RESUMO
The first example of conjugation of open-resorcinarenes with chlorambucil, ibuprofen, naproxen and indomethacin are presented. The cytotoxic properties of the obtained conjugates were tested against the cancer cell lines U-251, PC-3, K-562, HCT-15, MCF-7 and SKLU-1. It was found that the conjugate with chlorambucil, naproxen or indomethacin (having 8 moieties) was toxic towards cancer cell lines U-251 and K-562, with no activity against non-cancerous COS-7 cells. The conjugates with naproxen and indomethacin showed high selectivity towards U-251 tumor cells.
Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Fenilalanina/análogos & derivados , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Células COS , Calixarenos/síntese química , Calixarenos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chlorocebus aethiops , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Estrutura Molecular , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Relação Estrutura-AtividadeRESUMO
Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models that predict the bioactivity of organic molecules by using only bi-dimensional molecular information. The diNsGF derivatives were predicted as cholinesterase inhibitors. Experimentally, all of the synthesized diNsGF derivatives showed moderate inhibitory activities against acetylcholinesterase (AChE) and poor activities against butyrylcholinesterase (BuChE). Compound 7a has significant activity and selectivity against AChE, which reveals that the diNsGF scaffold could be improved to reach novel candidates by combining other chemical components of the Ugi-4CR in a high-throughput combinatorial screening experiment. Molecular docking experiments of diNsGF derivatives inside AChE suggest that these compounds placed the phenylalanine group at the peripheral site of AChE. The orientations and chemical interactions of diNsGF derivatives were analyzed, and the changeable groups were identified for future exploration of novel candidates that could lead to the improvement of diNsGF derivative inhibitory activities.
Assuntos
Inibidores da Colinesterase/síntese química , Fenilalanina/síntese química , Acetilcolinesterase/metabolismo , Sítios de Ligação , Butirilcolinesterase/metabolismo , Cianetos/química , Desenho de Fármacos , Cinética , Simulação de Acoplamento Molecular , Estrutura Molecular , Ligação Proteica , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
METHODS: The synthesis of conjugates of flutamide with resorcinarene-PAMAM-dendrimers as well as alkyl and ethyl phenyl chains in the lower part of the macrocycle as a nucleus and diethylenetriamines in the dendritic branches gives the opportunity to obtain conjugates in one step of synthesis with 16 and 64 flutamide moieties in the structure. RESULTS: The in vitro anticancer studies showed that the conjugates of flutamide are more active than the free flutamide and the flutamide derivatives, thus diminishing the amount of flutamide used. The resorcinarenedendrimer- flutamide conjugates with a high drug payload improve the activity of the drug. CONCLUSION: This is important in delivering a sufficient amount of flutamide and suggests that the dendrimer facilitates more of the drug being introduced into cells. It was also observed that the new conjugates are less toxic than the anti-androgens.
Assuntos
Antineoplásicos/farmacologia , Calixarenos/farmacologia , Dendrímeros/farmacologia , Portadores de Fármacos/farmacologia , Flutamida/farmacologia , Fenilalanina/análogos & derivados , Antineoplásicos/síntese química , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Calixarenos/síntese química , Calixarenos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Dendrímeros/síntese química , Dendrímeros/química , Portadores de Fármacos/síntese química , Portadores de Fármacos/química , Flutamida/síntese química , Flutamida/química , Humanos , Modelos Moleculares , Neoplasias/tratamento farmacológico , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologiaRESUMO
Two sulfonated resorcinarenes were synthesized by reacting C-tetra(butyl) resorcinarene or C-tetra(2-(methylthio)ethyl)resorcinarene with formaldehyde in the presence of sodium sulfite. Their structures were determined via FT-IR, 1H-NMR, 13C-NMR and mass spectrometry. Thermal gravimetric analyses of the derivatives were also carried out and revealed the presence of water molecules in the solid state. The sulfonated product of C-tetra(butyl)resorcinarene was characterized by an X-ray crystal structure determination. The asymmetric unit contains eight molecules of water and two of acetone, and analysis indicated that sulfonated resorcinarene prefers a cone configuration (rccc conformation) in the solid state. In the crystal array, classical hydrogen bond interactions O-H···O and intermolecular contacts were observed. In the crystal packing, a linear array of capsules of sulfonated resorcinarenes was generated for a chain of sodium atoms and sulfonate groups.
Assuntos
Alcanossulfonatos/síntese química , Calixarenos/síntese química , Formaldeído/química , Fenilalanina/análogos & derivados , Sulfitos/química , Acetona/química , Cristalografia por Raios X , Ligação de Hidrogênio , Conformação Molecular , Fenilalanina/síntese química , Solubilidade , Água/químicaRESUMO
Peptide-based nanostructures derived from natural amino acids are superior building blocks for biocompatible devices as they can be used in a bottom-up process without the need for expensive lithography. A dense nanostructured network of l,l-diphenylalanine (FF) was synthesized using the solid-vapor-phase technique. Formation of the nanostructures and structure-phase relationship were investigated by electron microscopy and Raman scattering. Thin films of l,l-diphenylalanine micro/nanostructures (FF-MNSs) were used as the dielectric layer in pentacene-based field-effect transistors (FETs) and metal-insulator-semiconductor diodes both in bottom-gate and in top-gate structures. Bias stress studies show that FF-MNS-based pentacene FETs are more resistant to degradation than pentacene FETs using FF thin film (without any nanostructures) as the dielectric layer when both are subjected to sustained electric fields. Furthermore, it is demonstrated that the FF-MNSs can be functionalized for detection of enzyme-analyte interactions. This work opens up a novel and facile route toward scalable organic electronics using peptide nanostructures as scaffolding and as a platform for biosensing.
