RESUMEN
New binuclear copper(II) [Cu(II)] tetraligand complexes (six examples) with sulfanylpyrazole ligands were synthesized. Electron spin resonance (ESR) studies have shown that in solution the complexes are transformed to the mononuclear one. Fungicidal properties against Candida albicans were found for the Cu complexes with benzyl and phenyl substituents. An in vitro evaluation of the cytotoxic properties of Cu chelates against HEK293, Jurkat, MCF-7, and THP-1 cells identified the Cu complex with the cyclohexylsulfanyl substituent in the pyrazole core as the lead compound, whereas the Cu complex without a sulfur atom in the pyrazole ligand had virtually no cytotoxic or fungicidal activity. The lead Cu(II) complex was more active than cisplatin. Effect of the S-containing Cu complex on apoptosis and cell cycle distribution has been investigated as well.
Asunto(s)
Antifúngicos , Candida albicans , Complejos de Coordinación , Cobre , Pirazoles , Cobre/química , Cobre/farmacología , Humanos , Pirazoles/química , Pirazoles/farmacología , Pirazoles/síntesis química , Complejos de Coordinación/farmacología , Complejos de Coordinación/química , Complejos de Coordinación/síntesis química , Ligandos , Candida albicans/efectos de los fármacos , Antifúngicos/farmacología , Antifúngicos/química , Antifúngicos/síntesis química , Cristalografía por Rayos X , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Apoptosis/efectos de los fármacos , Citostáticos/farmacología , Citostáticos/química , Citostáticos/síntesis químicaRESUMEN
Hyaluronan, a linear glycosaminoglycan comprising D-N-acetylglucosamine and D-glucuronic acid, is the main component of the extracellular matrix. Its influence on cell proliferation, migration, inflammation, signalling, and other functions, depends heavily on its molecular weight and chemical modification. Unsaturated HA oligosaccharides are available in defined length and purity. Their potential therapeutic utility can be further improved by chemical modification, e. g., reduction. No synthesis of such modified oligosaccharides, either stepwise or by hyaluronan cleavage, has been reported yet. Here we show a three-step synthesis (esterification, depolymerization and reduction) of unsaturated even numbered hyaluronan oligosaccharides with carboxylates and the reducing terminus reduced to an alcohol. Particular oligosaccharides were synthesised. The modified oligosaccharides are not cleaved by mammalian or bacterial hyaluronidase and do not affect the growth of mouse and human fibroblasts. Further, MTT and NRU viability tests showed that they inhibit the growth of human colon carcinoma cells HT-29 by 20-50 % in concentrations 500-1000 µg/mL. Interestingly, this effect takes place regardless of CD44 receptor expression and was not observed with unmodified HA oligosaccharides. These compounds could serve as enzymatically stable building blocks for biologically active substances.
Asunto(s)
Proliferación Celular , Citostáticos , Ácido Hialurónico , Hialuronoglucosaminidasa , Oligosacáridos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Humanos , Oligosacáridos/química , Oligosacáridos/farmacología , Animales , Ratones , Proliferación Celular/efectos de los fármacos , Hialuronoglucosaminidasa/metabolismo , Hialuronoglucosaminidasa/antagonistas & inhibidores , Citostáticos/farmacología , Citostáticos/química , Citostáticos/síntesis química , Células HT29 , Receptores de Hialuranos/metabolismo , Fibroblastos/efectos de los fármacosRESUMEN
Aim: The aim of this study was to synthesize new coumarin-based compounds and evaluate their antibacterial and antitumor potential. Results: Using transition metal-catalyzed reactions, a series of 7-hydroxycoumarin derivatives were synthesized with aliphatic and aryl moiety attached directly at C-3 of the coumarin ring and through the ethynyl or 1,2,3-triazole linker. The 3-substituted coumarin derivative bearing bistrifluoromethylphenyl at the C-4 position of 1,2,3-triazole (33) showed strong and selective antiproliferative activity against cervical carcinoma cells. The 7-hydroxy-4-methylcoumarin with a phenyl ring directly attached to coumarin at C-3 (10) showed good potency against the methicillin-resistant Staphylococcus aureus and vancomycin-resistant strains. Conclusion: The most active coumarin derivatives owe their antiproliferative potential to the 3,5-ditrifluoromethylphenyl substituent (in 33) and antibacterial activity to the aromatic moiety (in 10); their structure can be optimized further for improved effect.
