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Marine Drugs ◽  
2022 ◽  
Vol 20 (1) ◽  
pp. 65
Author(s):  
Marcello Casertano ◽  
Massimo Genovese ◽  
Paolo Paoli ◽  
Alice Santi ◽  
Anna Aiello ◽  
...  

The chemical investigation of the Mediterranean ascidian Clavelina lepadiformis has led to the isolation of a new lepadin, named lepadin L, and two known metabolites belonging to the same family, lepadins A and B. The planar structure and relative configuration of the decahydroquinoline ring of lepadin L were established both by means of HR-ESIMS and by a detailed as extensive analysis of 1D and 2D NMR spectra. Moreover, microscale derivatization of the new alkaloid lepadin L was performed to assess the relative configuration of the functionalized alkyl side chain. Lepadins A, B, and L were tested for their cytotoxic activity on a panel of cancer cell lines (human melanoma [A375], human breast [MDA-MB-468], human colon adenocarcinoma [HT29], human colorectal carcinoma [HCT116], and mouse myoblast [C2C12]). Interestingly, a deeper investigation into the mechanism of action of the most cytotoxic metabolite, lepadin A, on the A375 cells has highlighted its ability to induce a strongly inhibition of cell migration, G2/M phase cell cycle arrest and a dose-dependent decrease of cell clonogenity, suggesting that it is able to impair self-renewing capacity of A375 cells.


2022 ◽  
Vol 12 ◽  
Author(s):  
Ke Ye ◽  
Xiao Lv ◽  
Xian Zhang ◽  
Pan-Pan Wei ◽  
Zheng-Hui Li ◽  
...  

Five new isopimarane diterpenes, robustaditerpene A-E (1–5), which include 19-nor-isopimarane skeleton and isopimarane skeleton, were isolated from the liquid fermentation of the endophytic fungus Ilyonectria robusta collected from Bletilla striata. The structure elucidation and relative configuration assignments of all compounds were accomplished by interpretation of NMR and HRESIMS spectrometric analyses and 13C NMR calculation. And the absolute configuration of 1-5 were identified by single-crystal X-ray diffraction and ECD calculation. Compound 3 inhibited lipopolysaccharide-induced B lymphocytes cell proliferation with an IC50 value at 17.42 ± 1.57 μM while compound 5 inhibited concanavalin A-induced T lymphocytes cell proliferation with an IC50 value at 75.22 ± 6.10 μM. These data suggested that compounds 3 and 5 may possess potential immunosuppressive prospect.


Pharmaceutics ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2088
Author(s):  
Andrea Vasas ◽  
Ildikó Lajter ◽  
Norbert Kúsz ◽  
Sándor Balázs Király ◽  
Tibor Kovács ◽  
...  

Seven new germacranolides (1–3, 5–8), among them a heterodimer (7), and known germacranolide (4), eudesmane (9) and isodaucane (10) sesquiterpenes were isolated from the aerial parts of Neurolaena lobata. Their structures were determined by using a combination of different spectroscopic methods, including HR-ESIMS and 1D and 2D NMR techniques supported by DFT-NMR calculations. The enantiomeric purity of the new compounds was investigated by chiral HPLC analysis, while their absolute configurations were determined by TDDFT-ECD and OR calculations. Due to the conformationally flexible macrocycles and difficulties in assigning the relative configuration, 13C and 1H NMR chemical shift and ECD and OR calculations were performed on several stereoisomers of two derivatives. The isolated compounds (1–10) were shown to have noteworthy antiproliferative activities against three human cervical tumor cell line with different HPV status (HeLa, SiHa and C33A). Additionally, lobatolide C (6) exhibited substantial antiproliferative properties, antimigratory effect, and it induced cell cycle disturbance in SiHa cells.


Marine Drugs ◽  
2021 ◽  
Vol 19 (12) ◽  
pp. 680
Author(s):  
Louise C. Forster ◽  
Jack K. Clegg ◽  
Karen L. Cheney ◽  
Mary J. Garson

Extracts of the mantle and viscera of the Indo-Pacific nudibranchs Goniobranchus aureopurpureus and Goniobranchus sp. 1 afforded 11 new diterpenoids (1–11), all of which possess a tetracyclic spongian-16-one scaffold with extensive oxidation at C-6, C-7, C-11, C-12, C-13, and/or C-20. The structures and relative configuration were investigated by NMR experiments, while X-ray crystallography provided the absolute configuration of 1, including a 2′S configuration for the 2-methylbutanoate substituent located at C-7. Dissection of animal tissue revealed that the mantle and viscera tissues differed in their metabolite composition with diterpenes 1–11 present in the mantle tissue of the two nudibranch species.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Firouz Matloubi Moghaddam ◽  
Vahid Saberi ◽  
Ashkan Karimi

