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1.
Int J Biol Macromol ; 272(Pt 2): 132690, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38825270

RESUMO

A rising quantity of drugs has been discharged into the aquatic environment, posing a substantial hazard to public health. In the current work, a novel hydrogel (i.Carr@Bent@PTC), comprised of iota-carrageenan, bentonite, and 4-phenyl-3-thiosemicarbazide, was successfully prepared. The introduction of 4-phenyl-3-thiosemicarbazide and bentonite in iota-carrageenan significantly increased the mechanical strength of iota-carrageenan hydrogel and improved its degree of swelling, which can be attributed to the hydrophilic properties of PTC and Bent. The recorded contact angle was 70.8°, 59.1°, 53.9°, and 34.6° for pristine i.Carr, i.Carr@Bent, and i.Carr@Bent@PTC, respectively. The low contact angle measurement of the Bent and PTC loaded-i.Carr hydrogel was attributed to the hydrophilic Bent and PTC. The ternary i.Carr@Bent@PTC hydrogel demonstrated broad pH adaptability and excellent adsorption capacities for sulfamethoxazole (SMX) and losartan potassium (LP), i.e., 467.61 mg. g-1 and 274.43 mg. g-1 at 298.15 K, respectively. The pseudo-first-order (PSO) model provided a better fit for the adsorption kinetics. The adsorption of SMX and LP can be better explained by employing the Sips and Langmuir isotherm models. As revealed by XPS and FTIR investigations, π-π stacking, complexation, electrostatic interaction, and hydrogen bonding were primarily involved in the adsorption mechanisms.


Assuntos
Bentonita , Carragenina , Hidrogéis , Losartan , Semicarbazidas , Sulfametoxazol , Poluentes Químicos da Água , Carragenina/química , Adsorção , Semicarbazidas/química , Losartan/química , Hidrogéis/química , Bentonita/química , Poluentes Químicos da Água/química , Sulfametoxazol/química , Concentração de Íons de Hidrogênio , Cinética , Purificação da Água/métodos , Interações Hidrofóbicas e Hidrofílicas
2.
Int J Mol Sci ; 25(10)2024 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-38791321

RESUMO

The interactions with calf thymus DNA (CT-DNA) of three Schiff bases formed by the condensation of hesperetin with benzohydrazide (HHSB or L1H3), isoniazid (HIN or L2H3), or thiosemicarbazide (HTSC or L3H3) and their CuII complexes (CuHHSB, CuHIN, and CuHTSC with the general formula [CuLnH2(AcO)]) were evaluated in aqueous solution both experimentally and theoretically. UV-Vis studies indicate that the ligands and complexes exhibit hypochromism, which suggests helical ordering in the DNA helix. The intrinsic binding constants (Kb) of the Cu compounds with CT-DNA, in the range (2.3-9.2) × 106, from CuHTSC to CuHHSB, were higher than other copper-based potential drugs, suggesting that π-π stacking interaction due to the presence of the aromatic rings favors the binding. Thiazole orange (TO) assays confirmed that ligands and Cu complexes displace TO from the DNA binding site, quenching the fluorescence emission. DFT calculations allow for an assessment of the equilibrium between [Cu(LnH2)(AcO)] and [Cu(LnH2)(H2O)]+, the tautomer that binds CuII, amido (am) and not imido (im), and the coordination mode of HTSC (O-, N, S), instead of (O-, N, NH2). The docking studies indicate that the intercalative is preferred over the minor groove binding to CT-DNA with the order [Cu(L1H2am)(AcO)] > [Cu(L2H2am)(AcO)] ≈ TO ≈ L1H3 > [Cu(L3H2am)(AcO)], in line with the experimental Kb constants, obtained from the UV-Vis spectroscopy. Moreover, dockings predict that the binding strength of [Cu(L1H2am)(AcO)] is larger than [Cu(L1H2am)(H2O)]+. Overall, the results suggest that when different enantiomers, tautomers, and donor sets are possible for a metal complex, a computational approach should be recommended to predict the type and strength of binding to DNA and, in general, to macromolecules.


