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Marine Drugs Mar 2021Novel drug leads for malaria therapy are urgently needed because of the widespread emergence of resistance to all available drugs. Screening of the Harbor Branch...
Novel drug leads for malaria therapy are urgently needed because of the widespread emergence of resistance to all available drugs. Screening of the Harbor Branch enriched fraction library against the chloroquine-resistant strain (Dd2) followed by bioassay-guided fractionation led to the identification of two potent antiplasmodials; a novel diterpene designated as bebrycin A () and the known C21 degraded terpene nitenin (). A SYBR Green I assay was used to establish a Dd2 EC of 1.08 ± 0.21 and 0.29 ± 0.02 µM for bebrycin A and nitenin, respectively. Further analysis was then performed to assess the stage specificity of the inhibitors antiplasmodial effects on the Dd2 intraerythrocytic life cycle. Exposure to bebrycin A was found to block parasite maturation at the schizont stage if added any time prior to late schizogony at 42 hours post invasion, (HPI). In contrast, early life cycle exposure to nitenin (prior to 18 HPI) was identified as crucial to parasite inhibition, suggesting nitenin may target the maturation of the parasite during the transition from ring to early trophozoite (6-18 HPI), a novel property among known antimalarials.
Topics: Animals; Anthozoa; Antimalarials; Diterpenes; Hep G2 Cells; Humans; Life Cycle Stages; Malaria, Falciparum; Molecular Structure; Plasmodium falciparum; Porifera; Structure-Activity Relationship; Time Factors
PubMed: 33805935
DOI: 10.3390/md19040179 -
Accounts of Chemical Research Jan 2021Three-dimensional cage-like natural products represent astounding and long-term challenges in the research endeavors of total synthesis. A central issue that synthetic...
Three-dimensional cage-like natural products represent astounding and long-term challenges in the research endeavors of total synthesis. A central issue that synthetic chemists need to address lies in how to efficiently construct the polycyclic frameworks as well as to install the requisite substituent groups. The diterpenoid alkaloids that biogenetically originate from amination of diterpenes and diversify through late-stage skeletal reorganization belong to such a natural product category. As the characteristic components of the and species, these molecules display a rich array of biological activities, some of which are used as clinical drugs. More strikingly, their intricate and beautiful architectures have rendered the diterpenoid alkaloids elusive targets in the synthetic community. The successful preparation of these intriguing compounds relies on the development of innovative synthetic strategies.Our laboratory has explored the total synthesis of a variety of diterpenoid alkaloids and their biogenetically related diterpenes over the past decade. In doing so, we have accessed 6 different types of skeletons (atisine-, denudatine-, arcutane-, arcutine-, napelline-, and hetidine-type) and achieved the total synthesis of 6 natural products (isoazitine, dihydroajaconine, gymnandine, atropurpuran, arcutinine, and liangshanone). Strategically, an oxidative dearomatization/Diels-Alder (OD/DA) cycloaddition sequence was widely employed in our synthesis to form the ubiquitous [2.2.2]-bicyclic ring unit and its related ring-distorted derivatives in these complex target molecules. This protocol, in combination with additional bond-forming key steps, allowed us to prepare the corresponding polycyclic alkaloids and a biogenetically associated diterpene. For example, bioinspired C-H activation, -pinacol, and -Prins cyclizations were used toward a unified approach to the atisine-, denudatine-, and hetidine-type alkaloids via ajaconine intermediates in our first work. To pursue the synthesis of atropurpuran and related arcutine alkaloids, we harnessed a ketyl-olefin radical cyclization to assemble the carbocycle and an -Wacker cyclization to construct the unusual pyrrolidine ring. Furthermore, a one-pot alkene cleavage/Mannich cyclization tactic, sequential Robinson annulation, and intramolecular aldol addition were developed, which facilitated the formation of the napelline alkaloid scaffold and the first total synthesis of liangshanone. Finally, the utility of the Mannich cyclization and enyne cycloisomerization reactions allowed for access to the highly functionalized A/E and C/D ring fragments of aconitine (regarded as the "Holy Grail" of diterpenoid alkaloids). This Account provides insight into our synthetic designs and approaches used toward the synthesis of diterpenoid alkaloids and relevant diterpenes. These endeavors lay a foundation for uncovering the biological profiles of associated molecules and also serve as a reference for preparing other three-dimensionally fascinating natural products.