Asunto(s)
Antibacterianos/farmacología , Cumarinas/farmacología , Citostáticos/farmacología , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Elementos de Transición/química , Staphylococcus aureus Resistente a Vancomicina/efectos de los fármacos , Antibacterianos/síntesis química , Antibacterianos/química , Catálisis , Cumarinas/síntesis química , Cumarinas/química , Citostáticos/síntesis química , Citostáticos/química , Humanos , Pruebas de Sensibilidad Microbiana , Estructura MolecularRESUMEN
This review summarizes recent developments in conjugation techniques for the synthesis of cell-penetrating peptide (CPP)-drug conjugates targeting cancer cells. We will focus on small organic molecules as well as metal complexes that were used as cytostatic payloads. Moreover, two principle ways of coupling chemistry will be discussed direct conjugation as well as the use of bifunctional linkers. While direct conjugation of the drug to the CPP is still popular, the use of bifunctional linkers seems to gain increasing attention as it offers more advantages related to the linker chemistry. Thus, three main categories of linkers will be highlighted, forming either disulfide acid-sensitive or stimuli-sensitive bonds. All techniques will be thoroughly discussed by their pros and cons with the aim to help the reader in the choice of the optimal conjugation technique that might be used for the synthesis of a given CPP-drug conjugate.
Asunto(s)
Péptidos de Penetración Celular/administración & dosificación , Péptidos de Penetración Celular/síntesis química , Citostáticos/administración & dosificación , Citostáticos/síntesis química , Sistemas de Liberación de Medicamentos/métodos , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Citostáticos/química , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/síntesis química , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/tendencias , Humanos , Estructura Molecular , Fenómenos Químicos OrgánicosRESUMEN
We investigated the aluminium-salen complex MBR-8 as a potential anti-cancer agent. To see apoptotic effects induced by MBR-8, alone and in combination with common cytostatic drugs, DNA-fragmentations were studied using the flow cytometric analysis. Western blot analysis and measurement of the mitochondrial membrane potential with a JC-1 dye were employed to identify the pathway of apoptosis. An impressive overcoming of multidrug-resistance in leukemia (Nalm6) cells was observed. Additionally, solid tumor cells including Burkitt-like lymphoma (BJAB) and mamma carcinoma cells (MCF-7) are affected by MBR-8 in the same way. Western blot analysis revealed activation of caspase-3. MBR-8 showed very pronounced selectivity with regard to tumor cells and high synergistic effects in Nalm6 and daunorubicin-resistant Nalm6 cells when administered in combination with vincristine, daunorubicin and doxorubicin. The aluminium-salen complex MBR-8 showed very promising anti-cancer properties which warrant further development towards a cytostatic agent for future chemotherapy. Studies on aluminium compounds for cancer therapy are rare, and our report adds to this important body of knowledge.
Asunto(s)
Aluminio/farmacología , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Complejos de Coordinación/farmacología , Citostáticos/farmacología , Etilenodiaminas/farmacología , Aluminio/química , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Complejos de Coordinación/síntesis química , Complejos de Coordinación/química , Citostáticos/síntesis química , Citostáticos/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Etilenodiaminas/química , HumanosRESUMEN
We report the synthesis of MnO nanoparticles (AI-MnO NAPs) using biological molecules of Abutilon indicum leaf extract. Further, they were evaluated for antibacterial and cytotoxicity activity against different pathogenic microbes (Escherichia coli, Bordetella bronchiseptica, Staphylococcus aureus, and Bacillus subtilis) and HeLa cancerous cells. Synthesized NAPs were also investigated for photocatalytic dye degradation potential against methylene blue (MB), and adsorption activity against Cr(VI) was also determined. Results from Scanning electron microscope (SEM), X-ray powder diffraction (XRD), Energy-dispersive X-ray (EDX), and Fourier-transform infrared spectroscopy (FTIR) confirmed the successful synthesis of NAPs with spherical morphology and crystalline nature. Biological activity results demonstrated that synthesized AI-MnO NAPs exhibited significant antibacterial and cytotoxicity propensities against pathogenic microbes and cancerous cells, respectively, compared with plant extract. Moreover, synthesized AI-MnO NAPs demonstrated the comparable biological activities results to standard drugs. These excellent biological activities results are attributed to the existence of the plant's biological molecules on their surfaces and small particle size (synergetic effect). Synthesized NAPs displayed better MB-photocatalyzing properties under sunlight than an ultraviolet lamp. The Cr(VI) adsorption result showed that synthesized NAPs efficiently adsorbed more Cr(VI) at higher acidic pH than at basic pH. Hence, the current findings suggest that Abutilon indicum is a valuable source for tailoring the potential of NAPs toward various enhanced biological, photocatalytic, and adsorption activities. Consequently, the plant's biological molecule-mediated synthesized AI-MnO NAPs could be excellent contenders for future therapeutic applications.
