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1.
Nucl Med Biol ; 132-133: 108911, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38614036

RESUMEN

INTRODUCTION: The pretargeting approach consists of in vivo ligation between pre-injected antibodies and low-molecular-weight radiolabeled effectors. The advantage of the pretargeting approach is to improve a tumor-to-background ratio, but the disadvantage is to compromise tumor accumulation. In this study, we applied albumin binder (ALB) to the pretargeting approach to overcome low tumor accumulation. METHODS: We synthesized two novel trifunctional effectors containing an ALB moiety, a chelator, and a different tetrazine and two corresponding effectors without an ALB moiety. Albumin-binding assays and stability assays were performed using 111In-labeled effectors. Measurements of reaction rate constant were conducted using 111In-labeled effectors and anti-HER2 antibody trastuzumab modified by trans-cyclooctene, which drives the click reaction with tetrazine. Biodistribution studies using HER2-expressing tumor-bearing mice were performed with or without the pretargeting approach. RESULTS: In albumin-binding assays, ALB-containing effectors exhibited a marked binding to albumin. Two ALB-containing effectors showed the difference in the reactivity and the slight difference in the stability. In biodistribution studies without the pretargeting approach, two ALB-containing effectors showed different pharmacokinetics in blood retention. With the pretargeting approach, the tumor accumulation was improved by the introduction of ALB and the highest tumor accumulation was observed in using the ALB-containing effector with higher blood retention. CONCLUSION: These results suggest that the application of ALB to the pretargeting approach is effective to improve tumor accumulation, and the structure of tetrazine influences the utility of ALB-containing effectors.


Asunto(s)
Quelantes , Animales , Ratones , Quelantes/química , Quelantes/síntesis química , Distribución Tisular , Línea Celular Tumoral , Humanos , Técnicas de Química Sintética , Femenino , Albúminas/química , Receptor ErbB-2/metabolismo , Trastuzumab/química , Trastuzumab/farmacocinética
2.
Ultrason Sonochem ; 105: 106858, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38564910

RESUMEN

Zinc sulfide/graphitic Carbon Nitride binary nanosheets were synthesized by using a novel sonochemical pathway with high electrocatalytic ability. The as- obtained samples were characterized by various analytical methods such as Transmission Electron Microscopy (TEM), Field emission scanning electron microscopy (FESEM), Energy-dispersive X-ray spectroscopy (EDS), X-ray diffraction analysis (XRD), and X-ray photoelectron spectroscopy (XPS) to evaluate the properties of ZnS@CNS synthesized by this new route. Subsequently, the electrical and electrochemical performance of the proposed electrodes were characterized by using EIS and CV to establish an electroactive ability of the nanocomposites. The complete properties like structural and physical of ZnS@CNS were analyzed. As-prepared binary nanocomposite was applied towards the detection of anticancer drug (flutamide) by various electrochemical methods such as cyclic voltammetry (CV), differential pulse voltammetry (DPV) and amperometry. The glassy carbon electrode modified with a ZnS@CNS composite demonstrates a remarkable electrocatalytic efficiency for detecting flutamide in a pH 7.0 (PBS). The composite modified electrode shows synergistic effect of ZnS and CNS catalyst. The electrochemical sensing performance of the linear range was improved significantly due to high electroactive sites and rapid electron transport pathways. Crucially, the electrochemical method was successfully demonstrated in biological fluids which reveals its potential real-time applicability in the analysis of drug.


Asunto(s)
Antineoplásicos , Electrodos , Grafito , Compuestos de Nitrógeno , Sulfuros , Ondas Ultrasónicas , Compuestos de Zinc , Compuestos de Zinc/química , Sulfuros/química , Antineoplásicos/química , Grafito/química , Flutamida/análisis , Flutamida/química , Técnicas Electroquímicas/métodos , Técnicas de Química Sintética , Electroquímica , Límite de Detección , Catálisis , Nanocompuestos/química , Nanoestructuras/química
3.
Int J Biol Macromol ; 266(Pt 1): 131211, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38552688