Assuntos
Nanoestruturas/química , Peptídeos/química , Fenilalanina/análogos & derivados , Transistores Eletrônicos , Dipeptídeos , Microscopia Eletrônica , Peptídeos/síntese química , Fenilalanina/síntese química , Fenilalanina/química , Análise Espectral RamanRESUMO
Asperphenamate is a natural phenylalanine derivative. This compound was produced through a new, two-step synthetic route. It was also evaluated by the antimicrobial activity of the pure substance against Escherichia coli, Staphylococcus aureus and Cladosporium herbarum.
Assuntos
Antibacterianos/síntese química , Antifúngicos/síntese química , Fenilalanina/análogos & derivados , Antibacterianos/química , Antibacterianos/farmacologia , Antifúngicos/química , Antifúngicos/farmacologia , Cladosporium/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Cromatografia Gasosa-Espectrometria de Massas , Testes de Sensibilidade Microbiana , Ressonância Magnética Nuclear Biomolecular , Fenilalanina/síntese química , Fenilalanina/química , Fenilalanina/farmacologia , Espectrofotometria Infravermelho , Staphylococcus aureus/efeitos dos fármacosRESUMO
Two series of 5 and 6-substituted 1,3-benzodioxole peptidyl derivatives were synthesized and evaluated as antitumour and antimicrobial agents. The compounds that could be conveniently prepared in a few steps processes from natural safrole have been characterised by IR and 1H-NMR spectroscopy. In vivo antitumor activity tests showed that some of the compounds were able to inhibit carcinoma S-180 tumour growth in mice. The in vitro antimicrobial activity of all compounds revealed that they are able to promote the growth of some organisms, including Bacillus subtilis.
Assuntos
Antibacterianos/síntese química , Antineoplásicos/síntese química , Dioxóis/síntese química , Peptídeos/síntese química , Fenilalanina/análogos & derivados , Animais , Antibacterianos/farmacologia , Antineoplásicos/farmacologia , Bacillus subtilis/efeitos dos fármacos , Bacillus subtilis/crescimento & desenvolvimento , Comportamento Animal/efeitos dos fármacos , Dioxóis/farmacologia , Dioxóis/toxicidade , Avaliação Pré-Clínica de Medicamentos , Dose Letal Mediana , Camundongos , Peptídeos/farmacologia , Fenilalanina/síntese química , Fenilalanina/farmacologia , Fenilalanina/toxicidade , Safrol/química , Sarcoma 180/tratamento farmacológicoRESUMO
We explored the unique substrate specificity of the primary S(1) subsite of human urinary kallikrein (hK1), which accepts both Phe and Arg, using internally quenched fluorescent peptides Abz-F-X-S-R-Q-EDDnp and Abz-G-F-S-P-F-X-S-S-R-P-Q-EDDnp [Abz is o-aminobenzoic acid; EDDnp is N-(2,4-dinitrophenyl)ethylenediamine], which were based on the human kininogen sequence at the C-terminal region of bradykinin. Position X, which in natural sequence stands for Arg, received the following synthetic basic non-natural amino acids: 4-(aminomethyl)phenylalanine (Amf), 4-guanidine phenylalanine (Gnf), 4-(aminomethyl)-N-isopropylphenylalanine (Iaf), N(im)-(dimethyl)histidine [H(2Me)], 3-pyridylalanine (Pya), 4-piperidinylalanine (Ppa), 4-(aminomethyl)cyclohexylalanine (Ama), and 4-(aminocyclohexyl)alanine (Aca). Only Abz-F-Amf-S-R-Q-EDDnp and Abz-F-H(2Me)]-S-R-Q-EDDnp were efficiently hydrolyzed, and all others were resistant to hydrolysis. However, Abz-F-Ama-S-R-Q-EDDnp inhibited hK1 with a K(i) of 50 nM with high specificity compared to human plasma kallikrein, thrombin, plasmin, and trypsin. The Abz-G-F-S-P-F-X-S-S-R-P-Q-EDDnp series were more susceptible to hK1, although the peptides with Gnf, Pya, and Ama were resistant to it. Unexpectedly, the peptides in which X is His, Lys, H(2Me), Amf, Iaf, Ppa, and Aca were cleaved at amino or at carboxyl sites of these amino acids, indicating that the S(1)' subsite has significant preference for basic residues. Human plasma kallikrein did not hydrolyze any peptide of this series except the natural sequence where X is Arg. In conclusion, the S(1) subsite of hK1 accepts amino acids with combined basic and aromatic side chain, although for the S(1)-P(1) interaction the preference is for aliphatic and basic side chains.