RESUMEN
HIV-1 integrase is an essential enzyme for retroviral replication. It is involved in the integration of HIV DNA into host chromosomal DNA and appears to have no functional equivalent in human cells. Therefore it is an attractive and rational target for selective anti-AIDS therapy. A great number of HIV-1 integrase inhibitors have been described in the last decade and numerous reviews have been published. The biochemical mechanism of HIV-1 DNA integration, the enzyme structure and the possible targets for drug intervention have been thoroughly analyzed. Structure-based drug design including both ligand-based (pharmacophore) and target-based (docking) methods has also been discussed. The recent report of the crystal structure of HIV-1 integrase core domain with an inhibitor has given a new boost leading in the last two years to the emergence of diketoacids (DKAs). To date, with the dicaffeoyltartaric acids they are the only two classes of molecules that meet the criteria necessary to be considered lead molecules in the search for clinically useful inhibitors of HIV-1 integrase. After a survey of the function and the structure of this enzyme and the different available assays for the identification of new IN inhibitors, structure-activity relationships of HIV-1 integrase inhibitors that are expected to interact with the active site (or in its vicinity) will be discussed with emphasis on their different proposed mechanisms of action.
Asunto(s)
Fármacos Anti-VIH/química , Inhibidores de Integrasa VIH/química , Fármacos Anti-VIH/metabolismo , Fármacos Anti-VIH/farmacología , Ácidos Cafeicos/química , Ácidos Cafeicos/metabolismo , Ácidos Cafeicos/farmacología , Catálisis , ADN Viral/efectos de los fármacos , ADN Viral/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Flavonoides/farmacología , Integrasa de VIH/efectos de los fármacos , Integrasa de VIH/metabolismo , Inhibidores de Integrasa VIH/metabolismo , Inhibidores de Integrasa VIH/farmacología , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Cetoácidos/química , Cetoácidos/metabolismo , Cetoácidos/farmacología , Ligandos , Modelos Moleculares , Estructura Molecular , Naftalenosulfonatos/química , Naftalenosulfonatos/metabolismo , Naftalenosulfonatos/farmacología , Oligonucleótidos/química , Oligonucleótidos/metabolismo , Oligonucleótidos/farmacología , Péptidos/química , Péptidos/metabolismo , Péptidos/farmacología , Fenoles/química , Fenoles/metabolismo , Fenoles/farmacología , Polifenoles , Relación Estructura-Actividad , Succinatos/química , Succinatos/metabolismo , Succinatos/farmacología , Integración Viral/efectos de los fármacosRESUMEN
Fourteen catechol and bis-catechol derivatives have been synthesised and tested for their HIV-1 inhibitory activities. The six more active molecules have been tested for their antiviral activity and cytotoxicity. We have found that bis-catechols 1 and 2 are the most active HIV-1 integrase inhibitor whereas the best antiviral compound is 4.
Asunto(s)
Catecoles/síntesis química , Catecoles/farmacología , Inhibidores de Integrasa VIH/síntesis química , Inhibidores de Integrasa VIH/farmacología , Línea Celular , VIH-1/efectos de los fármacos , VIH-1/enzimología , Humanos , Espectroscopía de Resonancia Magnética , Pruebas de Sensibilidad Microbiana , Replicación Viral/efectos de los fármacosRESUMEN
Three polyhydroxy-2-phenylnaphthalenes (1-3) and the oxy analogue of tetrahydroxypavinan (4) were prepared and evaluated for their antioxidant properties (inhibition of diphenylpycrylhydrazyl radical (DPPH), reduction of iron (III) ion) and inhibition of 5-lipoxygenase (5-LO) activity. Their three-dimensional structures were established on the basis of spectroscopic data and semiempirical calculations. Compounds 1 and 2 were found as potent 5-LO inhibitors as nordihydroguaiaretic acid (NDGA), whereas 4 is 2.5 times less potent than NDGA. The reliability of the 3-D structures with the 5-LO inhibition properties is discussed. Their antioxidant properties show that tested compounds are expected to act as redox inhibitors.
Asunto(s)
Araquidonato 5-Lipooxigenasa/efectos de los fármacos , Bepridil/análogos & derivados , Inhibidores de la Lipooxigenasa/síntesis química , Picratos , Animales , Antioxidantes/síntesis química , Antioxidantes/farmacología , Araquidonato 5-Lipooxigenasa/metabolismo , Bepridil/metabolismo , Compuestos de Bifenilo , Catecoles , Indicadores y Reactivos , Hierro/metabolismo , Cinética , Inhibidores de la Lipooxigenasa/farmacología , Estructura Molecular , Oxidación-Reducción , Ratas , Relación Estructura-Actividad , Células Tumorales CultivadasRESUMEN
Five peptides related to the N-terminal sequence of the vasoactive intestinal peptide (VIP) have been synthesized. Two-dimensional nuclear magnetic resonance (2D-NMR) experiments (i.e., correlated spectroscopy [COSY]) and low temperature coefficient measurements for particular NH chemical shifts suggest the presence of hydrogen bondings in both VIP (1-7, and VIP (1-11) fragments. Nuclear Over-hauser enhancement spectroscopy (NOESY) show that aromatic interactions stabilize a preferred conformation. The crucial role of the first histidine residue, which is a determinant for the biological activity, is explained by specific interactions with the aromatic protons of Phe6 and Tyr10.