RESUMEN

Our study aimed at developing polymer micelles that possess redox sensitivity and excellent controlled release properties. 3,3'-dithiodipropionic acid (DTDPA, Abbreviation in synthetic polymers: SS) was introduced as ROS (Reactive oxygen species)response bond and connecting arm to couple hydroxyethyl starch (HES) with oleanolic acid (OA), resulting in the synthesis of four distinct grafting ratios of HES-SS-OA. FTIR (Fourier Transform infrared spectroscopy) and 1H NMR (1H Nuclear magnetic resonance spectra) were used to verify the triumphant combination of HES-SS-OA. Polymer micelles were found to encapsulate OA in an amorphous form, as indicated by the results of XRD (X-ray diffraction) and DSC (Differential scanning calorimetry). When the OA grafting rate on HES increased from 7.72 % to 11.75 %, the particle size decreased from 297.79 nm to 201.39 nm as the polymer micelles became compact due to enhanced hydrophobicity. In addition, the zeta potential changed from -16.42 mv to -25.78 mv, the PDI (polydispersity index) decreased from 0.3649 to 0.2435, and the critical micelle concentration (CMC) decreased from 0.0955 mg/mL to 0.0123 mg/mL. Results of erythrocyte hemolysis, cytotoxicity and cellular uptake illustrated that HES-SS-OA had excellent biocompatibility and minimal cytotoxicity for AML-12 cells. Disulfide bond breakage of HES-SS-OA in the presence of H2O2 and GSH confirmed the redox sensitivity of the HES-SS-OA micelles and their excellent controlled release properties for OA. These findings suggest that HES-SS-OA can be potentially used in the future as a healthcare drug and medicine for the prevention or adjuvant treatment of inflammation.


Asunto(s)
Derivados de Hidroxietil Almidón , Micelas , Ácido Oleanólico , Oxidación-Reducción , Derivados de Hidroxietil Almidón/química , Ácido Oleanólico/química , Polímeros/química , Liberación de Fármacos , Portadores de Fármacos/química , Humanos , Hemólisis/efectos de los fármacos , Técnicas de Química Sintética , Animales , Tamaño de la Partícula
4.
J Org Chem ; 89(7): 4261-4282, 2024 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-38508870

RESUMEN

Small molecule therapeutics represent the majority of the FDA-approved drugs. Yet, many attractive targets are poorly tractable by small molecules, generating a need for new therapeutic modalities. Due to their biocompatibility profile and structural versatility, peptide-based therapeutics are a possible solution. Additionally, in the past two decades, advances in peptide design, delivery, formulation, and devices have occurred, making therapeutic peptides an attractive modality. However, peptide manufacturing is often limited to solid-phase peptide synthesis (SPPS), liquid phase peptide synthesis (LPPS), and to a lesser extent hybrid SPPS/LPPS, with SPPS emerging as a predominant platform technology for peptide synthesis. SPPS involves the use of excess solvents and reagents which negatively impact the environment, thus highlighting the need for newer technologies to reduce the environmental footprint. Herein, fourteen American Chemical Society Green Chemistry Institute Pharmaceutical Roundtable (ACS GCIPR) member companies with peptide-based therapeutics in their portfolio have compiled Process Mass Intensity (PMI) metrics to help inform the sustainability efforts in peptide synthesis. This includes PMI assessment on 40 synthetic peptide processes at various development stages in pharma, classified according to the development phase. This is the most comprehensive assessment of synthetic peptide environmental metrics to date. The synthetic peptide manufacturing process was divided into stages (synthesis, purification, isolation) to determine their respective PMI. On average, solid-phase peptide synthesis (SPPS) (PMI ≈ 13,000) does not compare favorably with other modalities such as small molecules (PMI median 168-308) and biopharmaceuticals (PMI ≈ 8300). Thus, the high PMI for peptide synthesis warrants more environmentally friendly processes in peptide manufacturing.


Asunto(s)
Péptidos , Técnicas de Síntesis en Fase Sólida , Péptidos/química , Técnicas de Química Sintética , Solventes
5.
Molecules ; 29(4)2024 Feb 10.
Artículo en Inglés | MEDLINE | ID: mdl-38398574

RESUMEN

The monogenic rare disease Cystic Fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance (CFTR) protein, an anion channel expressed at the apical plasma membrane of epithelial cells. The discovery and subsequent development of CFTR modulators-small molecules acting on the basic molecular defect in CF-have revolutionized the standard of care for people with CF (PwCF), thus drastically improving their clinical features, prognosis, and quality of life. Currently, four of these drugs are approved for clinical use: potentiator ivacaftor (VX-770) alone or in combination with correctors lumacaftor, (VX-809), tezacaftor (VX-661), and elexacaftor (VX-445). Noteworthily, the triple combinatorial therapy composed of ivacaftor, tezacaftor, and elexacaftor constitutes the most effective modulator therapy nowadays for the majority of PwCF. In this review, we exploit the organic synthesis of ivacaftor, tezacaftor, and elexacaftor by providing a retrosynthetic drug analysis for these CFTR modulators. Furthermore, we describe the current understanding of the mechanisms of action (MoA's) of these compounds by discussing several studies that report the key findings on the molecular mechanisms underlying their action on the CFTR protein.


