Current Medicinal Chemistry - Volume 25, Issue 10, 2018

Background: Natural phenolics are secondary plant metabolites, which can be divided into several categories with the common structural feature of phenolic hydroxyl. The biological activity of phenolics is often modified and enhanced by prenylation by prenyl and geranyl; higher terpenoid chains are rare. The type of prenyl connection and modification affects their biological activity. Objective: This review summarizes information about prenylated phenols and some of their potential sources, and provides an overview of their anti-inflammatory potential in vitro and in vivo. Method: The literature search was performed using SciFinder and keywords prenyl, phenol, and inflammation. For individual compounds, an additional search was performed to find information about further activities and mechanisms of effects. Result: We summarized the effects of prenylated phenolics in vitro in cellular or biochemical systems on the production and release of inflammation-related cytokines; their effects on inhibition of cyclooxygenases and lipoxygenases; the effects on production of nitric oxide, antiradical and antioxidant activity; and the effect on the inhibition of the release of enzymes and mediators from neutrophils, mast cells and macrophages. The information about the antiphlogistic potential of prenylated phenolics is further supported by a review of their action in animal models. Conclusion: Almost 400 prenylated phenols were reviewed to overview their antiinflammatory effect. The bioactivity of several prenylated phenols was confirmed also using in vivo assays. A pool of natural prenylated phenols represents a source of inspiration for synthesis, and prenylated phenols as components of various medicinal plants used to combat inflammation could be their active principles.

Background: Although Cannabis sativa L. is one of the most versatile plant species with multipurpose use both as medical, alimentary source and as psychoactive abuse, its biomedical relevance focused the attention on major cannabinoids. Phytochemical characterization of cannabis highlights the presence of various non-cannabinoids constituents including flavonoids, spiroindans, dihyrostilbenes, dihydrophenanthrenes, lignanamides, steroids and alkaloids. This review aims to identify polyphenols present in this plant, their biosynthesis, their bioactivities and their synthesis, when this occurred. Methods: We undertook a systematic research focused on bibliographic databases including all noncannabinoids phenolics in various C. sativa strains from their isolation, structural elucidation, their biological activity to their synthesis. Result: Nevertheless, attention has so far been focused only on cannabinoids (more than one hundred isolated), cannabis is a complex plant able to produce more than 480 chemical entities that represent almost all of the different biogenetic classes. Regarding phenolic compounds, the plant biosynthesises a plethora of unique non-cannabinoids second metabolites, such as prenylated flavonoids, stilbenoids derivatives and lignanammides. Conclusion: Cannabis is a plant with high pharmacological and nutrition values, its potentialities and applications are not only circumscribed to cannabinoids biological activities, but also defined by noncannabinoid compounds. The combination of other cannabinoids together with noncannabinoid components could enhance the beneficial effects of THC and could reduce undesirable side effects.

O-Prenyl coumarins (3,3-dimethylallyl, geranyl-, farnesyl- and related biosynthetic derivatives) represent a class of rarely occurring natural products. In the last two decades, such secondary metabolites have been found to possess promising and effective pharmacological properties, mainly in terms of anti-cancer and anti-inflammatory properties. To date, about 160 oxyprenylated coumarins have been extracted from plants, fungi, and bacteria. The genus Citrus has been demonstrated to be among the richest source of the title products. The aim of this comprehensive review is to make a survey of the so far reported literature citations about the main O-prenyl coumarins found in this genus from phytochemical and pharmacological point of views and for which no surveys of the in so far reported literature have been made.

Background: Dihydrostilbenoids, a diverse class of natural products differing from stilbenoids by the missing double bond in the ethylene chain linking the aromatic moieties, have been reported from fungi, mosses, ferns, and flowering plants. Objective: Occurrence, structure, and bioactivity of naturally occurring dihydroresveratrol type dihydrostilbenoids are discussed in this review. Method: A Reaxys database search for dihydroresveratrol derivatives with possible substitutions on all atoms, but excluding non-natural products and compounds featuring additional rings involving the ethyl connecting chain, was performed. Results: Structures include simple dihydroresveratrol derivatives, compounds substituted with complex side chains composed of acyl moieties and sugars, and compounds containing polycyclic cores attached to dihydrostilbenoid units. Dihydrostilbenoids have a wide spectrum of bioactivities ranging from expectable antioxidant and anti-inflammatory activities to interesting neuroprotective and anticancer activity. The anticancer activity in particular is very pronounced for some plant-derived dihydrostilbenoids and makes them interesting lead compounds for drug development. Apart from some reports on dihydroresveratrol derivatives as phytoalexins against plant-pathogenic fungi, only very limited information is available on the ecological role of these compounds for the organisms producing them. Conclusion: Dihydrostilbenoids are a class of natural products possessing significant biological activities; their scattered but not ubiquitous occurrence throughout the kingdoms of plants and fungi is not easily explained. We are convinced that future studies will identify new sources of dihydrostilbenoids, and we hope that the present review will inspire such studies and will help in directing such efforts to suitable source organisms and towards promising bioactivities.

Sesquiterpenes are natural products that have been extensively studied for their bioactivities, evidencing their potentiality as useful scaffolds for the development of drugs. Considering the different derivatives, the sesquiterpene lactones have been evaluated, especially on cancer cell and antineoplastic efficacy in in vivo studies. Their bioactivity is strictly related to the presence of the reactive α-methylene-γ-lactone group (αMγL). Nevertheless, several other sesquiterpenes lacking αMγL are known and have been studied for their biological effects and potential usefulness in the development of new drugs. In this review, we focused on several sesquiterpenes that are not presenting the αMγL moiety and may have future potential as scaffold for the development of new drugs, namely the bicyclic compounds belonging to the carotane type (daucanes) that present significant effects as antiproliferative and estrogenic agents. The monocyclic humulane derivatives correlated to zerumbone, and the bicyclic compound beta-caryophyllene and its derivatives that have been considered in the field of cancer and inflammation. It is noteworthy that published studies on sesquiterpenes, reported in this review, focus on pathologies of increasing importance, like estrogen, anti-proliferative, bone loss, immunity deficiency and anti-tumour activities. Some of the natural “old” sesquiterpenes can be considered for their possible role in drug discovery and in counteracting these “new” challenges.

Background: Plants produce several bioactive secondary metabolites whose are used as therapeutic agents to treat several diseases, among whom cancer. Triterpenes are secondary metabolites that exert inhibitory activity against multiple intracellular and extracellular targets in euchariotic cells. These targets are proteins involved in apoptosis, cell development and differentiation, angiogenesis, metastasis and inflammatory processes. The inhibition of their functions leads to decreased cellular growth, differentiation and migration, resulting in antitumor activity, as shown by several authors. Furthermore, during recent years synthetic triterpenoid derivatives have also been developed to implement potency and efficacy of starting compounds, allowing the obtainment of new agents having promising anticancer activity. Objective: In this review we report the latest results regarding anticancer activity of some of the most studied triterpenes in the field, as well as of their semi-synthetic derivatives, with the aim to summarize the role of triterpenes as molecular leads for the development of new classes of antitumor agents. Methods: We focused on the most recent literature regarding triterpenes in cancer treatment, highlighting the potential of developing new drugs starting from these natural compounds. Conclusion: Several “old” triterpenes as ursolic, betulinic and oleanolic acids were recently reconsidered as model compounds for the development of innovative anticancer agents. Their activity against proteins involved in tumor development enhances the opportunity to exploit these compounds as new multi-target therapeutic agents. Furthermore, the possibility to synthetize new compounds from their natural-occurring structures could be an alternative to overcome cellular resistance to drugs and could improve their therapeutic efficacy.