Tetracyclic Skeleton Research Articles

Meloslines A and B, two novel indole alkaloids from Alstonia scholaris

An unprecedented indole alkaloid melosline A (1), with 6/5/6/6 tetracyclic ring skeleton, together with a new alkaloid melosline B (2) and one known compound (3) were isolated from the leaves and twigs of Alstonia scholaris. The new structures were elucidated by comprehensive spectroscopic analysis. The absolute configuration of compound 1 was confirmed by comparison of experimental data with calculated electronic circular dichroism (ECD). Compound 1 exhibited moderate cytotoxicity against MCF-7 cancer cell lines. (C) 2017 Elsevier Ltd. All rights reserved.

Evaluation of the antioxidant properties of carexanes in AGS cells transfected with the Helicobacter pylori's protein HspB.

Naturally derived compounds represent a potential source of pharmacologically active drugs able to contrast different diseases, including gastric cancer, a multifactorial disease, in which the important role played by H.pylori infection has been demonstrated. Carexanes, stilbene derivatives, isolated from plants of the Carex distachya Desf., are unusual secondary metabolites with a tetracyclic skeleton arising from a cyclization of prenylstilbenoid precursors. In this study we firstly showed the ability of three purified carexanes CxB, CxG, and CxI to enhance the antioxidant response of AGS cells and to contrast the effect of the H.pylori's protein HspB. Among them CxI was the molecule that best modified the expression of genes involved in the antioxidant response. In particular, CxI was able to reduce Keap-1 gene expression and induce NQO1 gene expression, both at 4 and 24h in AGS cells, as showed by real time PCR. Nrf2 induction was evident only at 24h. Interestingly, the effect of CxI was stronger in HspB-transfected AGS cells, where Keap-1 gene expression was nearly abrogated. Finally, we demonstrated that CxI was able to reduce also COX-2 gene expression in HspB-transfected AGS cells, compared with untreated HspB-transfected cells, both at 4 and 24h. This study first report that carexanes might represent candidate molecules able to contrast the deleterious effect of HspB protein but also to reduce the inflammatory process induced by H.pylori infection.

Quest for steroidomimetics: Amino acids derived steroidal and nonsteroidal architectures

The chiral pool amino acids have been utilized for the construction of steroidal and non-steroidal architectures in the quest for steroidomimetics. Chirality derived from amino acid-based architectures provides new and easy to incorporate chiral chemical space, which is otherwise very difficult to introduce and comprised of several synthetic steps for asymmetric steroids. The different and exciting ligand-receptor interactions may arise from the use of each amino acid enantiomer that was introduced into the chiral steroidal backbone. The A and D rings of steroidal architectures can be mimicked by the phenyl group of the amino acid tyrosine. The Mitsunobu reaction, nucleophilic substitution and elimination, etc. were utilized for constructing diverse tri- and tetracyclic steroidal skeletons as well as benzofused seco-steroids from amino acids. These benzofused, amino acid-derived steroidal and nonsteroidal molecules had promising biological activity in hormonal related disorders.

Synthesis of trans,trans,cis-fused tetracyclic skeleton via radical domino cyclization

Limonoids are characterized by a polycyclic structure and show a wide variety of bioactivities. In particular, mesendanin L, 12-hydroxyamoorastatone, and meliatoosenin F have unique structures containing a trans-A/B/C and cis-C/D-fused tetracyclic skeleton. We synthesized the core structure of these limonoids via Mn(OAc)3 and Cu(OAc)2-mediated radical domino cyclization of an acyclic tetraene precursor having a terminal β-keto ester. To the best of our knowledge, this is the first example of the radical-mediated construction of a 6/6/6/5-membered tetracyclic skeleton.

Catalytic and Enantioselective Diels-Alder Reaction of Silyloxydiene That Incorporates a Pyrrolidine Ring, and Its Application to the Construction of Chiral Tri- and Tetracyclic Skeletons

Catalytic and Enantioselective Diels-Alder Reaction of Silyloxydiene That Incorporates a Pyrrolidine Ring, and Its Application to the Construction of Chiral Tri- and Tetracyclic Skeletons

Friedel–Crafts Chemistry. Part 48. Concise Synthesis of Condensed Azaheterocyclic [1,8]naphthyridinones, Azepino-, Azocino-, and Azoninoquinoline Systems via Friedel–Crafts Ring Closures

Unprecedented construction of a novel series of quinoline heteropolycycles (tetracyclic keto-analogues of [1,8]naphthyridinones, azepino-, azocino- and azonino[2,3-b]quinolinones systems) 10a–i by Friedel–Crafts cycliacylation reactions is described. Starting heterocyclic acids precursors 3a–i were prepared from easily accessible 2-chloroquinoline-3-carbaldehyde 1 via a three different synthetic pathways. Acid-catalyzed ring closures of the resulting tosylated acids were achieved under the influence of both Brønsted and Lewis acid catalysts. The present strategy enables a straightforward synthesis to fused tetracyclic quinolinone skeletons as demonstrated by concise and atom-economical syntheses.