Assuntos
Complexos de Coordenação , Cobre , DNA , Hesperidina , Bases de Schiff , DNA/química , DNA/metabolismo , Bases de Schiff/química , Hesperidina/química , Cobre/química , Complexos de Coordenação/química , Animais , Bovinos , Ligantes , Simulação de Acoplamento Molecular , Isoniazida/química , Semicarbazidas/química
3.
Molecules ; 29(7)2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38611813

RESUMO

Over the years, several new medicinal substances have been introduced for the treatment of diseases caused by bacteria and parasites. Unfortunately, due to the production of numerous defense mechanisms by microorganisms and parasites, they still pose a serious threat to humanity around the world. Therefore, laboratories all over the world are still working on finding new, effective methods of pharmacotherapy. This research work aimed to synthesize new compounds derived from 3-trifluoromethylbenzoic acid hydrazide and to determine their biological activity. The first stage of the research was to obtain seven new compounds, including six linear compounds and one derivative of 1,2,4-triazole. The PASS software was used to estimate the potential probabilities of biological activity of the newly obtained derivatives. Next, studies were carried out to determine the nematocidal potential of the compounds with the use of nematodes of the genus Rhabditis sp. and antibacterial activity using the ACCT standard strains. To determine the lack of cytotoxicity, tests were performed on two cell lines. Additionally, an antioxidant activity test was performed due to the importance of scavenging free radicals in infections with pathogenic microorganisms. The conducted research proved the anthelmintic and antibacterial potential of the newly obtained compounds. The most effective were two compounds with a 3-chlorophenyl substituent, both linear and cyclic derivatives. They demonstrated higher efficacy than the drugs used in treatment.


Assuntos
Antibacterianos , Antinematódeos , Semicarbazidas , Antibacterianos/farmacologia , Linhagem Celular , Hidrazinas
4.
Eur J Pharm Sci ; 198: 106778, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38653341

RESUMO

Uric acid, the metabolic product of purines, relies on xanthine oxidase (XOD) for production. XOD is a target for the development of drugs for hyperuricemia (HUA) and gout. Currently, treatment options remain limited for gout patients. 3, 4-Dihydroxy-5-nitrobenzaldehyde (DHNB) is a derivative of the natural product protocatechualdehyde with good biological activity. In this work, we identify a DHNB thiosemicarbazide class of compounds that targets XOD. 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazone can effectively inhibit XOD activity (IC50 value: 0.0437 µM) and exhibits a mixed inhibitory effect. In a mouse model of acute hyperuricemia, a moderate dose (10 mg/kg.w) of 3,4-dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide effectively controlled the serum uric acid content and significantly inhibited serum XOD activity. In addition, 3,4-Dihydroxy-5-nitrobenzaldehyde phenylthiosemicarbazide showed favorable safety profiles, and mice treated with the target compound did not show any symptoms of general toxicity following a single dose of 500 mg/kg. In the allopurinol group, 50 % of the mice died. These results provide a structural framework and mechanism of XOD inhibition that may facilitate the design of hyperuricemia and gout treatments.


Assuntos
Benzaldeídos , Gota , Hiperuricemia , Semicarbazidas , Xantina Oxidase , Animais , Hiperuricemia/tratamento farmacológico , Masculino , Semicarbazidas/farmacologia , Semicarbazidas/uso terapêutico , Semicarbazidas/química , Camundongos , Benzaldeídos/farmacologia , Benzaldeídos/uso terapêutico , Benzaldeídos/química , Gota/tratamento farmacológico , Xantina Oxidase/antagonistas & inibidores , Xantina Oxidase/metabolismo , Ácido Úrico/sangue , Humanos
5.
Molecules ; 29(6)2024 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-38542968

RESUMO

The search for new antibacterial compounds is still a huge challenge for scientists. Each new chemotherapy drug is not 100% effective when introduced into treatment. Bacteria quickly become resistant to known structures. One promising group of new compounds is thiosemicarbazides. In the presented work, we looked for the relationship between structure and antibacterial activity within the group of thiosemicarbazide derivatives. This is a continuation of our previous work. Here, we decided to check to what extent the position of the 3-methoxyphenyl substituent affects potency. We obtained new structures that differ in the positions of the substituent in the thiosemicarbazide skeleton. Based on the obtained results of the biological tests, it can be concluded that the substituent in position 1 of thiosemicarbazide derivatives significantly determines their activity. Generally, among the substituents used, trifluoromethylphenyl turned out to be the most promising. The MIC values for compounds with this substituent are 64 µg/mL towards Staphylococci sp. Using molecular docking, we tried to explain the mechanism behind the antibacterial activity of the tested compounds.