Topics: Alkaloids; Biological Products; Bridged Bicyclo Compounds; Cyclization; Cycloaddition Reaction; Diterpenes; Molecular Conformation; Oxidation-Reduction; Stereoisomerism
PubMed: 33351595
DOI: 10.1021/acs.accounts.0c00720 -
Medicinal Research Reviews Nov 2021Diterpenoids, including more than 18,000 compounds, represent an important class of metabolites that encompass both phytohormones and some industrially relevant... (Review)
Review
Diterpenoids, including more than 18,000 compounds, represent an important class of metabolites that encompass both phytohormones and some industrially relevant compounds. These molecules with complex, diverse structures and physiological activities, have high value in the pharmaceutical industry. Most medicinal diterpenoids are extracted from plants. Major advances in understanding the biosynthetic pathways of these active compounds are providing unprecedented opportunities for the industrial production of diterpenoids by metabolic engineering and synthetic biology. Here, we summarize recent developments in the field of diterpenoid biosynthesis from medicinal herbs. An overview of the pathways and known biosynthetic enzymes is presented. In particular, we look at the main findings from the past decade and review recent progress in the biosynthesis of different groups of ringed compounds. We also discuss diterpenoid production using synthetic biology and metabolic engineering strategies, and draw on new technologies and discoveries to bring together many components into a useful framework for diterpenoid production.
Topics: Biosynthetic Pathways; Diterpenes; Humans; Plants, Medicinal; Synthetic Biology
PubMed: 33938025
DOI: 10.1002/med.21816 -
Zhongguo Zhong Yao Za Zhi = Zhongguo... Dec 2021Five compounds were isolated from the alcohol extract of Olibanum by MCI, silica gel, ODS, and Sephadex LH-20 column chromatographies and preparative high-performance...
Five compounds were isolated from the alcohol extract of Olibanum by MCI, silica gel, ODS, and Sephadex LH-20 column chromatographies and preparative high-performance liquid chromatography(HPLC). On the basis of spectral data and literature data, the compounds were identified as:(1S,3R,4S,7R,11S,12R)-1:12,4:7-diepoxisonane-8(19)-ene-3,11-diol(1), boscartin A(2),(+)-resinolin(3),(+)-5-hydroxy-3,4-dimethyl-5-pentylfuran-2(5H)-one(4), and acerogenin A(5). Compound 1 is a new compound, and compounds 3-5 were isolated from Olibanum for the first time. The structure of compound 1 was determined by spectroscopic analysis and single-crystal X-ray diffraction. Compounds 1 and 2 were tested for PC12 neurotoxicity, and the results showed that they were both safe compounds.
Topics: Chromatography, High Pressure Liquid; Diterpenes; Frankincense; Molecular Structure
PubMed: 34994134
DOI: 10.19540/j.cnki.cjcmm.20210702.203 -
Structural diversity, biosynthesis, and health-promoting properties of brown algal meroditerpenoids.Critical Reviews in Biotechnology Dec 2022Marine algae that constitute hundreds of millions of tons of biomass are the oldest representatives of the plant kingdom. Recently, there has been growing interest in... (Review)
Review
Marine algae that constitute hundreds of millions of tons of biomass are the oldest representatives of the plant kingdom. Recently, there has been growing interest in the utilization of algae as sustainable feedstocks for natural products with an economic value. Among these natural products are the meroditerpenoids, which are renowned for their protective effects against oxidative stress, inflammation, cancer, obesity, diabetes, and neurodegenerative disorders. Meroditerpenoids have a mixed biosynthetic origin and display a wide range of structural diversity. Their basic structure consists of a ring system bearing a diterpenoid side chain. Structural variations are observed in terms of the functional groups and saturation/cyclization of the diterpenoid side chain. This review classifies algal meroditerpenoids as plastoquinones, chromanols, chromenes, chromones, cyclic meroditerpenoids, nahocols, and isonahocols and examines their potential applications in functional foods and biopharmacology. Their lipid solubility, low molecular weight, and propensity to cross the blood-brain barrier places meroditerpenoids as potential drug candidates. There is growing interest in the study of algal meroterpenoids, and recent research has reported the structure of several new meroterpenoids and their biological activities. Further research is needed to extend the use of algal meroditerpenoids in preclinical trials. Understanding the mechanism of their biosynthesis will allow the development of biosynthesis and biomimetic synthesis strategies for the industrial-scale production of meroditerpenoids and their synthetic derivatives to aid pharmaceutical research. This review is the first to summarize up-to-date information on all brown algae-derived meroditerpenoids.
