Laulimalide and peloruside A are microtubule‐stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X‐ray crystallography it is shown that ...laulimalide and peloruside A bind to a unique non‐taxane site on β‐tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane‐site M‐loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/peloruside A and epothilone A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M‐loop of β‐tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth.
Microtubule‐stabilizing agents: Laulimalide and peloruside A are attractive next‐generation microtubule‐stabilizing agents for use in combination chemotherapy with taxane‐site drugs. X‐ray crystallography shows that both compounds bind to a unique site on β‐tubulin. The data define the mechanism of action of laulimalide and peloruside on tubulin and microtubules.
The islands of the South Pacific Ocean have been in the limelight for natural product biodiscovery, due to their unique and pristine tropical waters and environment. The Kingdom of Tonga is an ...archipelago in the central Indo-Pacific Ocean, consisting of 176 islands, 36 of which are inhabited, flourishing with a rich diversity of flora and fauna. Many unique natural products with interesting bioactivities have been reported from Indo-Pacific marine sponges and other invertebrate phyla; however, there have not been any reviews published to date specifically regarding natural products from Tongan marine organisms. This review covers both known and new/novel Marine Natural Products (MNPs) and their biological activities reported from organisms collected within Tongan territorial waters up to December 2020, and includes 109 MNPs in total, the majority from the phylum Porifera. The significant biological activity of these metabolites was dominated by cytotoxicity and, by reviewing these natural products, it is apparent that the bulk of the new and interesting biologically active compounds were from organisms collected from one particular island, emphasizing the geographic variability in the chemistry between these organisms collected at different locations.
This Article describes research on chemical reactions on molecules attached to the surface of silicon quantum dots that have been performed to produce quantum dots with reactive surface ...functionalities such as diols and epoxides. Characterization of the surface reactions includes NMR and FT-IR studies, and the quantum dots were characterized by transmission electron microscopy (TEM) and energy dispersive spectroscopy (EDS). Cytotoxicity and cell viability assay conducted on silicon dots capped with polar molecules indicated low toxicity with quantum dots with more reactive functionalities found to be more toxic. The silicon quantum dots photoluminesce and have been used as a blue chromophore for the biological imaging of cells.
Covering: 2000 up to 2016
Peloruside A, a macrocyclic secondary metabolite from a New Zealand marine sponge,
Mycale hentscheli
, has shown potent antiproliferative activity in cultured cancer cells ...as well as inhibitory effects on tumor growth in mouse models. The compound also has promising effects against cell models of neurodegenerative and autoimmune diseases. In mechanistic studies, peloruside A shares with paclitaxel (Taxol®) the ability to stabilize microtubules by binding to β-tubulin. Peloruside A, however, occupies a unique external site on β-tubulin that does not overlap the classical taxoid site that is located on the inside of the microtubule. As such, peloruside A has been of central importance in defining a new microtubule-stabilizer binding site localized on the exterior surface of the microtubule that has led to increased interest in the design of an upscaled total synthesis of the natural product and its analogues. Here, we review advances in the biochemical and biological validation of peloruside A as an attractive therapeutic candidate for the treatment of cancer, neurodegeneration, and autoimmune disease.
Peloruside A, a microtubule-stabilizing agent isolated from a marine sponge, is a potential therapeutic candidate for the treatment of cancer, neurodegeneration, and autoimmune disease.
Marine natural products Blunt, John W; Copp, Brent R; Munro, Murray H G ...
Natural product reports,
02/2011, Letnik:
28, Številka:
2
Journal Article
Recenzirano
Covering: 2009. Previous review: Nat. Prod. Rep., 2010, 27, 165 This review covers the literature published in 2009 for marine natural products, with 857 citations (588 for the period January to ...December 2009) referring to compounds isolated from marine microorganisms and phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1011 for 2009), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.
Marine natural products Blunt, John W; Copp, Brent R; Munro, Murray H G ...