Assuntos
Antibacterianos , Semicarbazidas , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Antibacterianos/farmacologia , Antibacterianos/química , Semicarbazidas/farmacologia , Semicarbazidas/química , Testes de Sensibilidade Microbiana , Estrutura Molecular
6.
J Mater Chem B ; 12(14): 3469-3480, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38506072

RESUMO

Semicarbazide (SEM) is a metabolite of antibiotic nitrofurazone and a food contaminant in food production, showing potential carcinogenic, mutagenic, teratogenic, and toxic effects on human health. It is urgent to develop a highly efficient and sensitive assay for visual detection of SEM. In this paper, a pyrrolopyrrole cyanine fluorescent probe (PPCy-1) was reported for visualization and quantitative analysis of SEM through a chromophore reaction sensing mechanism for the first time. The probe towards SEM exhibited a fast response (10 min), a low detection limit (0.18 µM), high selectivity, and distinct dual ratiometric fluorescence turn-on and colorimetric modes. Its practicability was further verified by detecting SEM in meat, water, and honey samples with satisfactory recovery values. More importantly, a smartphone-assisted portable testing platform was constructed based on a PPCy-1-immobilized test paper or a polyamide thin film with a color scanning APP for real-time and on-site detection of SEM. This work provides low-cost, convenient, and rapid assays for visual SEM detection, which have potential applications in food safety monitoring.


Assuntos
Antibacterianos , Smartphone , Humanos , Antibacterianos/análise , Semicarbazidas , Espectrometria de Fluorescência
7.
J Chromatogr A ; 1720: 464782, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-38442498

RESUMO

Semicarbazide, as a derivative of urea, constitutes a great variety of functional molecules for different needs. Herein, novel stationary phases with an incorporated semicarbazide group were proposed. Using aliphatic (docosanoyl, C22) and aromatic (benzoyl, Bz) hydrazides, the semicarbazide-embedded ligands were synthesized before chemical modification of the silica gel, allowing for an accurate interpretation of the chromatographic properties of the corresponding packings. The new stationary phases were water-wettable, due to the presence of highly polar groups. In particular, Bz-semicarbazide (Bz-SCD) stationary phase was sufficiently hydrophilic to run in hydrophilic interaction (HILIC) mode, whilst the C22 (C22-SCD) equivalent, in spite of its reversed-phase nature, was markedly less hydrophobic than the referenced polar-embedded ones. The versatility of C22-SCD was demonstrated with a large selection of analytes, including geometric isomers and standard mixtures of polycyclic aromatic hydrocarbons, sulfonamides, sulfonylurea, substituted ureas, pyridines and carbamates, fat-soluble colorants, antifungal metabolites, angiotensin II receptor blockers and calcium channel blockers.


Assuntos
Cromatografia de Fase Reversa , Semicarbazidas , Dióxido de Silício , Cromatografia Líquida/métodos , Interações Hidrofóbicas e Hidrofílicas , Isomerismo , Dióxido de Silício/química
8.
Environ Sci Pollut Res Int ; 31(14): 21591-21609, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38396177

