RESUMEN
In the last 50 years, nucleoside analogs have been introduced to drug therapy as antivirals for different types of cancer due to their interference in cellular proliferation. Among the first line of nucleoside treatment drugs, ribavirin (RBV) is a synthetic N-nucleoside with a 1,2,4-triazole moiety that acts as a broad-spectrum antiviral. It is on the World Health Organization (WHO) list of essential medicines. However, this important drug therapy causes several side effects due to its nonspecific mechanism of action. There is thus a need for a continuous study of its scaffold. A particular approach consists of connecting d-ribose to the nitrogen-containing base with a C-C bond. It provides more stability against enzymatic action and a better pharmacologic profile. The coronavirus disease (COVID) pandemic has increased the need for more solutions for the treatment of viral infections. Among these solutions, remdesivir, the first C-nucleoside, has been approved by the Food and Drug Administration (FDA) for clinical use against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It drew attention to the study of the C-nucleoside scaffold. Different C-nucleoside patterns have been synthesized over the years. They show many important activities against viruses and cancer cell lines. 1,2,3-Triazolyl-C-nucleoside derivatives are a prolific and efficient subclass of RBV analogs close to the already-known RBV with a C-C bond modification. These compounds are often prepared by alkynylation of the d-ribose ring followed by azide-alkyne cycloaddition. They are reported to be active against the Crimean-Congo hemorrhagic fever virus and several tumoral cell lines, showing promising biological potential. In this review, we explore such approaches to 1,2,3-triazolyl-C-nucleosides and their evolution over the years.
Asunto(s)
Antivirales , Nucleósidos , Nucleósidos/farmacología , Nucleósidos/química , Antivirales/farmacología , Antivirales/química , Ribosa/farmacología , Relación Estructura-Actividad , SARS-CoV-2 , Línea Celular Tumoral , BiologíaRESUMEN
5'-Phosphorylated nucleoside derivatives are molecules that can be found in all living organisms and viruses. Over the last century, the development of structural analogs that could disrupt the transcription and translation of genetic information culminated in the development of clinically relevant anticancer and antiviral drugs. However, clinically effective broad-spectrum antiviral compounds or treatments are lacking. This viewpoint proposes that molecules that inhibit nucleotide biosynthesis may sensitize virus-infected cells toward direct-acting antiviral nucleosides. Such potentially synergistic combinations might allow the repurposing of drugs, leading to the development of new combination therapies.
Asunto(s)
Antivirales , Hepatitis C Crónica , Humanos , Antivirales/farmacología , Antivirales/química , Nucleósidos/farmacología , Nucleósidos/química , Relación Estructura-Actividad , Hepatitis C Crónica/tratamiento farmacológico , Nucleótidos/farmacologíaRESUMEN
The chemistry of 1,2,3-triazoles gained much attention since the discovery of the copper catalyzed Alkyne-azide cycloaddition (CuAAC) reaction which delivers exclusively the 1,4-regioisomer in high yields. On the other hand there is still no universal methodology capable of delivering the N2 substituted regioisomer. The unique properties of these N2-substituted 1,2,3-triazoles have stimulated synthetic efforts on the developments of methodologies capable of delivering it in high yield and selectivity. These efforts are the subject of the presented review.
Asunto(s)
Triazoles/química , Catálisis , Reacción de Cicloadición , Estructura Molecular , Triazoles/síntesis químicaRESUMEN
Tuberculosis (TB) remains a serious public health problem aggravated by the emergence of M. tuberculosis (Mtb) strains resistant to multiple drugs (MDR). Delay in TB treatment, common in the MDR-TB cases, can lead to deleterious life-threatening inflammation in susceptible hyper-reactive individuals, encouraging the discovery of new anti-Mtb drugs and the use of adjunctive therapy based on anti-inflammatory interventions. In this study, a series of forty synthetic chalcones was evaluated in vitro for their anti-inflammatory and antimycobacterial properties and in silico for pharmacokinetic parameters. Seven compounds strongly inhibited NO and PGE2 production by LPS-stimulated macrophages through the specific inhibition of iNOS and COX-2 expression, respectively, with compounds 4 and 5 standing out in this respect. Four of the seven most active compounds were able to inhibit production of TNF-α and IL-1ß. Chalcones that were not toxic to cultured macrophages were tested for antimycobacterial activity. Eight compounds were able to inhibit growth of the M. bovis BCG and Mtb H37Rv strains in bacterial cultures and in infected macrophages. Four of them, including compounds 4 and 5, were active against a hypervirulent clinical Mtb isolate as well. In silico analysis of ADMET properties showed that the evaluated chalcones displayed satisfactory pharmacokinetic parameters. In conclusion, the obtained data demonstrate that at least two of the studied chalcones, compounds 4 and 5, are promising antimycobacterial and anti-inflammatory agents, especially focusing on an anti-tuberculosis dual treatment approach.
Asunto(s)
Antiinflamatorios/farmacología , Antituberculosos/farmacología , Chalconas/farmacología , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis/tratamiento farmacológico , Animales , Línea Celular , Ciclooxigenasa 2/metabolismo , Dinoprostona/metabolismo , Interleucina-1beta/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Óxido Nítrico Sintasa de Tipo II/metabolismo , Óxidos de Nitrógeno/metabolismo , Tuberculosis/metabolismo , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Lipases are triacyl glycerol acyl hydrolases, which catalyze hydrolysis of esters, esterification and transesterification reactions, among others. Some of these enzymes have a large hydrophobic pocket covered by an alpha-helical mobile surface loop (the lid). Protein-protein interactions can occur through adsorption of two open lids of individual lipases. We investigated the conformation and oligomeric state of Thermomyces lanuginosus lipase (TLL) in solution by spectroscopic and mass spectrometry techniques. Information about oligomerization of this important industrial enzyme is only available for TLL crystals; therefore, we have done a throughout investigation of the conformation of this lipase in solution. SDS-PAGE and mass spectrometry analysis of size-exclusion chromatography eluted fractions indicated the presence of both monomeric and dimeric populations of TLL. The stability of the enzyme upon thermal and guanidine hydrochloride treatment was examined by circular dichroism and fluorescence emission spectroscopy. Small angle x-ray scattering and ion mobility mass spectrometry analysis revealed that TLL is found as a mixture of monomers and dimers at the assayed concentrations. Although previous x-ray diffraction data showed TLL as a dimer in the crystal (PDB: 1DT3), to our knowledge our report is the first evidencing that TLL co-exists as stable dimeric and monomeric forms in solution.
Asunto(s)
Ascomicetos/enzimología , Lipasa/química , Ascomicetos/química , Dicroismo Circular , Espectrometría de Masas , Modelos Moleculares , Multimerización de Proteína , Dispersión del Ángulo Pequeño , Espectrometría de Fluorescencia , Difracción de Rayos XRESUMEN
Lecitase Ultra was immobilized on Amberlites XAD2 and XAD4, through physical entrapping under conventional stirring or ultrasound irradiation, and characterized by standard techniques. The resulting immobilized biocatalysts were utilized in the valorization of an acidic food-derived residue from a palm oil refining process to produce monoacylglycerols from isopropylidene glycerol under batch and continuous flow conditions. Results indicated that the immobilized biocatalysts could moderately convert the food waste residue (max. conversion 50-60 %), exhibiting interesting stability under continuous flow conditions.