Asunto(s)
Antibacterianos/síntesis química , Citostáticos/síntesis química , Malvaceae/química , Compuestos de Manganeso/química , Nanopartículas/química , Óxidos/química , Extractos Vegetales/química , Adsorción , Antibacterianos/farmacología , Bacillus subtilis/efectos de los fármacos , Bordetella bronchiseptica/efectos de los fármacos , Citostáticos/farmacología , Tecnología Química Verde , Células HeLa , Humanos , Staphylococcus aureus/efectos de los fármacosRESUMEN
Six novel organotin phosphonate complexes, [(Me3Sn)4(HL1)4]n1, [(Me3Sn)2(HL2)2]n2, [(Me3Sn)2L3(H2O)]n3, [(Ph3Sn)(HL1)]64, [(Ph3Sn)2L2]n5 and [(Ph3Sn)2L3]66, derived from phosphonic acid ligands [NaHL1 = 1-C10H7OPO2(OH)Na, H2L2 = 1-C10H7PO(OH)2, H2L3 = 2-C10H7PO(OH)2], have been synthesized and characterized by elemental analysis, FT-IR, NMR (1H, 13C, 31P and 119Sn) spectroscopy and X-ray crystallography. The structural analysis reveals that complexes 1 and 5 display 1D infinite zig-zag chain structures, and complex 2 shows 1D right-handed helical chain structure, while complex 3 displays 1D left-handed helical chain structure. Complexes 4 and 6 are 24-membered macrocyclic rings interconnected by P, O and Sn atoms. Additionally, the molecules of complexes 1 and 3 are further linked through intermolecular π···π and O-H···O interaction into supramolecular structures, respectively. Furthermore, we preliminarily estimated in vitro cytostatic activity of complexes 1-6 against the human cervix tumor cells (HeLa), human hepatocellular carcinoma cells (HepG-2) and human normal breast cells (HBL-100). Importantly, the anti-proliferative properties and possible pathway of complex 6 are investigated, and the results demonstrate that complex 6 could induce apoptotic cell death via an overload of intracellular reactive oxygen species (ROS) levels and the dysfunctional depolarization of mitochondrial membranes.
Asunto(s)
Citostáticos/química , Citostáticos/farmacología , Compuestos Orgánicos de Estaño/química , Compuestos Orgánicos de Estaño/farmacología , Ácidos Fosforosos/química , Apoptosis/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Cristalografía por Rayos X , Citostáticos/síntesis química , Femenino , Células HeLa , Humanos , Ligandos , Neoplasias Hepáticas/patología , Espectroscopía de Resonancia Magnética , Masculino , Estructura Molecular , Compuestos Orgánicos de Estaño/síntesis química , Ácidos Fosforosos/farmacología , Especies Reactivas de Oxígeno/metabolismo , Espectroscopía Infrarroja por Transformada de Fourier , Estaño/química , Neoplasias del Cuello Uterino/patologíaRESUMEN
We describe the synthesis of drug-dye conjugate 1 between anaplastic lymphoma kinase inhibitor Crizotinib and heptamethine cyanine dye IR-786. The drug-dye conjugate 1 was evaluated in three different patient-derived glioblastoma cell lines and showed potent cytotoxic activity with nanomolar potency (EC50: 50.9â¯nM). We also demonstrate evidence for antiproliferative activity of 1 with single digit nanomolar potency (IC50: 4.7â¯nM). Furthermore, the cytotoxic effects conveyed a dramatic, 110-fold improvement over Crizotinib. This improvement was even more pronounced (492-fold) when 1 was combined with Temozolomide, the standard drug for treatment for glioblastoma. This work lays the foundation for future exploration of similar tyrosine kinase inhibitor drug-dye conjugates for the treatment of glioblastoma.