RESUMO

Herein, we report the synthesis of an oxidized pine needle-thiosemicarbazone Schiff base (OPN-TSC) from whole pine needles (WPN) as a dual-purpose adsorbent to remove a cationic dye, methylene blue (MB), and Hg2+ ions in separate processes. The adsorbent was synthesized by periodate oxidation of WPN followed by a reaction with thiosemicarbazide. The syntheses of OPN and OPN-TSC were confirmed by FTIR, XRD, FESEM, EDS, BET, and surface charge analysis. The emergence of new peaks at 1729 cm-1 (-CHO stretching) and 1639 cm-1 (-COO- stretching) in the FTIR spectrum of OPN confirmed the oxidation of WPN to OPN. FTIR spectrum of OPN-TSC has a peak at 1604 cm-1 (C = N stretching), confirming the functionalization of OPN to OPN-TSC. XRD studies revealed an increase in the crystallinity of OPN and a decrease in the crystallinity of OPN-TSC because of the attachment of thiosemicarbazide to OPN. The values of %removal for MB and Hg2+ ions by OPN-TSC were found to be 87.36% and 98.2% with maximum adsorption capacity of 279.3 mg/g and 196 mg/g for MB and Hg2+ ions, respectively. The adsorption of MB followed pseudo-second-order kinetics with correlation coefficient (R2 of 0.99383) and Freundlich isotherm (R2 = 0.97239), whereas Hg2+ ion removal demonstrated the Elovich (R2 = 0.97076) and Langmuir isotherm (R2 = 0.95110). OPN-TSC is regenerable with significant recyclability up to 10 cycles for both the adsorbates. The studies established OPN-TSC as a low-cost, sustainable, biodegradable, environmentally benign, and promising adsorbent for the removal of hazardous cationic dyes and toxic metal ions from wastewater and industrial effluents, especially the textile effluents.


Assuntos
Mercúrio , Semicarbazidas , Poluentes Químicos da Água , Corantes , Azul de Metileno , Adsorção , Íons
9.
Int J Biol Macromol ; 263(Pt 1): 130255, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38368988

RESUMO

Developing an efficient adsorbent for Ru3+ ions in wastewater is crucial for both environmental protection and resource recovery. This study introduces a novel approach using cellulose-based adsorbents, specifically modified with furan-thiosemicarbazide (FTC), to enhance their selectivity for Ru3+ ions. By cross-linking the Ru3+/FTC-modified cellulose (FTC-CE) complex with a bis(maleimido)ethane (BME) cross-linker, we created a Ru3+ ion-imprinted sorbent (Ru-II-CE) that exhibits a strong affinity and selectivity for Ru3+ ions. The synthesis process was thoroughly characterized using NMR and FTIR spectroscopy, while the surface morphology of the sorbent particles was examined with scanning electron microscopy. The Ru-II-CE sorbent demonstrated exceptional selectivity for Ru3+ among competing metal cations, achieving optimal adsorption at a pH of 5. Its adsorption capacity was notably high at 215 mg/g, fitting well with the Langmuir isotherm model, and it followed pseudo-second-order kinetics. This study highlights the potential of FTC-CE for targeted Ru3+ removal from wastewater, offering a promising solution for heavy metal decontamination.


Assuntos
Rutênio , Semicarbazidas , Poluentes Químicos da Água , Águas Residuárias , Celulose/química , Íons , Adsorção , Concentração de Íons de Hidrogênio , Poluentes Químicos da Água/química , Cinética
10.
Sci Rep ; 14(1): 3809, 2024 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-38360831

RESUMO

The high mortality rate of colon cancer indicates the insufficient efficacy of current chemotherapy. Thus, the discussion on engineered metal nanoparticles in the treatment of the disease has been considered. In this study, silver nanoparticles were functionalized with glutamine and conjugated with thiosemiccarbazide. Then, anticancer mechanism of Ag@Gln-TSC NPs in a colon cancer cell line (SW480) was investigated. Characterizing Ag@Gln-TSC NPs by FT-IR, XRD, EDS-mapping, DLS, zeta potential, and SEM and TEM microscopy revealed that the Ag@Gln-TSC NPs were correctly synthesized, the particles were spherical, with surface charge of - 27.3 mV, high thermal stability and low agglomeration level. Using MTT assay we found that Ag@Gln-TSC NPs were significantly more toxic for colon cancer cells than normal fibroblast cells with IC50 of 88 and 186 µg/mL, respectively. Flow cytometry analysis showed that treating colon cancer cells with Ag@Gln-TSC NPs leads to a considerable increase in the frequency of apoptotic cells (85.9% of the cells) and increased cell cycle arrest at the S phase. Also, several apoptotic features, including hyperactivity of caspase-3 (5.15 folds), increased expression of CASP8 gene (3.8 folds), and apoptotic nuclear alterations were noticed in the nanoparticle treated cells. Furthermore, treating colon cancer cells with Ag@Gln-TSC NPs caused significant down-regulation of the HULC Lnc-RNA and PPFIA4 oncogene by 0.3 and 0.6 folds, respectively. Overall, this work showed that Ag@Gln-TSC NPs can effectively inhibit colon cancer cells through the activation of apoptotic pathways, a feature that can be considered more in studies in the field of colon cancer treatment.


