Divergent synthesis of complex diterpenes through a hybrid oxidative approach

Polycyclic diterpenes exhibit many important biological activities, but de novo synthetic access to these molecules is highly challenging because of their structural complexity. Semisynthetic access has also been limited by the lack of chemical tools for scaffold modifications. We report a chemoenzymatic platform to access highly oxidized diterpenes by a hybrid oxidative approach that strategically combines chemical and enzymatic oxidation methods. This approach allows for selective oxidations of previously inaccessible sites on the parent carbocycles and enables abiotic skeletal rearrangements to additional underlying architectures. We synthesized a total of nine complex natural products with rich oxygenation patterns and skeletal diversity in 10 steps or less from ent-steviol.

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Palladium-Catalyzed Coupling Reactions on Functionalized 2-Trifluoromethyl-4-chromenone Scaffolds: Synthesis of Highly Functionalized Trifluoromethyl Heterocycles

Synthesis ◽

10.1055/s-0037-1610669 ◽

2018 ◽

Vol 51 (06) ◽

pp. 1342-1352 ◽

Cited By ~ 5

Author(s):

Javier Izquierdo ◽

Atul Jain ◽

Sarki Abdulkadir ◽

Gary Schiltz

Keyword(s):

Natural Products ◽

Organic Synthesis ◽

Biological Activities ◽

Structural Complexity ◽

Biologically Active ◽

Coupling Reactions ◽

Trifluoromethyl Group ◽

Palladium Catalyzed ◽

Active Natural

The chromenone core is an ubiquitous group in biologically active natural products and has been extensively used in organic synthesis. Fluorine-derived compounds, including those with a trifluoromethyl group (CF3), have shown enhanced biological activities in numerous pharmaceuticals compared with their non-fluorinated analogues. 2-Trifluoromethylchromenones can be readily functionalized at the 8- and 7-positions, providing chromenones cores of high structural complexity, which are excellent precursors for numerous trifluoromethyl heterocycles.

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Synthetic Approaches to Tetracyclic Pyrrole Imidazole Marine Alkaloids

Natural Product Communications ◽

10.1177/1934578x1300800722 ◽

2013 ◽

Vol 8 (7) ◽

pp. 1934578X1300800 ◽

Cited By ~ 1

Author(s):

Takuya Imaoka ◽

Makoto Iwata ◽

Takafumi Akimoto ◽

Kazuo Nagasawa

Keyword(s):

Natural Products ◽

Total Synthesis ◽

Anticancer Activity ◽

Biological Activities ◽

Structural Complexity ◽

Marine Alkaloids ◽

Ring Systems ◽

Agonistic Activity ◽

Synthetic Approaches

Oroidin derived pyrrole imidazole marine alkaloids (PIAs) are attractive targets for synthetic organic chemists because of their structural complexity and diversity as well as their interesting biological activities. A number of efforts have been carried out to develop strategies for the synthesis of these natural products. Members of PIAs ( eg., 2-7) which contain tetracyclic ring systems possessing characteristic cyclic guanidine or urea moieties show significant biological activities including anticancer activity and agonistic activity against the adrenoceptor. In this review investigations of the total synthesis of the representative tetracyclic PIAs dibromophakellin (2) and dibromophakellstatin (3) are described.

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Making drugs out of sunlight and ‘thin air’: an emerging synergy of synthetic biology and natural product chemistry

The Biochemist ◽

10.1042/bio20200044 ◽

2020 ◽

Vol 42 (4) ◽

pp. 34-39

Author(s):

Michael J. Stephenson ◽

Anne Osbourn

Keyword(s):