Asunto(s)
Antineoplásicos/farmacología , Neoplasias Encefálicas/tratamiento farmacológico , Carbocianinas/farmacología , Crizotinib/farmacología , Citostáticos/farmacología , Colorantes Fluorescentes/farmacología , Glioblastoma/tratamiento farmacológico , Antineoplásicos/síntesis química , Antineoplásicos/química , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Carbocianinas/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Crizotinib/química , Citostáticos/síntesis química , Citostáticos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Colorantes Fluorescentes/síntesis química , Colorantes Fluorescentes/química , Glioblastoma/diagnóstico por imagen , Glioblastoma/metabolismo , Humanos , Estructura Molecular , Imagen Óptica , Relación Estructura-ActividadRESUMEN
A small library of 3'-deoxy-C3'-substituted xylofuranosyl-pyrimidine nucleoside analogues were prepared by photoinduced thiol-ene addition of various thiols, including normal and branched alkyl-, 2-hydroxyethyl, benzyl-, and sugar thiols, to 3'-exomethylene derivatives of 2',5'-di-O-tert-butyldimethylsilyl-protected ribothymidine and uridine. The bioactivity of these derivatives was studied on tumorous SCC (mouse squamous carcinoma cell) and immortalized control HaCaT (human keratinocyte) cell lines. Several alkyl-substituted analogues elicited promising cytostatic activity in low micromolar concentrations with a slight selectivity toward tumor cells. Near-infrared live-cell imaging revealed SCC tumor cell-specific mitotic blockade via genotoxicity of analogue 10, bearing an n-butyl side chain. This analogue essentially affects the chromatin structure of SCC tumor cells, inducing a condensed nuclear material and micronuclei as also supported by fluorescent microscopy. The results highlight that thiol-ene chemistry represents an efficient strategy to discover novel nucleoside analogues with non-natural sugar structures as anticancer agents.
Asunto(s)
Citostáticos/síntesis química , Citostáticos/farmacología , Conformación Molecular , Nucleósidos/síntesis química , Nucleósidos/farmacología , Xilosa/química , Espectroscopía de Resonancia Magnética con Carbono-13 , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Dimetilsulfóxido/farmacología , Humanos , Concentración 50 Inhibidora , Espectroscopía de Protones por Resonancia Magnética , Compuestos de Sulfhidrilo/químicaRESUMEN
A new simplified, epoxide-free epothilone analog was prepared incorporating an N-(2-hydroxyethyl)-benzimidazole side chain, which binds to microtubules with high affinity and inhibits cancer cell growth in vitro with nM potency. Building on this scaffold, a disulfide-linked conjugate with the purported EGFR-binding (EGFR, epidermal growth factor receptor) peptide GE11 was then prepared. The conjugate retained significant microtubule-binding affinity, in spite of the size of the peptide attached to the benzimidazole side chain. The antiproliferative activity of the conjugate was significantly lower than for the parent scaffold and, surprisingly, was independent of the EGFR expression status of cells. Our data indicate that the disulfide-based conjugation with the GE11 peptide is not a viable approach for effective tumor-targeting of highly potent epothilones and probably not for other cytotoxics.
