RESUMEN
The first detailed phytochemical analysis of the cannabigerol (CBG)-rich chemotype IV of Cannabis sativa L. resulted in the isolation of the expected cannabigerolic acid/cannabigerol (CBGA/CBG) and cannabidiolic acid/cannabidiol (CBDA/CBD) and of nine new phytocannabinoids (5-13), which were fully characterized by HR-ESIMS and 1D and 2D NMR. These included mono- or dihydroxylated CBGA/CBG analogues, a congener with a truncated side chain (10), cyclocannabigerol B (11), and the CBD derivatives named cannabifuranols (12 and 13). Cyclocannabigerol B and cannabifuranols are characterized by a novel phytocannabinoid structural architecture. The isolated phytocannabinoids were assayed on the receptor channels TRPA1 and TRPM8, unveiling a potent dual TRPA1 agonist/TRPM8 antagonist profile for compounds 6, 7, and 14. Chiral separation of the two enantiomers of 5 resulted in the discovery of a synergistic effect of the two enantiomers on TRPA1.
Asunto(s)
Cannabinoides , Cannabis , Canal Catiónico TRPA1 , Canales Catiónicos TRPM , Canales de Potencial de Receptor Transitorio , Cannabis/química , Canal Catiónico TRPA1/antagonistas & inhibidores , Cannabinoides/farmacología , Cannabinoides/química , Cannabinoides/aislamiento & purificación , Canales Catiónicos TRPM/antagonistas & inhibidores , Estructura Molecular , Canales de Potencial de Receptor Transitorio/antagonistas & inhibidores , Canales de Potencial de Receptor Transitorio/efectos de los fármacos , Fitoquímicos/farmacología , Fitoquímicos/aislamiento & purificación , Fitoquímicos/química , Humanos , Cannabidiol/farmacología , Cannabidiol/química , Canales de Calcio/metabolismoRESUMEN
A phytochemical analysis of mother liquors obtained from crystallization of CBD from hemp (Cannabis sativa), guided by LC-MS/MS and molecular networking profiling and completed by isolation and NMR-based characterization of constituents, resulted in the identification of 13 phytocannabinoids. Among them, anhydrocannabimovone (5), isolated for the first time as a natural product, and three new hydroxylated CBD analogues (1,2-dihydroxycannabidiol, 6, 3,4-dehydro-1,2-dihydroxycannabidiol, 7, and hexocannabitriol, 8) were obtained. Hexocannabitriol (8) potently modulated, in a ROS-independent way, the Nrf2 pathway, outperforming all other cannabinoids obtained in this study and qualifying as a potential new chemopreventive chemotype against cancer and other degenerative diseases.
Asunto(s)
Cannabidiol , Cannabinoides , Cannabis , Cannabidiol/farmacología , Cannabinoides/química , Cannabis/química , Cromatografía Liquida , Espectrometría de Masas en Tándem/métodosRESUMEN
Cannabitwinol (CBDD, 3), the second member of a new class of dimeric phytocannabinoids in which two units are connected by a methylene bridge, was isolated from a hemp (Cannabis sativa L.) industrial extract. The structural characterization of cannabitwinol, complicated by broadening of 1H NMR signals and lack of expected 2D NMR correlations at room temperature, was fully carried out in methanol-d4 at -30 °C. All the attempts to prepare CBDD by reaction of CBD with formaldehyde or its iminium analogue (Eschenmoser salt) failed, suggesting that this sterically congested dimer is the result of enzymatic reactions on the corresponding monomeric acids. Analysis of the cannabitwinol profile of transient receptor potential (TRP) modulation evidenced the impact of dimerization, revealing a selectivity for channels activated by a decrease of temperature (TRPM8 and TRPA1) and the lack of significant affinity for those activated by an increase of temperature (e.g., TRPV1). The putative binding modes of cannabitwinol with TRPA1 and TRPM8 were investigated in detail by a molecular docking study using the homology models of both channels.
Asunto(s)
Cannabinoides/química , Cannabinoides/farmacología , Cannabis/química , Cannabinoides/biosíntesis , Espectroscopía de Resonancia Magnética , Modelos Moleculares , Simulación del Acoplamiento Molecular , Estructura Molecular , Canal Catiónico TRPA1/efectos de los fármacos , Canales Catiónicos TRPM/efectos de los fármacos , Canales Catiónicos TRPV/efectos de los fármacos , Temperatura , Canales de Potencial de Receptor Transitorio/efectos de los fármacosRESUMEN
20-(S)-Camptothecin (CPT) is a natural alkaloid extracted from the bark of Camptotheca acuminata (Chinese happy tree). It acts as a DNA topoisomerase 1 poison with an interesting antitumor activity and its use is limited by low stability and solubility and unpredictable drug-drug interactions. Since the late 20th century, it has been widely used in cancer therapy and, since extraction yields from plant tissues are very low, various synthetic routes have been developed to satisfy the increase in demand for CPT. Moreover, SAR studies have allowed for the development of more potent CPT analogues topotecan and irinotecan. Unfortunately, resistance has already occurred in several tumour lines. Additional studies are needed to better understand the relationship between substituents and resistance, its clinical relevance and the impact of related gene polymorphism. One of the latest research approaches focuses on modifying the delivery mode to improve tumour cell uptake and reduce toxicity.
Asunto(s)
Antineoplásicos Fitogénicos/química , Camptotecina/análogos & derivados , Medicina Tradicional , Antineoplásicos Fitogénicos/uso terapéutico , Antineoplásicos Fitogénicos/toxicidad , Apoptosis/efectos de los fármacos , Camptotheca/química , Camptotheca/metabolismo , Camptotecina/uso terapéutico , Camptotecina/toxicidad , ADN-Topoisomerasas de Tipo I/química , ADN-Topoisomerasas de Tipo I/metabolismo , Humanos , Neoplasias/tratamiento farmacológico , Relación Estructura-ActividadRESUMEN
The development of biomaterials able to act against a wide range of bacteria, including antibiotic resistant bacteria, is of great importance since bacterial colonization is one of the main causes of implant failure. In this work, we explored the possibility to functionalize hydroxyapatite (HA) nanocrystals with some monocyclic N-thio-substituted ß-lactams. To this aim, a series of non-polar azetidinones have been synthesized and characterized. The amount of azetidinones loaded on HA could be properly controlled on changing the polarity of the loading solution and it can reach values up to 17 wt%. Data on cumulative release in aqueous solution show different trends which can be related to the lipophilicity of the molecules and can be modulated by suitable groups on the azetidinone. The examined ß-lactams-HA composites display good antibacterial activity against reference Gram-positive and Gram-negative bacteria. However, the results of citotoxicity and antibacterial tests indicate that HA loaded with 4-acetoxy-1-(methylthio)-azetidin-2-one displays the best performance. In fact, this material strongly inhibited the bacterial growth of both methicillin resistant and methicillin susceptible clinical isolates of S. aureus from surgical bone biopsies, showing to be a very good candidate as a new functional biomaterial with enhanced antibacterial activity.