Natural Products ◽

Synthetic Biology ◽

Natural Product ◽

Large Scale ◽

Production Systems ◽

Biological Activities ◽

Structural Complexity ◽

Scale Production ◽

Natural Product Chemistry ◽

Product Chemistry

Nature has long served as a rich source of structurally diverse small organic molecules with medicinally relevant biological activities. Despite the historical success of these so-called natural products, the enthusiasm of big pharma to explore these compounds as leads in drug design has waxed and waned. A major contributor to this is their often inherent structural complexity. Such compounds are difficult (often impossible) to access synthetically, a hurdle that can stifle lead development and hinder sustainable large-scale production of promising leads for clinical evaluation. However, in recent years, an emerging synergy between synthetic biology and natural product chemistry offers the potential for a renaissance in our ability to access natural products for drug discovery and development. Advances in genome sequencing, bioinformatics and the maturing of heterologous expression platforms are increasing, enabling the study, and ultimately, the manipulation of plant biosynthetic pathways. The triterpenes are one of the most structurally diverse families of natural products and arguably one of the most underrepresented in the clinic. The plant kingdom is the richest source of triterpene diversity, with >20,000 triterpenes reported so far. Transient expression of genes for candidate enzymes and pathways in amenable plant species is emerging as a powerful and rapid means of investigating and harnessing the plant enzymes involved in generating this diversity. Such platforms also have the potential to serve as production systems in their own right, with the possibility of upscaling these discoveries into commercially useful products using the same overall basic procedure. Ultimately, the carbon source for generation of high-value compounds in plants is photosynthesis. Therefore, we could, with the help of plants, be producing new medicines out of sunlight and ‘thin air’ in green factories in the not too distant future.

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De novo biosynthesis of bioactive isoflavonoids by engineered yeast cell factories

Nature Communications ◽

10.1038/s41467-021-26361-1 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Quanli Liu ◽

Yi Liu ◽

Gang Li ◽

Otto Savolainen ◽

Yun Chen ◽

...

Keyword(s):

Natural Products ◽

Yeast Cell ◽

De Novo ◽

Structural Complexity ◽

Value Added ◽

Fine Tuning ◽

Attractive Alternative ◽

Efficient Production ◽

De Novo Biosynthesis ◽

Cell Factories

AbstractIsoflavonoids comprise a class of plant natural products with great nutraceutical, pharmaceutical and agricultural significance. Their low abundance in nature and structural complexity however hampers access to these phytochemicals through traditional crop-based manufacturing or chemical synthesis. Microbial bioproduction therefore represents an attractive alternative. Here, we engineer the metabolism of Saccharomyces cerevisiae to become a platform for efficient production of daidzein, a core chemical scaffold for isoflavonoid biosynthesis, and demonstrate its application towards producing bioactive glucosides from glucose, following the screening-reconstruction-application engineering framework. First, we rebuild daidzein biosynthesis in yeast and its production is then improved by 94-fold through screening biosynthetic enzymes, identifying rate-limiting steps, implementing dynamic control, engineering substrate trafficking and fine-tuning competing metabolic processes. The optimized strain produces up to 85.4 mg L−1 of daidzein and introducing plant glycosyltransferases in this strain results in production of bioactive puerarin (72.8 mg L−1) and daidzin (73.2 mg L−1). Our work provides a promising step towards developing synthetic yeast cell factories for de novo biosynthesis of value-added isoflavonoids and the multi-phased framework may be extended to engineer pathways of complex natural products in other microbial hosts.

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Pyrone-derived Marine Natural Products: A Review on Isolation, Bio-activities and Synthesis

Current Organic Chemistry ◽

10.2174/1385272824666200217101400 ◽

2020 ◽

Vol 24 (4) ◽

pp. 354-401 ◽

Cited By ~ 2

Author(s):

Keisham S. Singh

Keyword(s):