Asunto(s)
Citostáticos/síntesis química , Epotilonas/farmacología , Microtúbulos/metabolismo , Péptidos/farmacología , Moduladores de Tubulina/síntesis química , Animales , Bovinos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citostáticos/farmacología , Epotilonas/química , Receptores ErbB/metabolismo , Células HEK293 , Humanos , Péptidos/química , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/farmacologíaRESUMEN
The lipophilization of ß-d-riboguanosine (1) with various symmetric as well as asymmetric ketones is described (â3a-3f). The formation of the corresponding O-2',3'-ketals is accompanied by the appearance of various fluorescent by-products which were isolated chromatographically as mixtures and tentatively analyzed by ESI-MS spectrometry. The mainly formed guanosine nucleolipids were isolated and characterized by elemental analyses, 1 H-, 13 C-NMR and UV spectroscopy. For a drug profiling, static topological polar surface areas as well as 10 logPOW values were calculated by an increment-based method as well as experimentally for the systems 1-octanol-H2 O and cyclohexane-H2 O. The guanosine-O-2',3'-ketal derivatives 3b and 3a could be crystallized in (D6 )DMSO - the latter after one year of standing at ambient temperature. X-ray analysis revealed the formation of self-assembled ribbons consisting of two structurally similar 3b nucleolipid conformers as well as integrated (D6 )DMSO molecules. In the case of 3a â DMSO, the ribbon is formed by a single type of guanosine nucleolipid molecules. The crystalline material 3b â DMSO was further analyzed by differential scanning calorimetry (DSC) and temperature-dependent polarization microscopy. Crystallization was also performed on interdigitated electrodes (Au, distance, 5â µm) and visualized by scanning electron microscopy. Resistance and amperage measurements clearly demonstrate that the electrode-bridging 3b crystals are electrically conducting. All O-2',3'-guanosine ketals were tested on their cytostatic/cytotoxic activity towards phorbol 12-myristate 13-acetate (PMA)-differentiated human THP-1 macrophages as well as against human astrocytoma/oligodendroglioma GOS-3 cells and against rat malignant neuroectodermal BT4Ca cells.
Asunto(s)
Citostáticos/síntesis química , Guanosina/química , Lípidos/química , Animales , Rastreo Diferencial de Calorimetría , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Cristalografía por Rayos X , Citostáticos/química , Citostáticos/farmacología , Electricidad , Humanos , Enlace de Hidrógeno , Lípidos/síntesis química , Lípidos/farmacología , Espectroscopía de Resonancia Magnética , Conformación Molecular , Ratas , Espectrometría de Masa por Ionización de ElectrosprayRESUMEN
BACKGROUND: Compounding of cytostatic drugs requires strict aseptic procedures, while exposure to toxic drugs and repetitive manual movements should be minimized. Furthermore, reuse of vials is desirable to lower the costs. To assess if all this might be safely achieved with a robot, this study aimed at qualifying the aseptic preparation process with the robotic system APOTECAchemo. METHODS: The aseptic compounding of patient-individual cytostatic solutions was simulated with media fill simulation tests to qualify the performance according to European GMP Annex 1. The contamination in the environment was measured in critical places using settle plates, contact plates, active air sampling and particle counting. Media-fill simulation tests were prepared in 3 production batches. The second part of the study evaluated the microbiological shelf-life of commercial drug vials after repeated puncturing. On six days, fifty syringes of 15â¯ml media were prepared from the same 50 vials with the robot. After each preparation, vials were covered with an IVA seal upon unloading from the robot to protect them from microbiological contamination. RESULTS: No microbiological contamination was found in any of the 96 media fill preparations, nor in any of the 300 syringes that were prepared with repeated puncturing. The compounding area met class A limits, while class A criteria were not fulfilled by the contact plates and settle plates placed on the right side of the loading area. There, the average colony forming units (cfu) were 3 and 1.17, respectively, meeting class B criteria. CONCLUSIONS: Robotical compounding of cytostatic drugs with APOTECAchemo meets the microbiological requirements of the European GMP. In addition, the robot can reuse vials repeatedly and safely, thereby enabling extended usage.
Asunto(s)
Asepsia/métodos , Citostáticos/síntesis química , Composición de Medicamentos/métodos , Contaminación de Medicamentos/prevención & control , Servicio de Farmacia en Hospital/métodos , Robótica/métodos , Asepsia/instrumentación , Composición de Medicamentos/instrumentación , Fenómenos Microbiológicos , Robótica/instrumentaciónRESUMEN
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common way of treating inflammatory disorders. Their widespread use helped reveal their other modes of action as pharmaceuticals, such as a profound effect on various cancers. Celecoxib has proven to be a very prominent member of this group with cytostatic activities. On the other hand, the highly dynamic field of drug design is constantly searching for new ways of modifying known structures to obtain more powerful and less harmful drugs. A very interesting development is the implementation of carboranes in pharmacologically active structures, mostly as phenyl mimetics. Herein we report the synthesis of three carborane-containing derivatives of the COX-2-selective NSAID celecoxib. The new compounds proved to have promising cytostatic potential against various melanoma and colorectal adenocarcinoma cell lines. Inhibited proliferation accompanied by caspase-independent apoptotic cell death was found to be the main cause of decreased cell viability upon treatment with the most efficient celecoxib analogue, 3 b (4-[5-(1,7-dicarba-closo-dodecaboranyl)-3-trifluoromethyl-1H-pyrazol-1-yl]-1-methylsulfonylbenzene).