Vulgarisins B–D, three novel diterpenoids with a rare skeleton isolated from Prunella vulgaris Linn

Three new diterpenoids, vulgarisins B–D (1–3), have been isolated from a medicinal plant Prunella vulgaris Linn. These diterpenoids contain a rare 5/6/4/5 fused tetracyclic ring skeleton. Their structures were determined through the analysis of spectroscopic data, and the absolute configuration were further confirmed by single crystal X-ray diffraction as well as CD analysis. All the compounds were evaluated for their cytotoxicity activity, vulgarisins B (1) and C (2) demonstrated modest cytotoxicity activity against human lung carcinoma A549 cell line.

ChemInform Abstract: 20‐Nor‐isopimarane Cycloethers from the Deep‐Sea Sediment‐Derived Fungus Aspergillus wentii SD‐310.

AbstractAsperethers A—E (I—IV), five new 20‐nor‐isopimarane diterpenoids, are isolated from the title fungus.

ChemInform Abstract: Silver‐Catalyzed Intramolecular C‐2 Selective Acylation of Indoles with Aldehydes: An Atom‐Economical Entry to Indole‐Indolone Scaffolds.

AbstractThe approach is possible under conditions A), B) or C) and affords various functionalized tetracyclic nitrogen skeletons, suitable as new drug‐like components.

General synthesis, structure, and optical properties of benzothiophene-fused benzoheteroles containing Group 15 and 16 elements

A series of benzothieno[3,2-b]benzoheteroles containing Group 15 (N, P, As, and Sb) and Group 16 (O, S, Se, and Te) elements were synthesized by a versatile method. X-ray analyses revealed that all the tetracyclic heteroacene skeletons were planar. A linear relationship was found between the excitation energies of Group 16-heteroacenes and their atomic radius, in contrast to Group 15-heteroacenes. Density functional theory calculations and electrochemical measurements were performed to understand the structure–optical property relationship.

Total Syntheses of 7,20-Oxa-Bridged Dinorditerpenes: Antihepatitis C Virus Active (+)-Elevenol from Flueggea virosa and (+)-Przewalskin.

An efficient stereoselective synthetic approach to 7-20 oxa-bridged abietane type natural products is reported. Key steps are an asymmetric Mukaiyama aldol addition to construct the C3 stereocenter and an intramolecular organocatalyzed Stetter-type Michael addition followed by a Tishchenko reaction. An intramolecular lactone-enolate arylation delivers the tetracyclic skeleton. This synthetic strategy was applied for the first total synthesis of (+)-elevenol, an antihepatitis C active compound from Fluegga virosa, and the first total synthesis of (+)-przewalskin.

Antitubercular and cytotoxic tigliane-type diterpenoids from Croton tiglium

Five new tigliane diterpene esters (1–5), highly oxygenated tetracyclic diterpenoid carbon skeleton, together with three known analogues (6–8) were isolated from the leaves of Croton tiglium. Extensive NMR and mass spectroscopic analysis were used to elucidate their structures. Most of the isolated compounds were tested for their cytotoxic and antitubercular activities. Among them, the cytotoxic activities of these tigliane-type diterpenes strongly depend on the species of the tumor cells. Especially, these bioactivity compounds showed strong cytotoxic activities against the K562 cell line, and their inhibition effects were close to the positive control Taxol. Furthermore, compounds 1, 2, 6, and 7 showed potent antitubercular activities with MIC values of 19.5, 20.9, 20.5, and 13.4μM, respectively.

ChemInform Abstract: Montecrinanes A—C: Triterpenes with an Unprecedented Rearranged Tetracyclic Skeleton from Celastrus vulcanicola. Insights into Triterpenoid Biosynthesis Based on DFT Calculations.

Three new triterpenoids with an unprecedented 6/6/6/6-fused tetracyclic carbon skeleton, montecrinanes A-C (1-3), were isolated from the root bark of Celastrus vulcanicola, along with known D:B-friedobaccharanes (4-6), and lupane-type triterpenes (7-12). The stereostructures of the new metabolites were elucidated based on spectroscopic (1D and 2D NMR) and spectrometric (HR-EIMS and HR-ESIMS) techniques. Their absolute configurations were determined by both NMR spectroscopy, with (R)-(-)-α-methoxyphenylacetic acid as a chiral derivatizing agent, and biogenetic considerations. Biogenetic pathways for montecrinane and D:B-friedobaccharane skeletons were proposed and studied by DFT methods. The theoretical results support the energetic feasibility of the putative biogenetic pathways, in which the 1,2-methyl shift from the secondary baccharenyl cation represents a novel and key reaction step for a new montecrinane skeleton.