Natural Products ◽

Marine Natural Products ◽

Marine Fungi ◽

Kojic Acid ◽

Biological Activities ◽

Biological Significance ◽

Pyrone Ring ◽

Enol Ethers ◽

Bioactive Natural Products ◽

Marine Metabolites

Marine natural products (MNPs) containing pyrone rings have been isolated from numerous marine organisms, and also produced by marine fungi and bacteria, particularly, actinomycetes. They constitute a versatile structure unit of bioactive natural products that exhibit various biological activities such as antibiotic, antifungal, cytotoxic, neurotoxic, phytotoxic and anti-tyrosinase. The two structure isomers of pyrone ring are γ- pyrone and α-pyrone. In terms of chemical motif, γ-pyrone is the vinologous form of α- pyrone which possesses a lactone ring. Actinomycete bacteria are responsible for the production of several α-pyrone compounds such as elijopyrones A-D, salinipyrones and violapyrones etc. to name a few. A class of pyrone metabolites, polypropionates which have fascinating carbon skeleton, is primarily produced by marine molluscs. Interestingly, some of the pyrone polytketides which are found in cone snails are actually synthesized by actinomycete bacteria. Several pyrone derivatives have been obtained from marine fungi such as Aspergillums flavus, Altenaria sp., etc. The γ-pyrone derivative namely, kojic acid obtained from Aspergillus fungus has high commercial demand and finds various applications. Kojic acid and its derivative displayed inhibition of tyrosinase activity and, it is also extensively used as a ligand in coordination chemistry. Owing to their commercial and biological significance, the synthesis of pyrone containing compounds has been given attention over the past years. Few reviews on the total synthesis of pyrone containing natural products namely, polypropionate metabolites have been reported. However, these reviews skipped other marine pyrone metabolites and also omitted discussion on isolation and detailed biological activities. This review presents a brief account of the isolation of marine metabolites containing a pyrone ring and their reported bio-activities. Further, the review covers the synthesis of marine pyrone metabolites such as cyercene-A, placidenes, onchitriol-I, onchitriol-II, crispatene, photodeoxytrichidione, (-) membrenone-C, lihualide-B, macrocyclic enol ethers and auripyrones-A & B.

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Preparation, spectral properties and biological activities of 5-bromo-6-methyl-2'-deoxyuridine and 5-iodo-6-methyl-2'-deoxyuridine

Collection of Czechoslovak Chemical Communications ◽

10.1135/cccc19802364 ◽

1980 ◽

Vol 45 (8) ◽

pp. 2364-2370 ◽

Cited By ~ 3

Author(s):

Antonín Holý ◽

Erik De Clercq

Keyword(s):

Antiviral Activity ◽

Spectral Properties ◽

De Novo ◽

Biological Activities ◽

Rabbit Kidney ◽

Kidney Cells ◽

Cd Spectra ◽

Methyl Derivatives ◽

Primary Rabbit

Reaction of 3',5'-di-O-benzoyl-6-methyl-2'-deoxyuridine (IIa) with elementary bromine or iodine afforded 5-halogeno derivatives IIc and IId which on methanolysis gave 5-bromo-6-methyl-2'-deoxyurine (Ic) and 5-iodo-6-methyl-2'-deoxyurine (Id), respectively. The CD spectra of Ic, Id and 6-methyl-2'-deoxyuridine (Ia) are compared and discussed with regard to determination of the nucleoside conformation. Unlike 5-bromo- and 5-iodo-2'-deoxyuridine, the 6-methyl derivatives Ic and Id exhibit neither antibacterial nor antiviral activity. Nor do they exert any antimetabolic effect on the de novo DNA synthesis in primary rabbit kidney cells.

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Platelet-activating factor and the kidney

AJP Renal Physiology ◽

10.1152/ajprenal.1986.251.1.f1 ◽

1986 ◽

Vol 251 (1) ◽

pp. F1-F11 ◽

Cited By ~ 8

Author(s):

D. Schlondorff ◽

R. Neuwirth

Keyword(s):