Assuntos
Neoplasias do Colo , Nanopartículas Metálicas , Semicarbazidas , Humanos , Prata/farmacologia , Glutamina , Espectroscopia de Infravermelho com Transformada de Fourier , Apoptose , Neoplasias do Colo/tratamento farmacológico , Linhagem Celular Tumoral
11.
Environ Toxicol Pharmacol ; 107: 104389, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38360333

RESUMO

Semicarbazide (SEM), a marker residue used to monitor the use of prohibited drug nitrofurazone (NFZ), is commonly found in wild crustaceans, implying the natural origin. However, the difference between endogenous and exogenous SEM has rarely been investigated. So, tissue-bound SEM was determined in samples collected from giant river prawns cultured in an aquaculture farm and in samples from an experiment where giant river prawns were fed twice a day with NFZ at 30 mg/kg for 5 days. At day 10 of drug withdrawal, muscle SEM of the NFZ-fed prawn was 17.78 ng/g and depleted to 1.18 ng/g at day 90 (half-life 20.31 days) which was significantly higher than the control prawn (usually ≤ 0.1 ng/g). In contrast, the average SEM in the shell was independent of NFZ treatment. SEM was not found in the aquaculture farm samples, implying that the SEM in cultured prawn did not originate from SEM contamination.


Assuntos
Palaemonidae , Penaeidae , Semicarbazidas , Animais , Nitrofurazona , Administração Oral , Aquicultura
12.
Bioorg Chem ; 144: 107096, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38290186

RESUMO

In the pursuit of discovering new selective carbonic anhydrase (CA, EC 4.2.1.1) inhibitors, a small collection of novel thiosemicarbazides (5a-5t) were designed and synthesized starting from 2-(hydrazinocarbonyl)-3-phenyl-1H-indole-5-sulfonamide which was evaluated as a potent inhibitor of different CA isoforms in a previous study. The newly synthesized compounds were examined against four human carbonic anhydrases (hCA), namely transmembrane tumor-related hCA IX/XII and cytosolic widespread off-targets hCA I/II. In enzyme inhibition assays, all nineteen compounds display up to ∼340-fold selectivity for hCA IX/XII over off-target isoforms hCA I/II. Four compounds have enzyme inhibition values (Ki) lower than 10 nM against tumor-associated isoforms hCA IX/XII including two compounds in the subnanomolar range (5r and 5s; hCA XII; Ki: 0.69 and 0.87 nM). The potential binding interactions of the most potent compounds against hCA IX and XII, compounds 5s and 5r, respectively, were investigated using ensemble docking and molecular dynamics studies. Cell viability assays using human colorectal adenocarcinoma cell line HT-29 and healthy skin fibroblasts CCD-86Sk show that compound 5e selectively inhibits HT-29 cancer cell proliferation (IC50: 53.32 ± 7.74 µM for HT-29; IC50: 74.64 ± 14.15 µM for CCD-986Sk). Finally, Western blot assays show that compounds 5e and 5r significantly reduce the expression of hCA XII in HT-29 cells. Moreover, 5e shows better cytotoxic activity in hypoxia compared to normoxic conditions. Altogether, the newly designed compounds show stronger inhibition of the tumor-associated hCA IX and XII isoforms and several tested compounds show selective cytotoxicity as well as downregulation of hCA XII expression.


Assuntos
Inibidores da Anidrase Carbônica , Neoplasias , Semicarbazidas , Humanos , Anidrase Carbônica IX , Relação Estrutura-Atividade , Inibidores da Anidrase Carbônica/farmacologia , Inibidores da Anidrase Carbônica/química , Sulfonamidas/farmacologia , Sulfonamidas/química , Antígenos de Neoplasias/metabolismo , Anidrase Carbônica I , Isoformas de Proteínas/metabolismo , Indóis/farmacologia , Estrutura Molecular
13.
Talanta ; 270: 125530, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38091746

