Progress in the chemistry of organic natural products最新文献

Peptidylarginine deiminase (PAD) enzymes are of enormous interest in biomedicine. They catalyze the conversion of a positively-charged guanidinium at an arginine side chain into a neutral ureido group. As a result of this conversion, proteins acquire the non-ribosomally encoded amino acid "citrulline". This imposes critical influences on the structure and function of the target molecules. In multiple sclerosis, myelin hyper-citrullination promotes demyelination by reducing its compaction and triggers auto-antibody production. Immune responses to citrulline-containing proteins play a central role in the pathogenesis of autoimmune diseases. Moreover, auto-antibodies, specific to citrullinated proteins, such as collagen type I and II and filaggrin, are early detectable in rheumatoid arthritis, serving as diagnostic markers of the disease. Despite their significance, little is understood about the role in demyelinating disorders, diversified cancers, and auto-immune diseases. To impart their biological and pathological effects, it is crucial to better understand the reaction mechanism, kinetic properties, substrate selection, and specificities of peptidylarginine deiminase isoforms.Many aspects of PAD biochemistry and physiology have been ignored in past, but, herein is presented a comprehensive survey to improve our current understandings of the underlying mechanism and regulation of PAD enzymes.

Coumarins are the largest group of 1-benzopyran derivatives found in plants. The initial member of this group of compounds, coumarin (2H-1-benzopyran-2-one), a fragrant colorless compound, was first isolated from the Tonka bean (Dipteryx odorata, family Fabaceae) in 1820. The name coumarin comes from a French term for the tonka bean, coumarou. Since the discovery of coumarin, several of its derivatives, with umbelliferone (7-hydroxycoumarin) being the most common one, have been reported from various natural sources. The families Apiaceae, Asteraceae, and Rutaceae are the three major plant sources of coumarins.Generally, these plant secondary metabolites may be classified into simple, simple prenylated, simple geranylated, furano, pyrano, sesquiterpenyl and oligomeric coumarins. Using this standard classification, this chapter aims to present an account on the advances of the chemistry of naturally occurring coumarins, as reported in the literature during the period 2013-2015.In Sect. 1, the coumarins are introduced and their generic biosynthetic route discussed briefly. In Sect. 2, the largest of the three sections, various classes of natural coumarins are detailed, with their relevant structures and the citation of appropriate references. In a concluding section, it is highlighted that during the last 3 years, more than 400 coumarins have been reported in the literature. Many of these coumarins have been re-isolations of known compounds from known or new sources, most often associated with various biological activities. However, a substantial number of coumarins bearing new skeletons, especially dimers, prenylated furanocoumarins, sesquiterpenyl, and some unusual coumarins were also reported during the period of 2013-2015.Coumarin chemistry remains one of the major interest areas of phytochemists, especially because of their structural diversity and medicinal properties, along with the wide-ranging bioactivities of these compounds, inclusive of analgesic, anticoagulant anti-HIV, anti-inflammatory, antimicrobial, antineoplastic, antioxidant, and immunomodulatory effects. Despite significant advancements in the extraction, isolation, structure elucidation and bioactivity testing of naturally occurring coumarins, only a marginal advancement has been observed recently in relation to the study of their biosynthesis.

Nature, the most prolific source of biological and chemical diversity, has provided mankind with treatments for health problems since ancient times and continues to be the most promising reservoir of bioactive chemicals for the development of modern drugs. In addition to the terrestrial organisms that still remain a promising source of new bioactive metabolites, the marine environment, covering approximately 70% of the Earth's surface and containing a largely unexplored biodiversity, offers an enormous resource for the discovery of novel compounds. According to the MarinLit database, more than 27,000 metabolites from marine macro- and microorganisms have been isolated to date providing material and key structures for the development of new products in the pharmaceutical, food, cosmeceutical, chemical, and agrochemical sectors. Algae, which thrive in the euphotic zone, were among the first marine organisms that were investigated as sources of food, nutritional supplements, soil fertilizers, and bioactive metabolites.Red algae of the genus Laurencia are accepted unanimously as one of the richest sources of new secondary metabolites. Their cosmopolitan distribution, along with the chemical variation influenced to a significant degree by environmental and genetic factors, have resulted in an endless parade of metabolites, often featuring multiple halogenation sites.The present contribution, covering the literature until August 2015, offers a comprehensive view of the chemical wealth and the taxonomic problems currently impeding chemical and biological investigations of the genus Laurencia. Since mollusks feeding on Laurencia are, in many cases, bioaccumulating, and utilize algal metabolites as chemical weaponry against natural enemies, metabolites of postulated dietary origin of sea hares that feed on Laurencia species are also included in the present review. Altogether, 1047 secondary metabolites, often featuring new carbocyclic skeletons, have been included.The chapter addresses: (1) the "Laurencia complex", the botanical description and the growth and population dynamics of the genus, as well as its chemical diversity and ecological relations; (2) the secondary metabolites, which are organized according to their chemical structures and are classified into sesquiterpenes, diterpenes, triterpenes, acetogenins, indoles, aromatic compounds, steroids, and miscellaneous compounds, as well as their sources of isolation which are depicted in tabulated form, and (3) the biological activity organized according to the biological target and the ecological functions of Laurencia metabolites.

Despite a more recent isolation and chemical characterization when compared to phorbol, along with its chemical instability, limited distribution in Nature, and scarce availability, ingenol is the only Euphorbia diterpenoid that has undergone successful pharmaceutical development, with ingenol 3-angelate (ingenol mebutate, Picato(®)) entering the pharmaceutical market in 2012 for the treatment of actinic keratosis. The phytochemical, chemical, and biological literature on members of the ingenane class of diterpenoids is reviewed from their first isolation in 1968 through 2015, highlighting unresolved issues both common to phorboids (biogenesis, relationship between molecular targets, and in vivo activity) and specific to ingenol derivatives (two-dimensional representation, in-out stereoisomerism, versatility of binding mode to PKC, and inconsistencies in the structural elucidation of some classes of derivatives). The biogenesis of ingenol is discussed in the light of the Jakupovic proposal of a dissection between the formation of the macrocyclic Euphorbia diterpenoids and the phorboids, and the clinical development of ingenol mebutate is chronicled in the light of its "reverse-pharmacology" focus.