Topics: Phaeophyceae; Diterpenes; Biomass; Biological Products
PubMed: 34875939
DOI: 10.1080/07388551.2021.2001639 -
European Journal of Drug Metabolism and... Jan 2022Diterpene lactones have been identified as active compounds in several medicinal plants, including Andrographis paniculata (Burm. f.) Nees, which is a medicinal plant... (Review)
Review
Diterpene lactones have been identified as active compounds in several medicinal plants, including Andrographis paniculata (Burm. f.) Nees, which is a medicinal plant that has been used for centuries across the world. Andrographolide is the major diterpene from A. paniculata and the main bioactive constituent of this species. The effectiveness of diterpenes can be affected by factors that limit their oral bioavailability, such as their poor water solubility, slow dissolution rates, low gastrointestinal absorption, high chemical and metabolic instability, and rapid excretion. In this context, the purpose of the present review is to compile and compare literature data on the bioavailability of diterpene lactones from A. paniculata after oral administration in medicinal plant extracts or in their free forms and to highlight strategies that have been used to improve their oral bioavailability. Considering that medicinal plant extracts are commonly used as dried powder that is reconstituted in water before oral administration, novel pharmaceutical formulation strategies that are used to overcome difficulties with diterpene solubility are also compiled in this review. The use of self-microemulsifying drug delivery systems is a good strategy to enhance the dissolution and consequently the bioavailability of andrographolide after oral administration of A. paniculata extract formulations. On the other hand, herbosome technology, pH-sensitive nanoparticles, nanosuspensions, nanoemulsions, nanocrystal suspensions, nanocrystal-based solid dispersions, and solid dispersion systems are useful to formulate andrographolide in its free form and increase its oral bioavailability. The use of a suitable andrographolide delivery system is essential to achieve its therapeutic potential.
Topics: Administration, Oral; Andrographis paniculata; Biological Availability; Diterpenes; Drug Compounding; Humans; Lactones; Phytotherapy; Plant Extracts; Plants, Medicinal
PubMed: 34816382
DOI: 10.1007/s13318-021-00736-7 -
Journal of Natural Products Jul 2022The labdane diterpene hedychenone, isolated from , is an example of a furan-containing natural product. Herein, a new and efficient method for the synthesis of 19 new... (Review)
Review
The labdane diterpene hedychenone, isolated from , is an example of a furan-containing natural product. Herein, a new and efficient method for the synthesis of 19 new thio analogues of hedychenone is reported. The present methodology exhibits a broad substrate scope with good to excellent yields without metal or base under mild reaction conditions. The natural compound and four semisynthetic derivatives (, , , and ) exhibited strong α-glucosidase inhibition activity with IC values of 15.93 ± 0.29, 9.70 ± 0.33, 11.82 ± 0.06, 12.23 ± 0.33, and 12.15 ± 0.14 μg/mL, respectively. In addition, compound (6.0 ± 0.04 mm; zone of inhibition) displayed antibacterial activity against . This study increases the chemical diversity of bioactive hedychenone derivatives and provides a direction for the development of antidiabetic agents.