RESUMO

A colorimetric and fluorescent sensor, selective for Cu2+ ions, was synthesized in two steps using a rhodamine-based compound attached to the semicarbazide-picolylamine moiety (RBP). Spectroscopic measurements, including UV-Vis absorption and fluorescence emission, were conducted in the semi-aqueous medium containing acetonitrile/4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid, denoted as MeCN/HEPES buffer (2:8, v/v, pH 7.0). The sensor exhibited high selectivity towards Cu2+ ions compared to other cations and demonstrated remarkable sensitivity towards Cu2+ ions, with a limit of detection at the nanomolar level. The calculated transitions indicated a 1:1 stoichiometric binding of RBP to Cu2+ ions based on a 4-coordination mode involving additional chelation in the semi-aqueous medium. The sensing mechanism for the detection of Cu2+ ions was investigated using high-resolution mass spectroscopy. The sensor could be employed as a real-time chemosensor for monitoring Cu2+ ions. Furthermore, the sensor has the potential for utilization in the detection of Cu2+ ions in actual water samples with the high precision and accuracy, as indicated by the small relative standard derivation values. The 50th percentile cytotoxicity concentration of RBP was found to be 22.92 µM. Additionally, the fluorescence bioimaging capability of RBP was demonstrated for the detection of Cu2+ ions in human hepatocellular carcinoma (HepG2) cells.


Assuntos
Cobre , Corantes Fluorescentes , Semicarbazidas , Humanos , Rodaminas/química , Cobre/química , Fluorescência , Corantes Fluorescentes/toxicidade , Corantes Fluorescentes/química , Células Hep G2 , Cátions , Água , Espectrometria de Fluorescência
14.
J Labelled Comp Radiopharm ; 67(1): 18-24, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38044291

RESUMO

Nitrofurazone usage in food-producing animals is prohibited in most countries, including the United States. Regulatory agencies regularly monitor its use in domestic, export/import animals' food products by measuring the semicarbazide (SEM) metabolite as a biomarker of nitrofurazone exposure. However, the use of SEM is controversial because it is also produced in food naturally and thus gives false positive results. A cyano-metabolite, 4-cyano-2-oxobutyraldehyde semicarbazone (COBS), is proposed as an alternate specific marker of nitrofurazone to distinguish nitrofurazone from treated or untreated animals. A synthetic method was developed to produce COBS via metallic hydrogenation of nitrofurazone. The product was isolated and characterized by one- and two-dimensional nuclear magnetic spectroscopy (NMR) experiments, Fourier-transform infrared spectroscopy (FT-IR), and mass spectrometry. The developed synthetic procedure was further extended to synthesize isotopically labeled 4-[13 C]-cyano-2-oxo- [2, 3, 4-13 C3 ]-butyraldehyde semicarbazone. Labeled COBS is useful as an internal standard for its quantification in food-producing animals. Thus, the developed method provides a possibility for its commercial synthesis to procure COBS. This is the first synthesis of the alternate specific marker metabolite of nitrofurazone for possible usage in regulatory analysis to solve a real-world problem.


Assuntos
Nitrofurazona , Semicarbazonas , Animais , Nitrofurazona/análise , Nitrofurazona/metabolismo , Espectroscopia de Infravermelho com Transformada de Fourier , Semicarbazidas/análise , Semicarbazidas/química , Semicarbazidas/metabolismo
15.
Adv Mater ; 36(9): e2309315, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-37944553

RESUMO

Polypeptide materials offer scalability, biocompatibility, and biodegradability, rendering them an ideal platform for biomedical applications. However, the preparation of polypeptides with specific functional groups, such as semicarbazide moieties, remains challenging. This work reports, for the first time, the straightforward synthesis of well-defined methoxy-terminated poly(ethylene glycol)-b-polypeptide hybrid block copolymers (HBCPs) containing semicarbazide moieties. This synthesis involves implementing the direct polymerization of environment-stable N-phenoxycarbonyl-functionalized α-amino acid (NPCA) precursors, thereby avoiding the handling of labile N-carboxyanhydride (NCA) monomers. The resulting HBCPs containing semicarbazide moieties enable facile functionalization with aldehyde/ketone derivatives, forming pH-cleavable semicarbazone linkages for tailored drug release. Particularly, the intracellular pH-triggered hydrolysis of semicarbazone moieties restores the initial semicarbazide residues, facilitating endo-lysosomal escape and thus improving therapeutic outcomes. Furthermore, the integration of the hypoxic probe (Ir(btpna)(bpy)2 ) into the pH-responsive nanomedicines allows sequential responses to acidic and hypoxic tumor microenvironments, enabling precise detection of metastatic tumors. The innovative approach for designing bespoke functional polypeptides holds promise for advanced drug delivery and precision therapeutics.