Natural product reports,
02/2006, Letnik:
23, Številka:
1
Journal Article
Recenzirano
Odprti dostop
This review covers the literature published in 2004 for marine natural products, with 693 citations (491 for the period January to December 2004) referring to compounds isolated from marine ...microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, coelenterates, bryozoans, molluscs, tunicates and echinoderms. The emphasis is on new compounds (716 for 2004), together with their relevant biological activities, source organisms and country of origin. Biosynthetic studies (8), and syntheses (80), including those that lead to the revision of structures or stereochemistries, have been included.
This review covers the literature published in 2007 for marine natural products, with 948 citations(627 for the period January to December 2007) referring to compounds isolated from marine ...microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, cnidarians,bryozoans, molluscs, tunicates, echinoderms and true mangrove plants. The emphasis is on new compounds (961 for 2007), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.1 Introduction, 2 Reviews, 3 Marine microorganisms and phytoplankton, 4 Green algae, 5 Brown algae, 6 Red algae, 7 Sponges, 8 Cnidarians, 9 Bryozoans, 10 Molluscs, 11 Tunicates (ascidians),12 Echinoderms, 13 Miscellaneous, 14 Conclusion, 15 References.
Marine sponges have been a prolific source of unique bioactive compounds that are presumed to act as a deterrent to predation. Many of these compounds have potential therapeutic applications; ...however, the lack of efficient and sustainable synthetic routes frequently limits clinical development. Here, we describe a metagenomic investigation of
, a chemically gifted marine sponge that possesses multiple distinct chemotypes. We applied shotgun metagenomic sequencing, hybrid assembly of short- and long-read data, and metagenomic binning to obtain a comprehensive picture of the microbiome of five specimens, spanning three chemotypes. Our data revealed multiple producing species, each having relatively modest secondary metabolomes, that contribute collectively to the chemical arsenal of the holobiont. We assembled complete genomes for multiple new genera, including two species that produce the cytotoxic polyketides pateamine and mycalamide, as well as a third high-abundance symbiont harboring a proteusin-type biosynthetic pathway that appears to encode a new polytheonamide-like compound. We also identified an additional 188 biosynthetic gene clusters, including a pathway for biosynthesis of peloruside. These results suggest that multiple species cooperatively contribute to defensive symbiosis in
and reveal that the taxonomic diversity of secondary-metabolite-producing sponge symbionts is larger and richer than previously recognized.
is a marine sponge that is rich in bioactive small molecules. Here, we use direct metagenomic sequencing to elucidate highly complete and contiguous genomes for the major symbiotic bacteria of this sponge. We identify complete biosynthetic pathways for the three potent cytotoxic polyketides which have previously been isolated from
Remarkably, and in contrast to previous studies of marine sponges, we attribute each of these metabolites to a different producing microbe. We also find that the microbiome of
is stably maintained among individuals, even over long periods of time. Collectively, our data suggest a cooperative mode of defensive symbiosis in which multiple symbiotic bacterial species cooperatively contribute to the defensive chemical arsenal of the holobiont.
Marine natural products Blunt, John W; Copp, Brent R; Munro, Murray H G ...
Natural product reports,
01/2010, Letnik:
27, Številka:
2
Journal Article
Recenzirano
This review covers the literature published in 2008 for marine natural products, with 829 citations (613 for the period January to December 2008) referring to compounds isolated from marine ...microorganisms and phytoplankton, green algae, brown algae, red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms, mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1065 for 2008), together with the relevant biological activities, source organisms and country of origin. Biosynthetic studies, first syntheses, and syntheses that lead to the revision of structures or stereochemistries, have been included.
Marine natural products as secondary metabolites are a potential major source of new drugs for treating disease. In some cases, cytotoxic marine metabolites target the microtubules of the eukaryote ...cytoskeleton for reasons that will be discussed. This review covers the microtubule-targeting agents reported from sponges, corals, tunicates, and molluscs and the evidence that many of these secondary metabolites are produced by bacterial symbionts. The review finishes by discussing the directions for future development and production of clinically relevant amounts of these natural products and their analogues through aquaculture, chemical synthesis, and biosynthesis by bacterial symbionts.
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