Asunto(s)
Aminopiridinas , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Indoles , Pirazoles , Piridinas , Pirrolidinas , Quinolonas , Humanos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Calidad de Vida , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Benzodioxoles/farmacología , Benzodioxoles/uso terapéutico , Aminofenoles/farmacología , Aminofenoles/uso terapéutico , Mutación , Técnicas de Química Sintética
6.
J Am Chem Soc ; 146(6): 4270-4280, 2024 Feb 14.
Artículo en Inglés | MEDLINE | ID: mdl-38316681

RESUMEN

Peptide therapeutics have experienced a rapid resurgence over the past three decades. While a few peptide drugs are biologically produced, most are manufactured via chemical synthesis. The cycle of prior protection of the amino group of an α-amino acid, activation of its carboxyl group, aminolysis with the free amino group of a growing peptide chain, and deprotection of the N-terminus constitutes the principle of conventional C → N peptide chemical synthesis. The mandatory use of the Nα-protecting group invokes two additional operations for incorporating each amino acid, resulting in poor step- and atom-economy. The burgeoning demand in the peptide therapeutic market necessitates cost-effective and environmentally friendly peptide manufacturing strategies. Inverse peptide chemical synthesis using unprotected amino acids has been proposed as an ideal and appealing strategy. However, it has remained unsuccessful for over 60 years due to severe racemization/epimerization during N → C peptide chain elongation. Herein, this challenge has been successfully addressed by ynamide coupling reagent employing a transient protection strategy. The activation, transient protection, aminolysis, and in situ deprotection were performed in one pot, thus offering a practical peptide chemical synthesis strategy formally using unprotected amino acids as the starting material. Its robustness was exemplified by syntheses of peptide active pharmaceutical ingredients. It is also amenable to fragment condensation and inverse solid-phase peptide synthesis. The compatibility to green solvents further enhances its application potential in large-scale peptide production. This study offered a cost-effective, operational convenient, and environmentally benign approach to peptides.


Asunto(s)
Aminoácidos , Péptidos , Aminoácidos/química , Péptidos/química , Técnicas de Química Sintética , Péptido C , Biosíntesis de Péptidos , Técnicas de Síntesis en Fase Sólida
7.
Angew Chem Int Ed Engl ; 63(14): e202318897, 2024 Apr 02.
Artículo en Inglés | MEDLINE | ID: mdl-38326236

RESUMEN

Mirror-image proteins (D-proteins) are useful in biomedical research for purposes such as mirror-image screening for D-peptide drug discovery, but the chemical synthesis of many D-proteins is often low yielding due to the poor solubility or aggregation of their constituent peptide segments. Here, we report a Lys-C protease-cleavable solubilizing tag and its use to synthesize difficult-to-obtain D-proteins. Our tag is easily installed onto multiple amino acids such as DLys, DSer, DThr, and/or the N-terminal amino acid of hydrophobic D-peptides, is impervious to various reaction conditions, such as peptide synthesis, ligation, desulfurization, and transition metal-mediated deprotection, and yet can be completely removed by Lys-C protease under denaturing conditions to give the desired D-protein. The efficacy and practicality of the new method were exemplified in the synthesis of two challenging D-proteins: D-enantiomers of programmed cell death protein 1 IgV domain and SARS-CoV-2 envelope protein, in high yield. This work demonstrates that the enzymatic cleavage of solubilizing tags under denaturing conditions is feasible, thus paving the way for the production of more D-proteins.