Assuntos
Neoplasias , Semicarbazonas , Humanos , Neoplasias/tratamento farmacológico , Semicarbazidas , Peptídeos , Microambiente Tumoral
16.
Chem Biol Drug Des ; 103(1): e14355, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37776268

RESUMO

Thiosemicarbazide derivatives have been the focus of scientists owing to their broad biological activities such as anticancer, antimicrobial, and anti-inflammatory. Herein, we designed and synthesized a new thiosemicarbazide derivative (TS-1) and evaluated its antiproliferative potential against the human hepatocellular carcinoma cell line (HEPG2) and human umbilical vein endothelial cell line (ECV-304). Also, it was aimed to investigate the necroptotic and apoptotic cell death effects of TS-1 in HEPG2 cells, and these effects were supported by molecular docking. The new synthesized compound structure was characterized using various spectroscopic methods such as FT-IR, 1 H-NMR, 13 C-NMR, and elemental analysis. The cytotoxic activity of the tested compound was measured by the MTT assay. Apoptotic and necroptotic properties of the TS-1 were evaluated by indirect immunoperoxidase method using antibodies against Ki-67, Bax, Bcl-2, caspase-3, caspase-8, caspase-9, RIP3, and RIPK1. Apoptotic and necroptotic effects of TS-1 were supported by molecular docking. Compound TS-1 was synthesized as a pure compound with a high yield. The effective value of TS-1 was 10 µM in HEPG2 cells. TS-1 did not show any cytotoxic effect on ECV-304. Caspase-3 and RIPK1 immunoreactivities were significantly increased in HEPG2 cells after being treated with TS-1. As the results of the molecular docking studies, the molecular docking showed that the TS-1 exhibits H-bond interaction with various significant amino acid residues in the active site of both RIPK1. It could be concluded that TS-1 could be a promising novel therapeutic agent by inducing apoptosis rather than necroptosis in HEPG2 cells.


Assuntos
Antineoplásicos , Neoplasias Hepáticas , Semicarbazidas , Silicatos , Titânio , Humanos , Células Hep G2 , Caspase 3/metabolismo , Necroptose , Simulação de Acoplamento Molecular , Espectroscopia de Infravermelho com Transformada de Fourier , Apoptose , Antineoplásicos/química , Neoplasias Hepáticas/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Estrutura Molecular
17.
Toxicol In Vitro ; 95: 105741, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38030050

RESUMO

Due to the variability and ability of tumor to mutate, as well as the heterogeneity of tumor tissue, such drugs are sought that would act selectively and multidirectionally on the cancer cell. Therefore, two newly synthesized semicarbazide structured substances were evaluated for anticancer properties in our study: 1a and 1b. In order to evaluate the cytotoxicity and selectivity of the tested compounds, MTT and Neutral Red uptake assay on cell lines (HEK293, LN229, 769-P, HepG2 and NCI-H1563) and cell cycle analysis were performed. Acute toxicity and cardiotoxicity were also evaluated in the zebrafish model. The tested compounds (1a, 1b) showed cytotoxic activity, with the greatest selectivity noted against the glioblastoma multiforme cell line (LN229). However, compound 1b showed stronger selective activity than 1a. Both of compounds were shown to significantly affect the M phase of the cell cycle. Whereas, the conducted toxicological examination of newly synthesized thiosemicarbazide derivates showed, that direct exposition of Danio rerio embryos to compound 1a, but not 1b, causes a concentration-dependent increase in developmental malformations, indicating possible teratogenic effects.


