug leads. Their activity is highly sensitive to the length and nature of the linker connecting the E3 Ubiquitin Ligase (E3 Ubl) and target protein (TP) ligands, which therefore requires tedious optimization. The creation of "split PROTACs" from E3 Ubl and TP ligands modified with residues suitable for them to couple when simply mixed together would allow various combinations to be assessed in a combinatorial fashion, thus greatly easing the workload relative to a one-by-one synthesis of many different PROTACs (proteolysis targeting chimeras). We explore oxime chemistry here for this purpose. We show that PROTAC assembly occurs efficiently when the components are mixed at a high concentration, then added to cells. However, in situ coupling of the TP and E3 Ubl ligands is inefficient when these units are added to cells at lower concentrations.
Topics: Ligands; Oximes; Proteolysis; Ubiquitin-Protein Ligases
PubMed: 35802347
DOI: 10.1002/cbic.202200275 -
International Journal of Molecular... Nov 2023The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse... (Review)
Review
The present review explores the critical role of oxime and oxime ether moieties in enhancing the physicochemical and anticancer properties of structurally diverse molecular frameworks. Specific examples are carefully selected to illustrate the distinct contributions of these functional groups to general strategies for molecular design, modulation of biological activities, computational modeling, and structure-activity relationship studies. An extensive literature search was conducted across three databases, including PubMed, Google Scholar, and Scifinder, enabling us to create one of the most comprehensive overviews of how oximes and oxime ethers impact antitumor activities within a wide range of structural frameworks. This search focused on various combinations of keywords or their synonyms, related to the anticancer activity of oximes and oxime ethers, structure-activity relationships, mechanism of action, as well as molecular dynamics and docking studies. Each article was evaluated based on its scientific merit and the depth of the study, resulting in 268 cited references and more than 336 illustrative chemical structures carefully selected to support this analysis. As many previous reviews focus on one subclass of this extensive family of compounds, this report represents one of the rare and fully comprehensive assessments of the anticancer potential of this group of molecules across diverse molecular scaffolds.
Topics: Ether; Oximes; Ethers; Structure-Activity Relationship; Ethyl Ethers
PubMed: 38069175
DOI: 10.3390/ijms242316854