Asunto(s)
Péptidos , Proteínas , Proteínas/química , Péptidos/química , Aminoácidos/química , Técnicas de Química Sintética/métodos , Péptido Hidrolasas , Endopeptidasas
8.
Bioorg Med Chem Lett ; 99: 129621, 2024 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-38244941

RESUMEN

The progress of organicsyntheticmethod can promote late-stage lead compound modification and novel active compound discovery. Molecular editing technology in the field of organic synthesis, including peripheral and skeletal editing, facilitates rapid access to molecular diversity of a lead compound. Peripheral editing of CH bond activation is gradually used in lead optimization to afford novel active scaffolds and chemical space exploitation. To develop oridonin derivatives with high anti-inflammatory potency, novel oridonin sulfamides had been designed and synthesized by a scaffoldhopping strategy based on a visible-light photocatalysis peripheral editing. All novel compounds revealed measurable inhibition of IL-1ß and low cytotoxicity in THP-1 cells. The docking study indicated that the best active compound ZM640 was accommodated in thebinding site of NLRP3 with two hydrogen bond interaction. These preliminary results confirm that α, ß-unsaturated carbonyl of oridonin is not essential for NLRP3 inhibitory effect. This new oridonin scaffold has its potential to be further developed as a promising class of NLRP3 inhibitors.


Asunto(s)
Antineoplásicos , Diterpenos de Tipo Kaurano , Antineoplásicos/farmacología , Proteína con Dominio Pirina 3 de la Familia NLR , Diterpenos de Tipo Kaurano/farmacología , Diterpenos de Tipo Kaurano/química , Técnicas de Química Sintética
9.
Int J Mol Sci ; 24(24)2023 Dec 06.
Artículo en Inglés | MEDLINE | ID: mdl-38139025

RESUMEN

"Heptil" (unsymmetrical dimethylhydrazine-UDMH) is extensively employed worldwide as a propellant for rocket engines. However, UDMH constantly loses its properties as a result of its continuous and uncontrolled absorption of moisture, which cannot be rectified. This situation threatens its long-term usability. UDMH is an exceedingly toxic compound (Hazard Class 1), which complicates its transportation and disposal. Incineration is currently the only method used for its disposal, but this process generates oxidation by-products that are even more toxic than the original UDMH. A more benign approach involves its immediate reaction with a formalin solution to form 1,1-dimethyl-2-methylene hydrazone (MDH), which is significantly less toxic by an order of magnitude. MDH can then be polymerized under acidic conditions, and the resulting product can be burned, yielding substantial amounts of nitrogen oxides. This review seeks to shift the focus of MDH from incineration towards its application in the synthesis of relatively non-toxic and readily available analogs of various pharmaceutical substances. We aim to bring the attention of the international chemical community to the distinctive properties of MDH, as well as other hydrazones (such as glyoxal, acrolein, crotonal, and meta-crolyl), wherein each structural fragment can initiate unique transformations that have potential applications in molecular design, pharmaceutical research, and medicinal chemistry.


Asunto(s)
Acroleína , Glioxal , Dimetilhidrazinas/química , Formaldehído , Técnicas de Química Sintética
10.
Molecules ; 28(20)2023 Oct 19.
Artículo en Inglés | MEDLINE | ID: mdl-37894644

RESUMEN

Peptides are at the cutting edge of contemporary research for new potent, selective, and safe therapeutical agents. Their rise has reshaped the pharmaceutical landscape, providing solutions to challenges that traditional small molecules often cannot address. A wide variety of natural and modified peptides have been obtained and studied, and many others are advancing in clinical trials, covering multiple therapeutic areas. As the demand for peptide-based therapies grows, so does the need for sustainable and environmentally friendly synthesis methods. Traditional peptide synthesis, while effective, often involves environmentally draining processes, generating significant waste and consuming vast resources. The integration of green chemistry offers sustainable alternatives, prioritizing eco-friendly processes, waste reduction, and energy conservation. This review delves into the transformative potential of applying green chemistry principles to peptide synthesis by discussing relevant examples of the application of such approaches to the production of active pharmaceutical ingredients (APIs) with a peptide structure and how these efforts are critical for an effective green transition era in the pharmaceutical field.