Asunto(s)
Fragmentos de Péptidos/química , Péptido Intestinal Vasoactivo/química , Amidas/química , Enlace de Hidrógeno , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Fragmentos de Péptidos/síntesis química , Fenilalanina/química , Pliegue de Proteína , Estructura Secundaria de Proteína , Protones , Temperatura , Tirosina/químicaRESUMEN
The ability of hydroxylated metabolites of salicylic acid to scavenge reactive oxygen species and to inhibit arachidonic acid metabolism was investigated. The tested trihydroxybenzoic acids (THBAs) were potent scavengers of hydroxyl and superoxide anion radicals produced by Fenton reaction and xanthine/xanthine oxidase system or activated macrophages respectively. In the same tests, salicylic acid possessed moderate O2(-) and low OH'scavenging activities. Our results demonstrate that adding two hydroxyl groups to salicylic acid strongly increases the reactive oxygen species (ROS) scavenging activities. Adding two hydroxyl groups at position 4 and 5 (2,4,5-THBA) affords the most active ROS scavenging activity probably due to the ortho unsubstituted catechol moiety. In fact, we can consider that the ROS scavenging properties of salicylic acid are essentially due to its metabolic products such as 2,3- and 2,5-DHBAs, catechol and also to THBAs.
RESUMEN
The oxidative cleavage of 2,5-dihydroxybenzoic acid (gentisic acid), presumably into maleylpyruvate in basic aqueous solution has been shown by ESR spectra of semiquinonic radicals bearing a methylenic group. One of these radicals has been unambiguously attributed to 2,4,5-trihydroxyphenylacetic acid semiquinonic radical. The formation of an hydroxylated homogentisic acid from gentisic acid (a metabolite of aspirin) is of particular importance in the treatment of alkaptonuria and related inflammatory arthritis.
RESUMEN
The isolation and characterization is described of four novel cyclic polyethers, bistramides B [2], C [3], D [4], and K [5], which are closely related to the previously reported bistramide A [1] from the New Caledonian urochordata Lissoclinum bistratum. The structures of these metabolites were defined by spectroscopic methods. The four compounds exhibited in vitro cytotoxicity toward six tumor cell lines, including the human non-small cell lung carcinoma (NSCLC-N6) line. Cytofluorimetric analysis with bistramide K showed a complete block of NSCLC-N6 cells in the G1 phase. Bistramide D and particularly bistramide K are less toxic than bistramides A, B, and C and are thereby effective in vivo against NSCLC-N6.
Asunto(s)
Antineoplásicos/farmacología , Éteres Cíclicos/farmacología , Urocordados/química , Animales , Antineoplásicos/química , Antineoplásicos/aislamiento & purificación , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia Celular , Éteres Cíclicos/química , Éteres Cíclicos/aislamiento & purificación , Humanos , Neoplasias Pulmonares/patología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Células Tumorales CultivadasRESUMEN
The conformation of various regions of vasoactive intestinal peptide (VIP) has been analyzed by semiempirical methods, CD, and NMR spectroscopy, indicating that residues 11-21 are most likely to be helical, whereas the amino-terminal portion VIP(1-11) could exhibit two beta-turn structures. VIP(1-11) inhibits 125I-VIP binding to intact guinea pig tracheal epithelial cells and the VIP-induced smooth muscle response. However, the endecapeptide exhibits no effect on the muscle tone. All these data suggest that VIP(1-11) may be a useful tool in studying VIP receptor recognition, its regulation, and cellular functions.
Asunto(s)
Relajación Muscular/efectos de los fármacos , Fragmentos de Péptidos/farmacología , Tráquea/efectos de los fármacos , Péptido Intestinal Vasoactivo/farmacología , Secuencia de Aminoácidos , Animales , Unión Competitiva , Células Cultivadas , Células Epiteliales , Epitelio/efectos de los fármacos , Epitelio/metabolismo , Cobayas , Técnicas In Vitro , Cinética , Masculino , Datos de Secuencia Molecular , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/química , Conformación Proteica , Tráquea/fisiología , Péptido Intestinal Vasoactivo/síntesis química , Péptido Intestinal Vasoactivo/químicaRESUMEN
The redox properties of simple prenylated hydroquinone derivatives with cytotoxic properties have been studied by absorption and ESR spectroscopies. Both methods evidenced an autoxidation process in which the hydroquinones give rise to a semiquinone radical. Molecular oxygen is the electron acceptor, as demonstrated by spin trapping. No secondary radicals were found in the ESR spectra, either in the presence of hydroxyl anion (alkaline medium) or in the presence of glutathione. Nevertheless, a redox cycle can be initiated by glutathione, giving rise to substantial free-radical production. Thus, although not fully elucidated, the antitumor properties of the three hydroquinones described here can be correlated with their redox properties and their reactivity with thiol-containing peptides such as glutathione.
Asunto(s)
Antineoplásicos/química , Hidroquinonas/química , Animales , Espectroscopía de Resonancia por Spin del Electrón , Radicales Libres , Glutatión/química , Oxidación-Reducción , Oxígeno/química , Espectrofotometría , Espectrofotometría Ultravioleta , UrocordadosRESUMEN
The conformation of the synthetic pentapeptide Thr-Thr-Asn-Tyr-Thr, the C-terminal part of peptide T has been studied using 2D NMR experiments. The nuclear Overhauser effects (NOESY) and the low temperature coefficients for two particular NH chemical shifts allow the proposal for two distinct beta-turn arrangements. This conformation is not in accordance with recent reports but is consistent with observed beta-bends in two sequences of ribonuclease A. The semi-rigid conformation found in the pentapeptide in which the hydroxyl groups are exposed at the periphery of the molecule could be a crucial feature to explain the ability of peptide T to bind to a specific receptor and to correlate with the observed biological activity against HIV.