De Novo ◽

Mesangial Cells ◽

Biological Activities ◽

Platelet Activating Factor ◽

Calcium Ionophore ◽

Initial Step ◽

Renal Physiology ◽

Dependent Manner ◽

Glomerular Mesangial Cells ◽

Isolated Kidney

Platelet-activating factor (PAF) represents a group of phospholipids with the basic structure of 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine. A number of different cells are capable of producing PAF in response to various stimuli. The initial step of PAF formation is activation of phospholipase A2 in a calcium-dependent manner, yielding lyso-PAF. During this step arachidonic acid is also released and can be converted to its respective cyclooxygenase and lipoxygenase products. The lyso-PAF generated is then acetylated in position 2 of the glycerol backbone by a coenzyme A (CoA)-dependent acetyltransferase. An additional pathway may exist whereby PAF is generated de novo from 1-alkyl-2-acetyl-sn-glycerol by phosphocholine transferase. PAF inactivation in cells and blood is by specific acetylhydrolases. PAF exhibits a variety of biological activities including platelet and leukocyte aggregation and activation, increased vascular permeability, respiratory distress, decreased cardiac output, and hypotension. In the kidney PAF can produce decreases in blood flow, glomerular filtration, and fluid and electrolyte excretion. Intrarenal artery injection of PAF may also result in glomerular accumulation of platelets and leukocytes and mild proteinuria. PAF increases prostaglandin formation in the isolated kidney and in cultured glomerular mesangial cells. PAF also causes contraction of mesangial cells. Upon stimulation with calcium ionophore the isolated kidney, isolated glomeruli and medullary cells, and cultured mesangial cells are capable of producing PAF. The potential role for PAF in renal physiology and pathophysiology requires further investigation that may be complicated by 1) the multiple interactions of PAF, prostaglandins, and leukotrienes and 2) the autocoid nature of PAF, which may restrict its action to its site of generation.

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Partitioning Pattern of Natural Products Based on Molecular Properties Descriptors Representing Drug-Likeness

Symmetry ◽

10.3390/sym13040546 ◽

2021 ◽

Vol 13 (4) ◽

pp. 546

Author(s):

Miroslava Nedyalkova ◽

Vasil Simeonov

Keyword(s):

Natural Products ◽

Drug Discovery ◽

De Novo ◽

Target Prediction ◽

Natural Compounds ◽

Discovery Process ◽

Drug Discovery Process ◽

Unique Source ◽

The Times ◽

Partitioning Pattern

A cheminformatics procedure for a partitioning model based on 135 natural compounds including Flavonoids, Saponins, Alkaloids, Terpenes and Triterpenes with drug-like features based on a descriptors pool was developed. The knowledge about the applicability of natural products as a unique source for the development of new candidates towards deadly infectious disease is a contemporary challenge for drug discovery. We propose a partitioning scheme for unveiling drug-likeness candidates with properties that are important for a prompt and efficient drug discovery process. In the present study, the vantage point is about the matching of descriptors to build the partitioning model applied to natural compounds with diversity in structures and complexity of action towards the severe diseases, as the actual SARS-CoV-2 virus. In the times of the de novo design techniques, such tools based on a chemometric and symmetrical effect by the implied descriptors represent another noticeable sign for the power and level of the descriptors applicability in drug discovery in establishing activity and target prediction pipeline for unknown drugs properties.

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Natural products isolated from Casimiroa

Open Chemistry ◽

10.1515/chem-2020-0128 ◽

2020 ◽

Vol 18 (1) ◽

pp. 778-797

Author(s):

Khun Nay Win Tun ◽

Nanik Siti Aminah ◽

Alfinda Novi Kristanti ◽

Hnin Thanda Aung ◽

Yoshiaki Takaya

Keyword(s):

Natural Products ◽

Spectral Data ◽

Aromatic Compounds ◽

Biological Activities ◽

Chemical Constituents ◽

Quinoline Alkaloids

AbstractAbout 140 genera and more than 1,600 species belong to the Rutaceae family. They grow in temperate and tropical zones on both hemispheres, as trees, shrubs, and herbs. Casimiroa is one of the genera constituting 13 species, most of which are found in tropical and subtropical regions. Many chemical constituents have been derived from this genus, including quinoline alkaloids, flavonoids, coumarins, and N-benzoyltyramide derivatives. This article reviews different studies carried out on aromatic compounds of genus Casimiroa; their biological activities; the different skeletons of coumarins, alkaloids, flavonoids, and others; and their characteristic NMR spectral data.

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Natural Products from Tongan Marine Organisms

Molecules ◽

10.3390/molecules26154534 ◽

2021 ◽

Vol 26 (15) ◽

pp. 4534

Author(s):

Taitusi Taufa ◽

Ramesh Subramani ◽

Peter Northcote ◽

Robert Keyzers

Keyword(s):

Natural Products ◽

Pacific Ocean ◽

Biological Activities ◽

Marine Sponges ◽

Marine Organisms ◽

Biologically Active ◽

Geographic Variability ◽

South Pacific Ocean ◽

New Novel ◽

Rich Diversity

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.

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