Asunto(s)
Antineoplásicos/farmacología , Celecoxib/farmacología , Inhibidores de la Ciclooxigenasa 2/farmacología , Citostáticos/farmacología , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Celecoxib/síntesis química , Celecoxib/química , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/patología , Ciclooxigenasa 2/metabolismo , Inhibidores de la Ciclooxigenasa 2/síntesis química , Inhibidores de la Ciclooxigenasa 2/química , Citostáticos/síntesis química , Citostáticos/química , Relación Dosis-Respuesta a Droga , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Melanoma/tratamiento farmacológico , Melanoma/patología , Ratones , Estructura Molecular , Relación Estructura-ActividadRESUMEN
As a part of the research aimed on identification of new nucleobase derivatives with improved biological properties, a series of novel 8-substituted acyclovir derivatives were synthesized. The 8-azidoguanosine 4 and novel 8-azidoacyclovir 9 were synthesized from commercially available guanosine 1 and acyclovir 6 which were transformed into 8-bromopurine derivatives 2 and 7 and hydrazine derivatives 3 and 8, respectively. 8-Triazolylguanosine 5 and 8-triazolylacyclovir analogs 10-12 were successfully synthesized via the Cu(I) catalyzed 1,3-dipolar cycloaddition reaction of azides 4 and 9 with propargyl alcohol, 4-pentyn-1-ol and 5-hexyn-1-ol. The novel 1,4-disubstituted 1,2,3-triazolyl compounds 5, 10-12 were evaluated for antiviral activity against selected DNA and RNA viruses and cytostatic activity against normal Madine Darby canine kidney (MDCK I) cells, and seven tumor cell lines (HeLa, CaCo-2, NCI-H358, Jurkat, K562, Raji and HuT78). While tested compounds exerted no antiviral activity at nontoxic concentrations, the 8-triazolyl acyclovir derivative 10, with the shortest alkyl substituent at the C-4 of triazole ring, was found to be the most active against the CaCo-2 cell line.
Asunto(s)
Aciclovir/química , Antivirales/química , Antivirales/farmacología , Citostáticos/química , Citostáticos/farmacología , Alquinos/química , Animales , Antivirales/síntesis química , Células CACO-2 , Reacción de Cicloadición , Citostáticos/síntesis química , Perros , Evaluación Preclínica de Medicamentos/métodos , Ensayos de Selección de Medicamentos Antitumorales , Guanosina/química , Humanos , Células Jurkat , Células K562 , Células de Riñón Canino Madin Darby , Espectroscopía de Resonancia Magnética , Propanoles/químicaRESUMEN
Structure-activity relationship studies on oleanolic acid (1) have resulted in facile syntheses of its new C-28 esters 2-7 by way of one-pot reaction of 1 with a variety of alkylating agents. Oleanolic acid and its new esters were studied for their in vitro antiproliferative effect on healthy human peripheral blood mononuclear cell isolated phytohemagglutinin activated T cells. Results showed that compounds 1, 3, and 5 exhibited significant inhibitory activity on T-cell proliferation. Compound 5 was found to be the most potent, with an IC50 value of 4.249 µg/mL, among all tested compounds, and its activity could be attributed to the presence of bromine atom in the molecule.
Asunto(s)
Proliferación Celular/efectos de los fármacos , Citostáticos/síntesis química , Ésteres/síntesis química , Ácido Oleanólico/análogos & derivados , Linfocitos T/efectos de los fármacos , Células Cultivadas , Citostáticos/farmacología , Ésteres/farmacología , Humanos , Concentración 50 Inhibidora , Linfocitos T/fisiologíaRESUMEN
1,3-Dipolar cycloaddition of N-methyl C-(diethoxyphosphoryl) nitrone to N3-substituted 6-bromo-2-vinyl-3H-quinazolin-4-ones gave (3-diethoxyphosphoryl) isoxazolidines substituted at C5 with quinazolinones modified at N3. All isoxazolidine cycloadducts were screened for antiviral activity against a broad spectrum of DNA and RNA viruses. Several isoxazolidines inhibited the replication of both thymidine kinase wild-type and deficient (TK⺠and TK-) varicella-zoster virus strains at EC50 in the 5.4â»13.6 µΜ range, as well as human cytomegalovirus (EC50 = 8.9â»12.5 µΜ). Isoxazolidines trans-11b, trans-11c, trans-11e, trans-11f/cis-11f, trans-11g, trans-11h, and trans-11i/cis-11i exhibited moderate cytostatic activity towards the human lymphocyte cell line CEM (IC50 = 9.6â»17 µM).