Asunto(s)
Péptidos , Péptidos/uso terapéutico , Péptidos/química , Técnicas de Química Sintética , Preparaciones Farmacéuticas
11.
Nature ; 622(7983): 507-513, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37730997

RESUMEN

Marine-derived cyclic imine toxins, portimine A and portimine B, have attracted attention because of their chemical structure and notable anti-cancer therapeutic potential1-4. However, access to large quantities of these toxins is currently not feasible, and the molecular mechanism underlying their potent activity remains unknown until now. To address this, a scalable and concise synthesis of portimines is presented, which benefits from the logic used in the two-phase terpenoid synthesis5,6 along with other tactics such as exploiting ring-chain tautomerization and skeletal reorganization to minimize protecting group chemistry through self-protection. Notably, this total synthesis enabled a structural reassignment of portimine B and an in-depth functional evaluation of portimine A, revealing that it induces apoptosis selectively in human cancer cell lines with high potency and is efficacious in vivo in tumour-clearance models. Finally, practical access to the portimines and their analogues simplified the development of photoaffinity analogues, which were used in chemical proteomic experiments to identify a primary target of portimine A as the 60S ribosomal export protein NMD3.


Asunto(s)
Antineoplásicos , Técnicas de Química Sintética , Iminas , Compuestos de Espiro , Humanos , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Iminas/síntesis química , Iminas/química , Iminas/farmacología , Neoplasias/tratamiento farmacológico , Proteómica , Ribosomas/metabolismo , Proteínas de Unión al ARN/metabolismo , Compuestos de Espiro/síntesis química , Compuestos de Espiro/química , Compuestos de Espiro/farmacología , Relación Estructura-Actividad , Antineoplásicos/síntesis química , Antineoplásicos/química , Antineoplásicos/farmacología
12.
Chemistry ; 29(57): e202301949, 2023 Oct 13.
Artículo en Inglés | MEDLINE | ID: mdl-37475574

RESUMEN

The creation of complementary products via templating is a hallmark feature of nucleic acid replication. Outside of nucleic acid-like molecules, the templated synthesis of a hetero-complementary copy is still rare. Herein we describe one cycle of templated synthesis that creates homomeric macrocyclic peptides guided by linear instructing strands. This strategy utilizes hydrazone formation to pre-organize peptide oligomeric monomers along the template on a solid support resin, and microwave-assisted peptide synthesis to couple monomers and cyclize the strands. With a flexible templating strand, we can alter the size of the complementary macrocycle products by increasing the length and number of the binding peptide oligomers, showing the potential to precisely tune the size of macrocyclic products. For the smaller macrocyclic peptides, the products can be released via hydrolysis and characterized by ESI-MS.


Asunto(s)
Ácidos Nucleicos , Péptidos , Péptidos/química , Técnicas de Química Sintética
13.
Bioorg Chem ; 138: 106660, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37320914

RESUMEN

Cancer is spreading worldwide and is one of the leading causes of death. The use of existing chemotherapeutic agents is frequently limited due to side effects. As a result, it is critical to investigate new agents for cancer treatment. In this context, we developed an electrochemical method for the synthesis of a series of thiol-linked pyrimidine derivatives (3a-3p) and explored their anti-cancer potential. The biological profile of the synthesized compounds was evaluated against breast (MDAMB-231 and MCF-7) and colorectal (HCT-116) cancer cell lines. 3b and 3d emerged to be the most potent agents, with IC50 values ranging between 0.98 to 2.45 µM. Target delineation studies followed by secondary anticancer parameters were evaluated for most potent compounds, 3b and 3d. The analysis revealed compounds possess DNA intercalation potential and selective inhibition towards human topoisomerase (hTopo1). The analysis was further corroborated by DNA binding studies and in silico-based molecular modeling studies that validated the intercalating binding mode between the compounds and the DNA.


Asunto(s)
Antineoplásicos , Uracilo , Humanos , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular , Técnicas de Química Sintética , ADN , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Estructura Molecular , Relación Estructura-Actividad , Uracilo/farmacología
14.
Chembiochem ; 24(14): e202300382, 2023 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-37305956

RESUMEN

Stereoselective carbon-carbon bond forming reactions are quintessential transformations in organic synthesis. One example is the Diels-Alder reaction, a [4+2] cycloaddition between a conjugated diene and a dienophile to form cyclohexenes. The development of biocatalysts for this reaction is paramount for unlocking sustainable routes to a plethora of important molecules. To obtain a comprehensive understanding of naturally evolved [4+2] cyclases, and to identify hitherto uncharacterised biocatalysts for this reaction, we constructed a library comprising forty-five enzymes with reported or predicted [4+2] cycloaddition activity. Thirty-one library members were successfully produced in recombinant form. In vitro assays employing a synthetic substrate incorporating a diene and a dienophile revealed broad-ranging cycloaddition activity amongst these polypeptides. The hypothetical protein Cyc15 was found to catalyse an intramolecular cycloaddition to generate a novel spirotetronate. The crystal structure of this enzyme, along with docking studies, establishes the basis for stereoselectivity in Cyc15, as compared to other spirotetronate cyclases.


