RESUMEN
Fifty-six methanol extracts obtained from the barks, flowers, leaves and stems of 30 Slovak trees, bushes and herbs used in the traditional medicine of the Small Carpathians, Slovakia, have been screened for antiprotease (trypsin, thrombin and urokinase) activity using chromogenic bioassay. In this study, 14 extracts showed the strong inhibition activity to protease trypsin with IC50 values below 10 microg/mL. The highest inhibition activities were observed for methanol extracts of Acer platanoides IC50 = 1.8 microg/mL, Rhus typhina IC50 = 1.2 microg/mL and Tamarix gallica IC50 = 1.7 microg/mL. However, the results of extracts tested on thrombin were generally different from those observed for trypsin. The most marked inhibition activity to thrombin were estimated for extracts of Castanea sativa IC50 = 73.2 microg/mL, Larix decidua IC50 = 96.9 microg/mL and Rhus typhina IC50 = 20.5 microg/mL. In addition, Acer platanoides and Rhus typhina were the only extracts which showed inhibition activity to urokinase with IC50 = 171.1 microg/mL and IC50 = 38.3 microg/mL, respectively. In addition, Rhus typhina showed the broadest spectrum of inhibition activity to all tested serine proteases and seems to be a prospective new source of natural products as inhibitors of serine proteases.
Asunto(s)
Plantas Medicinales/química , Inhibidores de Proteasas/farmacología , Peso Molecular , Extractos Vegetales/química , Extractos Vegetales/farmacología , Inhibidores de Proteasas/química , Inhibidores de Proteasas/aislamiento & purificación , Serina Proteasas/química , Serina Proteasas/metabolismo , Eslovaquia , Trombina/antagonistas & inhibidores , Árboles , Inhibidores de Tripsina/química , Inhibidores de Tripsina/aislamiento & purificación , Inhibidores de Tripsina/farmacologíaRESUMEN
Proteolytic processes are necessary for normal physiological functions in the body. Failure in the biological control mechanisms of proteolytic activities may cause various diseases, for example, it may enable tumor invasion and metastasis. In the metastatic process, proteolytic enzymes play an important role in mediating passage of the malignant cell through the cell membrane. Tumor cell migration and invasion into the surrounding extracellular matrix is facilitated by a variety of cell surface-associated proteolytic enzymes: matrix metalloproteinases (MMPs), cysteine proteases including cathepsins B and L, aspartic protease cathepsin D, and serine proteases including plasmin and urokinase plasminogen activator (uPA). Many of the natural and synthetic inhibitors of the proteases prevent the dissemination of cancer cells and have also inhibitory effect on tumor growth. Thus inhibition of protease activity by low molecular weight inhibitors represents a promising strategy for anticancer and antimetastatic therapy. The review surveys low molecular inhibitors of MMPs, uPA and lysosomal proteases.
Asunto(s)
Antineoplásicos , Metástasis de la Neoplasia/prevención & control , Inhibidores de Proteasas , Antineoplásicos/química , Antineoplásicos/metabolismo , Catepsinas/antagonistas & inhibidores , Diseño de Fármacos , Humanos , Inhibidores de la Metaloproteinasa de la Matriz , Neoplasias/enzimología , Neoplasias/prevención & control , Inhibidores de Proteasas/química , Inhibidores de Proteasas/metabolismo , Activador de Plasminógeno de Tipo Uroquinasa/antagonistas & inhibidoresRESUMEN
Viral infections represent various types of human, veterinary and plant diseases with a significant economic, ethic and demographic impact. Over the years a significant effort has been made to develop various means of prevention and therapy of viral diseases. Proteinases play an important role in the process of virus replication as well as in the pathophysiology of many viral diseases. The aim of this review is to assess the prospects of the application of proteinase inhibitors in antiviral therapy and to characterize viral proteinases of various classes. Six Human immunodeficiency virus (HIV) proteinase inhibitors have been approved for therapeutic use and can serve as examples of prospective application ofproteinase inhibitors to antiviral therapy.