Asunto(s)
Antivirales/síntesis química , Citomegalovirus/efectos de los fármacos , Citostáticos/síntesis química , Herpesvirus Humano 3/efectos de los fármacos , Isoxazoles/síntesis química , Quinazolinonas/síntesis química , Animales , Antivirales/farmacología , Línea Celular , Chlorocebus aethiops , Reacción de Cicloadición , Citomegalovirus/crecimiento & desarrollo , Citostáticos/farmacología , Perros , Diseño de Fármacos , Fibroblastos/efectos de los fármacos , Fibroblastos/virología , Células HeLa , Herpesvirus Humano 3/crecimiento & desarrollo , Humanos , Concentración 50 Inhibidora , Isoxazoles/farmacología , Células de Riñón Canino Madin Darby , Óxidos de Nitrógeno/química , Quinazolinonas/farmacología , Relación Estructura-Actividad , Células Vero , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Hydroxyurea (HU) is used to treat cancer. HU has a short half-life due to its small molecular weight and high polarity, therefore a high dosage of the drug should be used which introduces side effects and more rapid development of resistance. OBJECTIVE: The objective of the current study is to design new lipophilic analogues of hydroxyurea with higher stability and better cell penetration. The designed compounds were synthesized and then evaluated in terms of their cytostatic activities against two human cell lines. METHODS: The synthesis of designed ligands was achieved via two-step procedure. Detail of the synthesis and chemical characterization of the analogs are described. The cytotoxic activity of the designed ligands was evaluated in vitro against two different cancer cell lines at 24 and 48h using MTT test. RESULTS: Based on the IC50 values, all the designed and prepared compounds were more potent than hydroxyurea at 24 and 48h on both cell lines that the cytostatic activity at 48h was more than 24h. Drug-receptor interactions study indicated compound 7 as the most potent ligand, tightly bonded to surrounding amino acids in the active site of receptor via two strong hydrogen bonds and some hydrophobic interactions. CONCLUSION: Compound 7 with the suitable volume, log p and shape is the most active ligand against both cell lines. It is concluded or suggested that the size, shape and hydrophobic character of substituents strongly affect the pharmacodynamics and pharmacokinetics of these type of ligands.
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Simulación por Computador , Citostáticos/síntesis química , Hidroxiurea/síntesis química , Lípidos/síntesis química , Citostáticos/metabolismo , Células HeLa , Humanos , Hidroxiurea/metabolismo , Metabolismo de los Lípidos/fisiología , Simulación del Acoplamiento Molecular/métodosRESUMEN
Herein, we describe the synthesis of twenty-one novel water-soluble monocationic 2-aryl/heteroaryl-substituted 6-(2-imidazolinyl)benzothiazole mesylates 3a-3u and present the results of their anti-proliferative assays. Efficient syntheses were achieved by three complementary simple two-step synthetic protocols based on the condensation reaction of aryl/heteroaryl carbaldehydes or carboxylic acid. We developed an eco-friendly synthetic protocol using glycerol as green solvent, particularly appropriate for the condensation of thermally and acid-sensitive heterocycles such as furan, benzofuran, pyrrole, and indole. Screening of anti-proliferative activity was performed on four human tumour cell lines in vitro including pancreatic cancer (CFPAC-1), metastatic colon cancer (SW620), hepatocellular carcinoma (HepG2), and cervical cancer (HeLa), as well as in normal human fibroblast cell lines. All tested compounds showed strong to moderate anti-proliferative activity on tested cell lines depending on the structure containing aryl/heteroaryl moiety coupled to 6-(2-imidazolinyl)benzothiazole moiety. The most potent cytostatic effects on all tested cell lines with [Formula: see text] values ranging from 0.1 to 3.70 [Formula: see text] were observed for benzothiazoles substituted with naphthalene-2-yl 3c, benzofuran-2-yl 3e, indole-3-yl 3j, indole-2-yl 3k, quinoline-2-yl 3s, and