AbstractThe first diastereoselective synthesis of spirothiooxindoles is reported via the Michael reaction between thiooxindoles and dibenzalacetones. The reaction was conducted without any catalyst or additive under green conditions, i.e., ethanol as the solvent and at room temperature. In addition, the described robust method benefits from scalability, simple work-up, and column chromatography-free purification. This work demonstrates the art of governing regio- and stereoselectivity, which has been discussed in the light of Density Functional Theory calculations. Our method represents the first synthesis of spiro[cyclohexanone-thiooxindoles] with the relative configuration of the aryl moieties at the cyclohexanone ring as cis. The obtained cis-spirothiooxindoles, can be used to afford cis-spirooxindoles, which their synthesis had not been explored before. According to our molecular docking studies, cis-spirooxindoles demonstrate higher binding affinities than corresponding trans-spirooxindoles for the OPRT domain of the Leishmania donovani uridine 5′-monophosphate synthase (LdUMPS). Thus, the reported method may eventually be utilized to develop new hit compounds for leishmaniasis treatment.


2021 ◽  
Author(s):  
◽  
Muhammad Ali Hashmi

<p>Secondary metabolites from natural sources have revolutionized the modern drug industry by acting as lead compounds. Many commercial drugs have evolved originally from natural molecules before being synthesized in the laboratory for commercialization. Because of the importance of natural molecules, it is crucial to determine their structural properties carefully as it is essential for their synthesis and studying their pharmacological behaviour. Many natural molecules have flexible structures and can adopt many different conformations in solution at room temperature. Hence, the determination of their relative configuration is a challenging task with the available experimental techniques. For structural analysis of natural molecules and to study their properties, all conformers which might be responsible for their chemical properties have to be considered.  Theoretical chemistry has been very helpful in absolute structure determination of complex and conformationally flexible natural molecules by calculating their theoretical nuclear magnetic resonance, ultraviolet, infra red, and circular dichroism spectra etc. There are a number of software tools that offer conformational analysis by utilizing different molecular mechanics approaches. They produce a large number of possible conformers and are not general purpose, thus compromising accuracy. Apart from that, different force fields available for conformational analysis and minimization have been designed for specific molecular classes and do not produce good results beyond their scope.  In the past, there have been reports about a “build-up procedure” for predicting the low energy conformations of peptides by optimising smaller fragments of the molecule under study and then joining them while minimizing their energies using force fields. Later on, this method was extended to predict the structure of DNA from sequences. This method used force field methods and did not gain much popularity due to its various limitations.  Here, MICE-PES (Method for the Incremental Construction and Exploration of the Potential Energy Surface) is presented, an algorithm which performs a conformational analysis using high level quantum chemical calculations by building the molecule incrementally from its smallest possible analogue whose conformational degrees of freedom are very well separated than the rest of the molecule. MICE-PES has been validated through studies on known biomolecule 3-epi-xestoaminol whose absolute configuration has been determined already by experimental and theoretical methods. MICE-PES has also been used to assign the relative configuration of a natural product (meroterphenol C) whose configuration could not be established experimentally. Overall, the development of MICE-PES will be very helpful in solving problems in the study of conformationally flexible systems, in all aspects of organic chemistry.</p>


2021 ◽  
Author(s):  
◽  
Daniel Phipps

<p>In the search of chemical species with potential therapeutic biological activity, synthetic chemists have looked to nature for inspiration. Molecules built by biological machinery often have structures predisposed for biological interaction.  (-)-TAN-2483B and the related compounds (-)-TAN-2483A, and waol A are fungal metabolites that display biological activity in kinase inhibition and parathyroid-induced bone resorption. Though total syntheses of (-)-TAN-2483A and waol A have been achieved, the established methodology does not afford access to (-)-TAN-2483B owing to the unique relative configuration about the ring system.  Derivatives of D-galactal have been synthesised, and functionalised at the C-1 and C-2 positions, laying the groundwork for a route to (-)-TAN-2483B and analogues. Using D-galactal derivatives is advantageous as it circumvents some difficult transformations in the existing method for analogue synthesis.  The functionalities installed were halide and formyl groups at the C-2 position, and acetylenes at the C-1 position. The synthesis of 2-haloglycals from tri-O-acetyl-D-galactal using N-halosuccinimides was achieved in 32% and <37% for the bromo- and iodo- variants respectively. Vilsmeier-Haack formylation was explored using per-benzylated and per-acetylated galactals as substrates. Formylation of the per-benzylated species was achieved in 78% yield in accordance with literature values. Vilsmeier-Haack formylation on the per-acetylated galactal has not been reported and the glycal was found to be a poor substrate for the formylation. Theories regarding the incompatibility of the per-acetylated species with Vilsmeier-Haack conditions were developed.  Ferrier-type alkynylation of the 2-halo/formylglycals was explored, with yields up to 17% and 13% for the bromo- and iodo- species (unoptimised), and 7% for 2-formylglycal (after optimisation studies). The resulting 1-ethynyl-2-formyl/halo-2,3-unsaturated pyrans could be potential intermediates en route to the furanone ring of the target compound.</p>