Asunto(s)
Antivirales/farmacología , Inhibidores de Proteasas/farmacología , Proteínas Virales/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Antivirales/uso terapéutico , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Cisteína Endopeptidasas/metabolismo , Inhibidores de la Proteasa del VIH/clasificación , Inhibidores de la Proteasa del VIH/farmacología , Inhibidores de la Proteasa del VIH/uso terapéutico , Humanos , Metaloendopeptidasas/antagonistas & inhibidores , Metaloendopeptidasas/metabolismo , Modelos Biológicos , Modelos Moleculares , Oligopéptidos/metabolismo , Inhibidores de Proteasas/uso terapéutico , Serina Endopeptidasas/metabolismo , Virus/enzimologíaRESUMEN
Fourteen substituted 4-anilinoquinazolines have been tested for cytotoxic effect and structure activity relationships. The most active derivatives were substituted by chlorine or bromine group in the aromatic ring, in the pyrimidine ring by morpholine group and in the aniline skeleton by nitro group in position 4 or 2. Derivatives 6-bromo-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline, 6-bromo-2-morpholin-1-yl)-4-anilinoquinazoline, 2-(morpholin-1-yl)-4-(4'-bromoanilino)-quinazoline and 6-chloro-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline inhibited growth of tumor cell lines HeLa, B16 and L1210. Mutagenic data provided by Ames test showed, that the compounds 6-bromo-2-morpholin-1-yl)-4-anilinoquinazoline and 2-(morpholin-1-yl)- 4-(4'-bromoanilino)quinazoline did not exhibit the mutagenic effect, whereas the compounds 6-bromo-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline and 6-chloro-2-(morpholin-1-yl)-4-(4'-nitroanilino) quinazoline increased slightly the number of revertants of the strain TA 98 without metabolic activation. Concentration 26 micromol/L of 6-bromo-2-(morpholin-1-yl)-4-anilinoquinazoline induced necrosis of tumor cells B16. Concentration 5.2 micromol/l induced a significant increase of filamentous actin in the transformed HepG2 cells. Derivatives 6-bromo-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline, 6-bromo-2-morpholin-1-yl)-4-anilinoquinazoline, 2-(morpholin-1-yl)-4-(4'-bromoanilino)quinazoline and 6-chloro-2-(morpholin-1-yl)-4-(4'-nitroanilino)quinazoline exhibited antiprotease effect on plasmine. This results could be relevant for the anticancer properties of these compounds.
Asunto(s)
Inhibidores de Proteasas/farmacología , Quinazolinas/farmacología , Animales , Células CHO/efectos de los fármacos , Células CHO/fisiología , Cricetinae , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa/efectos de los fármacos , Células HeLa/fisiología , Humanos , Leucemia/patología , Melanoma/patología , Ratones , Pruebas de Mutagenicidad , Necrosis , Neoplasias Cutáneas/patología , Relación Estructura-Actividad , Células Tumorales Cultivadas/efectos de los fármacos , Células Tumorales Cultivadas/fisiologíaRESUMEN
Aspartic proteases play key roles in a variety of pathologies, including acquired immunodeficiency syndrome. Peptidomimetic inhibitors can act as drugs to combat these pathologies. We have developed an integrated methodology for preparing human immunodeficiency virus (HIV)-1 aspartic protease diaminodiol inhibitors, based on a computational method that predicts the potential inhibitory activity of the designed structures in terms of calculated enzyme-inhibitor complexation energies. This is combined with a versatile synthetic strategy that couples a high degree of stereochemical control in the central diaminodiol module with complete flexibility in the choice of side chains in the core and in flanking residues. A series of 23 tetrameric, pentameric and hexameric inhibitors, with a wide range of calculated relative complexation energies (-47.2 to +117 kJ.mol-1) and predicted hydrophobicities (logPo/w = 1.8-8.4) was thus assembled from readily available amino acids and carboxylic acids. The IC50 values for these compounds ranged from 3.2 nM to 90 microM, allowing study of correlations between structure and activity, and individuation of factors other than calculated complexation energies that determine the inhibition potency. Multivariable regression analysis revealed the importance of side-chain bulkiness and rigidity at the P2, P2' positions, suggesting possible improvements for the prediction process used to select candidate structures.