Asunto(s)
Carbono , Proteínas , Catálisis , Reacción de Cicloadición , Técnicas de Química Sintética
15.
Biomolecules ; 13(3)2023 03 02.
Artículo en Inglés | MEDLINE | ID: mdl-36979398

RESUMEN

Even with decades of research studies behind octacalcium phosphate (OCP), determination of OCP phase formation has proved to be a cumbersome challenge. Even though obtaining a large quantity of OCP is important for potential clinical uses, it still remains a hindrance to obtain high yields of pure OCP. Taking that into consideration, the purpose of this study was to scale-up OCP synthesis for the first time and to use a multi-technique approach to follow the phase transformation pathway at multiple time points. In the present study, OCP has been synthesized from α-tricalcium phosphate (α-TCP), and subsequently scaled-up tenfold and hundredfold (100 mg → 10 g). The hydrolysis mechanism has been followed and described by using XRD and FTIR spectroscopy, as well as Raman and SEM. Gradual transformation into the OCP phase transpired through dicalcium phosphate dihydrate (brushite, DCPD, up to ~36%) as an intermediary phase. Furthermore, the obtained transitional phases and final OCP phases (across all scale-up levels) were tested with human bone marrow-derived mesenchymal stem cells (hBMSCs), in order to see how different phase mixtures affect the cell viability, and also to corroborate the safety of the scaled-up product. Twelve out of seventeen specimens showed satisfactory percentages of cell viability and confirmed the prospective use of scaled-up OCP in further in vitro studies. The present study, therefore, provides the first scale-up process of OCP synthesis, an in depth understanding of the formation pathway, and investigation of the parameters able to contribute in the OCP phase formation.


Asunto(s)
Fosfatos de Calcio , Técnicas de Química Sintética , Cinética , Espectroscopía Infrarroja por Transformada de Fourier , Microscopía Electrónica de Rastreo , Espectrometría Raman , Rayos Láser , Difracción de Rayos X , Tamaño de la Partícula , Supervivencia Celular , Forma de la Célula , Humanos , Células Madre Mesenquimatosas/citología , Sistemas de Liberación de Medicamentos , Hidrólisis , Fosfatos de Calcio/síntesis química , Fosfatos de Calcio/química
17.
J Enzyme Inhib Med Chem ; 37(1): 2304-2319, 2022 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-36000176

RESUMEN

Oxadiazole is a five-membered heterocyclic compound containing two nitrogen atoms and one oxygen atom. The 1,3,4-oxadiazole and 1,2,4-oxadiazole have favourable physical, chemical, and pharmacokinetic properties, which significantly increase their pharmacological activity via hydrogen bond interactions with biomacromolecules. In recent years, oxadiazole has been demonstrated to be the biologically active unit in a number of compounds. Oxadiazole derivatives exhibit antibacterial, anti-inflammatory, anti-tuberculous, anti-fungal, anti-diabetic and anticancer activities. In this paper, we report a series of compounds containing oxadiazole rings that have been published in the last three years only (2020-2022) as there was no report or their activities described in any article in 2019, which will be useful to scientists in research fields of organic synthesis, medicinal chemistry, and pharmacology.


Asunto(s)
Química Farmacéutica , Oxadiazoles , Antibacterianos/farmacología , Técnicas de Química Sintética , Oxadiazoles/química , Oxadiazoles/farmacología
18.
Chem Rev ; 122(16): 13516-13546, 2022 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-35816287

RESUMEN

Since the last century, peptides have gained wide acceptance as drugs, with almost 100 already in the market and a large number in the pipeline. In this context, peptide synthesis has grown massively as a stringent field for pharmaceuticals around the globe. Three methodologies, namely, classical solution peptide synthesis (CSPS), solid-phase peptide synthesis (SPPS), and liquid-phase peptide synthesis (LPPS), have made significant contributions to the field. This review provides a comprehensive and integrated vision of LPPS as the third wave for peptide synthesis. LPPS combines the advantages of CSPS and SPPS, where peptide elongation is carried out in solution and the growing peptide chain is supported on a soluble tag, which confers characteristic properties. LPPS protocols allow the large-scale production of peptides and reduce the use of excess reagents and solvents, thus meeting the principles of green chemistry. In this review, tags associated with LPPS are broadly discussed under the following headings: polydisperse polyethylene glycol (PEG), membrane-enhanced peptide synthesis (MEPS), fluorous technology, ionic liquids (ILs), PolyCarbon, hydrophobic polymers, and group-assisted purification (GAP). It also highlights the signature accomplishments of LPPS tags and the limitations of the same.