Topics: Diterpenes; Hypoglycemic Agents; Molecular Structure; Sulfur; Zingiberaceae
PubMed: 35790346
DOI: 10.1021/acs.jnatprod.2c00112 -
Pathology, Research and Practice Jun 2020The anticancer properties of several labdane diterpenes have been well characterized, notably for andrographolide and sclareol. In contrast, the structurally related... (Review)
Review
The anticancer properties of several labdane diterpenes have been well characterized, notably for andrographolide and sclareol. In contrast, the structurally related natural product coronarin D (CRD), principally isolated from the ginger Hedychium coronarium, is much less known. Recently, different studies have underlined the anticancer activities of CRD and in particular its capacity to inhibit the growth and to induce the death of glioblastoma and carcinoma cell lines in vitro. The present review provides a global view of the activities and mechanism of action of CRD and the analogy with the other anticancer labdane diterpenes. CRD exerts its antiproliferative action via an activation of the MAPK pathway, notably by a stimulation of ERK/JNK phosphorylation, which subsequently leads to drug-induced inhibition of cell proliferation and activation of the intrinsic apoptotic pathway. Reactive oxygen species also play a role in the bioactivity of drug, but no well-defined molecular target has been characterized yet. CRD presents an interesting activity profile in vitro and warrants in vivo evaluations, notably for the treatment of glioblastoma.
Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Diterpenes; Humans; MAP Kinase Signaling System
PubMed: 32334892
DOI: 10.1016/j.prp.2020.152946 -
The Journal of Physical Chemistry. B Feb 2023Plants synthesize small molecule diterpenes composed of 20 carbons from precursor isopentenyl diphosphate and dimethylallyl disphosphate, manufacturing diverse compounds...
Plants synthesize small molecule diterpenes composed of 20 carbons from precursor isopentenyl diphosphate and dimethylallyl disphosphate, manufacturing diverse compounds used for defense, signaling, and other functions. Industrially, diterpenes are used as natural aromas and flavoring, as pharmaceuticals, and as natural insecticides or repellents. Despite diterpene ubiquity in plant systems, it remains unknown how plants control diterpene localization and transport. For many other small molecules, plant cells maintain transport proteins that control compound compartmentalization. However, for most diterpene compounds, specific transport proteins have not been identified, and so it has been hypothesized that diterpenes may cross biological membranes passively. Through molecular simulation, we study membrane transport for three complex diterpenes from among the many made by members of the family to determine their permeability coefficient across plasma membrane models. To facilitate accurate simulation, the intermolecular interactions for leubethanol, abietic acid, and sclareol were parametrized through the standard CHARMM methodology for incorporation into molecular simulations. To evaluate the effect of membrane composition on permeability, we simulate the three diterpenes in two membrane models derived from sorghum and yeast lipidomics data. We track permeation events within our unbiased simulations, and compare implied permeation coefficients with those calculated from Replica Exchange Umbrella Sampling calculations using the inhomogeneous solubility diffusion model. The diterpenes are observed to permeate freely through these membranes, indicating that a transport protein may not be needed to export these small molecules from plant cells. Moreover, the permeability is observed to be greater for plant-like membrane compositions when compared against animal-like membrane models. Increased permeability for diterpene molecules in plant membranes suggest that plants have tailored their membranes to facilitate low-energy transport processes for signaling molecules.
Topics: Terpenes; Plants; Cell Membrane; Diterpenes; Carrier Proteins; Permeability
PubMed: 36717085
DOI: 10.1021/acs.jpcb.2c07209 -
The Journal of Organic Chemistry Aug 2020Atropurpuran, isolated from the roots of , is a non-alkaloidal diterpene which possesses a unique pentacyclic skeleton that contains an unprecedented...
Atropurpuran, isolated from the roots of , is a non-alkaloidal diterpene which possesses a unique pentacyclic skeleton that contains an unprecedented tetracyclo[5.3.3.0.0]tridecane unit. We report herein the formal total synthesis of atropurpuran. The key features of our synthetic route are a high diastereoselective construction of the tri- and tetrasubstituted carbons (i.e., C4, C5, C10, and C20) through an Yb-catalyzed Mukaiyama aldol reaction in an aqueous medium and a one-pot operation including an intramolecular Diels-Alder reaction/ring-closing metathesis to construct the unique pentacyclic skeleton of atropurpuran.
Topics: Cycloaddition Reaction; Diterpenes; Stereoisomerism
PubMed: 32668903
DOI: 10.1021/acs.joc.0c01462