Assuntos
Neoplasias , Peixe-Zebra , Animais , Humanos , Células HEK293 , Semicarbazidas/toxicidade , Embrião não Mamífero
18.
Molecules ; 28(20)2023 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-37894587

RESUMO

Chromatographic methods, apart from in silico ones, are commonly used rapid techniques for the evaluation of certain properties of biologically active compounds used for their prediction of pharmacokinetic processes. Thiosemicarbazides are compounds possessing anticancer, antimicrobial, and other valuable biological activities. The aim of the investigation was to estimate the lipophilicity of 1-aryl-4-(phenoxy)acetylthiosemicarbazides, to predict their oral adsorption and the assessment of their % plasma-protein binding (%PPB). RP-HPLC chromatographic techniques with five diversified HPLC systems, including columns with surface-bonded octadecylsilanes (C-18), phosphatidylcholine (immobilized artificial membrane, IAM), cholesterol (Chol), and α1-acid glycoprotein (AGP) and human serum albumin (HSA), were applied. The measured lipophilicity of all investigated compounds was within the range recommended for potential drug candidates. However, some derivatives are strongly bonded to HSA (%PPB ≈ 100%), which may limit some pharmacokinetic processes. HPLC determined lipophilicity descriptors were compared with those obtained by various computational approaches.


Assuntos
Biomimética , Proteínas Sanguíneas , Humanos , Biomimética/métodos , Proteínas Sanguíneas/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Semicarbazidas , Membranas Artificiais
19.
Chem Biodivers ; 20(8): e202300609, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-37423889

RESUMO

In this article, we report the synthesis and cytotoxicity evaluation of novel indole-carrying semicarbazide derivatives (IS1-IS15). The target molecules were obtained by the reaction of aryl/alkyl isocyanates with 1H-indole-2-carbohydrazide that was in-house synthesized from 1H-indole-2-carboxylic acid. Following structural characterization by 1 H-NMR, 13 C-NMR, and HR-MS, IS1-IS15 were investigated for their cytotoxic activity against human breast cancer cell lines, MCF-7 and MDA-MB-231. According to the data obtained from the MTT assay, phenyl ring with a lipophilic group at its para-position and alkyl moiety were preferential substituents on the indole-semicarbazide scaffold for antiproliferative activity. The effect of IS12 (N-(4-chloro-3-(trifluoromethyl)phenyl)-2-(1H-indole-2-carbonyl)hydrazine-1-carboxamide), the compound that demonstrated remarkable antiproliferative activity on both cell lines, was also evaluated on the apoptotic pathway. Moreover, the calculation of critical descriptors constituting drug-likeness confirmed the position of the selected compounds in the anticancer drug development process. Finally, molecular docking studies suggested the inhibition of tubulin polymerization as the potential activity mechanism of this class of molecules.


Assuntos
Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Relação Estrutura-Atividade , Simulação de Acoplamento Molecular , Neoplasias da Mama/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Proliferação de Células , Antineoplásicos/química , Linhagem Celular , Indóis/química , Semicarbazidas/farmacologia , Estrutura Molecular , Linhagem Celular Tumoral
20.
Int J Mol Sci ; 24(6)2023 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-36982886

RESUMO

In 2020, breast cancer became the most frequently diagnosed type of cancer, with nearly 2.3 million new cases diagnosed. However, with early diagnosis and proper treatment, breast cancer has a good prognosis. Here, we investigated the effect of thiosemicarbazide derivatives, previously identified as dual inhibitors targeting topoisomerase IIα and indoleamine-2,3-dioxygenase 1 (IDO 1), on two distinct types of breast cancer cells (MCF-7 and MDA-MB-231). The investigated compounds (1-3) selectively suppressed the growth of breast cancer cells and promoted apoptosis via caspase-8- and caspase-9-related pathways. Moreover, these compounds caused S-phase cell cycle arrest and dose-dependently inhibited the activity of ATP-binding cassette transporters (MDR1, MRP1/2 and BCRP) in MCF-7 and MDA-MB-231 cells. Additionally, following incubation with compound 1, an increased number of autophagic cells within both types of the investigated breast cancer cells was observed. During preliminary testing of ADME-Tox properties, the possible hemolytic activities of compounds 1-3 and their effects on specific cytochrome P450 enzymes were evaluated.


Assuntos
Antineoplásicos , Neoplasias da Mama , Feminino , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antineoplásicos/química , Apoptose , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Células MCF-7 , Proteínas de Neoplasias/metabolismo , Semicarbazidas/farmacologia
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