Asunto(s)
Líquidos Iónicos , Péptidos , Técnicas de Química Sintética , Péptidos/química , Solventes/química
19.
Int J Mol Sci ; 23(7)2022 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-35408822

RESUMEN

Laccases (Lac) and tyrosinases (TYR) are mild oxidants with a great potential in research and industry. In this work, we review recent advances in their use in organic synthesis. We summarize recent examples of Lac-catalyzed oxidation, homocoupling and heterocoupling, and TYR-catalyzed ortho-hydroxylation of phenols. We highlight the combination of Lac and TYR with other enzymes or chemical catalysts. We also point out the biological and pharmaceutical potential of the products, such as dimers of piceid, lignols, isorhamnetin, rutin, caffeic acid, 4-hydroxychalcones, thiols, hybrid antibiotics, benzimidazoles, benzothiazoles, pyrimidine derivatives, hydroxytyrosols, alkylcatechols, halocatechols, or dihydrocaffeoyl esters, etc. These products include radical scavengers; antibacterial, antiviral, and antitumor compounds; and building blocks for bioactive compounds and drugs. We summarize the available enzyme sources and discuss the scalability of their use in organic synthesis. In conclusion, we assume that the intensive use of laccases and tyrosinases in organic synthesis will yield new bioactive compounds and, in the long-term, reduce the environmental impact of industrial organic chemistry.


Asunto(s)
Lacasa , Monofenol Monooxigenasa , Técnicas de Química Sintética , Lacasa/metabolismo , Monofenol Monooxigenasa/metabolismo , Oxidación-Reducción , Fenoles/química
20.
Med Chem ; 18(4): 463-472, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35341480

RESUMEN

BACKGROUND: Developing methods to synthesize highly functionalized and complex 1,2,3- triazoles from various combinations of substrates remains a significant challenge in organic synthesis. Thus, to the best of our knowledge, an organocatalytic approach to synthesize 1,2,3-triazoles derived from fatty acids has not been explored. OBJECTIVE: In this sense, we describe here the organocatalyzed synthesis and preliminary results of antitumor and cytotoxic activity of a range of 1,2,3-triazoles derived from fatty esters. METHODS: To synthesize 1,2,3-triazoles 3 derived from fatty ß-ketoesters, we performed the reaction of appropriate aryl azides 2a-j with ß -ketoesters 1a-c in the presence of 5 mol% of DBU using DMSO as a solvent at 70 °C for 24 h. The viability of 5637 cells was determined by measuring the reduction of soluble MTT to water-insoluble formazan. The IC50 concentration that inhibits 50% of cell growth and the results were obtained by at least three independent experiments in triplicate for each test. RESULTS: Through enolate-mediated organocatalysis, 1,2,3-triazoles 3 derived from fatty ß-ketoesters were synthesized in moderate to excellent yields by reacting fatty esters 1 with aryl azides 2 in the presence of a catalytic amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (5 mol%). All compounds derived from palmitic acetoacetate 1a were evaluated regarding induced cytotoxicity in vitro in a human bladder cancer cell line, and compounds 3a, 3d, 3e, and 3g were shown to be promising alternatives for bladder cancer treatment and presented the lowest inhibitory concentration of IC50. CONCLUSION: We described a synthetic procedure to prepare 1,2,3-triazoles derived from fatty ß - ketoesters by DBU-catalyzed 1,3-dipolar cycloaddition reactions of fatty esters with different aryl azides. Compounds derived from palmitic acetoacetate were screened for antitumor and cytotoxic activity in vitro in human bladder cancer cell lines, and compounds 3a, 3d, 3e, and 3g showed potential to treat bladder cancer.


Asunto(s)
Azidas , Triazoles , Catálisis , Técnicas de Química Sintética , Reacción de Cicloadición , Humanos , Triazoles/farmacología
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