2021 ◽  
Author(s):  
◽  
Muhammad Ali Hashmi

<p>Secondary metabolites from natural sources have revolutionized the modern drug industry by acting as lead compounds. Many commercial drugs have evolved originally from natural molecules before being synthesized in the laboratory for commercialization. Because of the importance of natural molecules, it is crucial to determine their structural properties carefully as it is essential for their synthesis and studying their pharmacological behaviour. Many natural molecules have flexible structures and can adopt many different conformations in solution at room temperature. Hence, the determination of their relative configuration is a challenging task with the available experimental techniques. For structural analysis of natural molecules and to study their properties, all conformers which might be responsible for their chemical properties have to be considered.  Theoretical chemistry has been very helpful in absolute structure determination of complex and conformationally flexible natural molecules by calculating their theoretical nuclear magnetic resonance, ultraviolet, infra red, and circular dichroism spectra etc. There are a number of software tools that offer conformational analysis by utilizing different molecular mechanics approaches. They produce a large number of possible conformers and are not general purpose, thus compromising accuracy. Apart from that, different force fields available for conformational analysis and minimization have been designed for specific molecular classes and do not produce good results beyond their scope.  In the past, there have been reports about a “build-up procedure” for predicting the low energy conformations of peptides by optimising smaller fragments of the molecule under study and then joining them while minimizing their energies using force fields. Later on, this method was extended to predict the structure of DNA from sequences. This method used force field methods and did not gain much popularity due to its various limitations.  Here, MICE-PES (Method for the Incremental Construction and Exploration of the Potential Energy Surface) is presented, an algorithm which performs a conformational analysis using high level quantum chemical calculations by building the molecule incrementally from its smallest possible analogue whose conformational degrees of freedom are very well separated than the rest of the molecule. MICE-PES has been validated through studies on known biomolecule 3-epi-xestoaminol whose absolute configuration has been determined already by experimental and theoretical methods. MICE-PES has also been used to assign the relative configuration of a natural product (meroterphenol C) whose configuration could not be established experimentally. Overall, the development of MICE-PES will be very helpful in solving problems in the study of conformationally flexible systems, in all aspects of organic chemistry.</p>


2021 ◽  
Author(s):  
◽  
Daniel Phipps

<p>In the search of chemical species with potential therapeutic biological activity, synthetic chemists have looked to nature for inspiration. Molecules built by biological machinery often have structures predisposed for biological interaction.  (-)-TAN-2483B and the related compounds (-)-TAN-2483A, and waol A are fungal metabolites that display biological activity in kinase inhibition and parathyroid-induced bone resorption. Though total syntheses of (-)-TAN-2483A and waol A have been achieved, the established methodology does not afford access to (-)-TAN-2483B owing to the unique relative configuration about the ring system.  Derivatives of D-galactal have been synthesised, and functionalised at the C-1 and C-2 positions, laying the groundwork for a route to (-)-TAN-2483B and analogues. Using D-galactal derivatives is advantageous as it circumvents some difficult transformations in the existing method for analogue synthesis.  The functionalities installed were halide and formyl groups at the C-2 position, and acetylenes at the C-1 position. The synthesis of 2-haloglycals from tri-O-acetyl-D-galactal using N-halosuccinimides was achieved in 32% and <37% for the bromo- and iodo- variants respectively. Vilsmeier-Haack formylation was explored using per-benzylated and per-acetylated galactals as substrates. Formylation of the per-benzylated species was achieved in 78% yield in accordance with literature values. Vilsmeier-Haack formylation on the per-acetylated galactal has not been reported and the glycal was found to be a poor substrate for the formylation. Theories regarding the incompatibility of the per-acetylated species with Vilsmeier-Haack conditions were developed.  Ferrier-type alkynylation of the 2-halo/formylglycals was explored, with yields up to 17% and 13% for the bromo- and iodo- species (unoptimised), and 7% for 2-formylglycal (after optimisation studies). The resulting 1-ethynyl-2-formyl/halo-2,3-unsaturated pyrans could be potential intermediates en route to the furanone ring of the target compound.</p>


2021 ◽  
Author(s):  
◽  
James Bebbington

<p>The variation in the data that a robot in the real world receives from its sensory inputs (i.e. its sensory data) will come from many sources. Much of this variation is the result of ground truths about the world, such as what class an object belongs to, its shape, its condition, and so on. Robots would like to infer this information so they can use it to reason. A considerable amount of additional variation in the data, however, arises as a result of the robot’s relative configuration compared to an object; that is, its relative position, orientation, focal depth, etc. Fortunately, a robot has direct control over this configural variation: it can perform actions such as tilting its head or shifting its gaze. The task of inferring ground truth from data is difficult, and is made much more difficult when data is affected by configural variation. This thesis explores an approach in which the robot learns to perform actions that minimize the amount of configural variation in its sensory data, making the task of inferring information about objects considerably easier. The value of this approach is demonstrated by classifying digits from the MNIST and USPS datasets that have been transformed in various ways so that they include various kinds of configural variation.</p>


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