quinoline-3-yl 3t and derivatives substituted with phenyl 3a, naphthalene-1-yl 3b, benzothiazole-2-yl 3g, benzothiazole-6-yl 3h, N-methylindole-3-yl 3l, benzimidazole-2-yl 3n, benzimidazole-5(6)-yl 3o, and quinolone-4-yl 3u with [Formula: see text] values ranging from 1.1 to 29.1 [Formula: see text]. Based on obtained anti-proliferative activities, 3D-QSAR models for five cell lines were derived. Molecular volume, molecular surface, the sum of hydrophobic surface areas, molecular mass, and possibility of making dispersion forces were identified by QSAR analyses as molecular properties that are positively correlated with anti-proliferative activity, while compound's capability to accept H-bond was identified as a negatively correlated property. Comparison of molecular properties identified for different cell lines enabled assumptions about similarity of mode of action through which anti-proliferative activities against different cell lines are accomplished. Novel compounds that are predicted to have enhanced activities in comparison with herein presented ones were designed using 3D-QSAR analysis as guideline.
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Benzotiazoles , Citostáticos , Mesilatos , Benzotiazoles/síntesis química , Benzotiazoles/química , Benzotiazoles/farmacología , Línea Celular , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Citostáticos/síntesis química , Citostáticos/química , Citostáticos/farmacología , Humanos , Mesilatos/síntesis química , Mesilatos/química , Mesilatos/farmacología , Modelos Moleculares , Relación Estructura-Actividad CuantitativaRESUMEN
The synthesis of hydroxyflavone derivatives is described. The acyl derivatives of 3-, 6-, 7-hydroxyflavones (compounds 2, 4, 6, respectively) and chrysin (5,7-dihydroxyflavone, 7) were obtained in high yields and evaluated in vitro for their cytotoxic activity against several cancer cell lines of different origin: MCF-7 (breast cancer), A549 (nonsmall cell lung cancer), MES-SA (uterine sarcoma), LoVo (colon cancer), drug-resistant human cancer cells (MES-SA/DX5, LoVo/DX) and also towards non-cancer cell line MCF-10A (normal breast epithelial cells). The flavones modified with acyl group showed higher antiproliferative activity than free hydroxyflavones. The highest activity was noted for 3-acetoxyflavone (2), which proved active against LoVo, LoVo/DX, and MES-SA cell lines (IC50 from 4.7 µM to 7.8 µM, respectively). The highest ability to overcome the barrier of resistance (resistance index=0.82) against the drug-resistant MES-SA/DX5 cells compared to the parental drug-sensitive MES-SA cell line was found for 7-acetoxyflavone (6).
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Antineoplásicos/síntesis química , Citostáticos/síntesis química , Flavonas/síntesis química , Antineoplásicos/farmacología , Línea Celular , Proliferación Celular/efectos de los fármacos , Citostáticos/farmacología , Resistencia a Antineoplásicos , Flavonas/farmacología , Humanos , Células MCF-7RESUMEN
Novel halogenated purines and pseudopurines with diverse aryl-substituted 1,2,3-triazoles were prepared. While p-(trifluoromethyl)-substituted 1,2,3-triazole in N-9 alkylated purine and 3-deazapurine was critical for strong albeit unselective activity on pancreatic adenocarcinoma cells CFPAC-1,1-(p-fluorophenyl)-1,2,3-triazole derivative of 7-deazapurine showed selective cytostatic effect on metastatic colon cancer cells SW620. Importantly, 1-(p-chlorophenyl)-1,2,3-triazole-tagged benzimidazole displayed the most pronounced and highly selective inhibitory effect in nM range on non-small cell lung cancer A549. This compound revealed to target molecular processes at the extracellular side and inside the plasma membrane regulated by GPLD1 and growth factor receptors PDGFR and IGF-1R leading to the inhibition of cell proliferation and induction of apoptosis mediated by p38 MAP kinase and NF-κB, respectively. Further optimisation of this compound as to reduce its toxicity in normal cells may lead to the development of novel agent effective against lung cancer.