Enantioselective Synthesis of (+)-Peganumine A

A gram-scale enantioselective total synthesis of (+)-peganumine A was accomplished in 7 steps from commercially available 6-methoxytryptamine. Key steps included (a) a Liebeskind-Srogl cross-coupling; (b) a one-pot construction of the tetracyclic skeleton from an ω-isocyano-γ-oxo-aldehyde via a sequence of an unprecedented C-C bond forming lactamization and a transannular condensation; (c) a one-pot organocatalytic process merging two achiral building blocks into an octacyclic structure via a sequence of enantioselective Pictet-Spengler reaction followed by a transannular cyclization. This last reaction created two spirocycles and a 2,7-diazabicyclo[2.2.1]heptan-3-one unit with excellent control of both the absolute and relative stereochemistry of the two newly created quaternary stereocenters.

Ready Access to the Echinopines Skeleton via Gold(I)-Catalyzed Alkoxycyclizations of Enynes.

The [3,5,5,7] tetracyclic skeleton of echinopines has been stereoselectively accessed through a gold(I)-catalyzed alkoxycyclization of cyclopropyl-tethered 1,6-enynes. The key bicyclo[4.2.1]nonane core of the enyne precursors was readily assembled by means of a Co-catalyzed [6 + 2] cycloaddition. Furthermore, the attempted alkoxycyclization of 1,5-enyne substrates revealed an uncovered cyclopropyl rearrangement that gives rise to [3,6,5,7] tetracyclic structures.

In vitro anti-Leishmania activity of tetracyclic iridoids from Morinda lucida, benth.

Leishmaniasis is an infectious disease transmitted by the sand fly. It is caused by over 20 different species of Leishmania and has affected over 14 million people worldwide. One of the main forms of control of leishmaniasis is chemotherapy, but this is limited by the high cost and/or toxicity of available drugs. We previously found three novel compounds with an iridoid tetracyclic skeleton to have activity against trypanosome parasites. In this study, we determined the activity of the three anti-trypanosome compounds against Leishmania using field strain, 010, and the lab strain Leishmania hertigi. The minimum inhibitory concentration (MIC) of the compounds against 010 was determined by microscopy while the IC50 of compounds against L. hertigi was determined by fluorescence-activated cell sorting with Guava viacount analysis. We found two of the three compounds, molucidin and ML-F52, to have anti-Leishmania activity against both strains. The fluor-microscope observation with DAPI stain revealed that both Molucidin and ML-F52 induced abnormal parasites with two sets of nucleus and kinetoplast in a cell, suggesting that compounds might inhibit cytokinesis in Leishmania parasites. Molucidin and ML-F52 might be good lead compounds for the development of new anti-Leishmania chemotherapy.

Bioactive Dibenzo-α-pyrone Derivatives from the Endophytic Fungus Rhizopycnis vagum Nitaf22.

Six new dibenzo-α-pyrones, rhizopycnolides A (1) and B (2) and rhizopycnins A-D (3-6), together with eight known congeners (7-14), were isolated from the endophytic fungus Rhizopycnis vagum Nitaf22 obtained from Nicotiana tabacum. The structures of the new compounds were unambiguously elucidated using NMR, HRESIMS, TDDFT ECD calculation, and X-ray crystallography data. Rhizopycnolides A (1) and B (2) feature an uncommon γ-butyrolactone-fused dibenzo-α-pyrone tetracyclic skeleton (6/6/6/5), while rhizopycnin B (4) was the first amino group containing dibenzo-α-pyrone. Rhizopycnolides A (1) and B (2) are proposed to be biosynthesized from polyketide and tricarboxylic acid cycle pathways. The isolated compounds were tested for their antibacterial, antifungal, and cytotoxic activities. Among them, rhizopycnolide A (1), rhizopycnins C (5) and D (6), TMC-264 (8), penicilliumolide D (11), and alternariol (12) were active against the tested pathogenic bacteria Agrobacterium tumefaciens, Bacillus subtilis, Pseudomonas lachrymans, Ralstonia solanacearum, Staphylococcus hemolyticus, and Xanthomonas vesicatoria with MIC values in the range 25-100 μg/mL. Rhizopycnin D (6) and TMC-264 (8) strongly inhibited the spore germination of Magnaporthe oryzae with IC50 values of 9.9 and 12.0 μg/mL, respectively. TMC-264 (8) showed potent cytotoxicity against five human cancer cell lines (HCT-116, HepG2, BGC-823, NCI-H1650, and A2780) with IC50 values of 3.2-7.8 μM.

Four new tetracyclic alkaloids with cis-decahydroquinoline motif from Myrioneuron effusum

Four new Myrioneuron alkaloids, mysumamides A–D (1–4), along with three known ones were isolated from the twigs and leaves of Myrioneuron effusum. All of these alkaloids possessed the tetracyclic skeleton and contained the decahydroquinoline (cis-DHQ) moiety. Their structures and relative configurations were elucidated on the basis of spectroscopic methods, especially 2D NMR techniques. The absolute configuration of 1 was determined by single-crystal X-ray diffraction. The cytotoxic activities of these compounds were also evaluated in vitro.

Euphorikanin A, a Diterpenoid Lactone with a Fused 5/6/7/3 Ring System from Euphorbia kansui.

Euphorikanin A (1), an unprecedented diterpenoid lactone which possesses a novel 5/6/7/3-fused tetracyclic ring skeleton, was isolated from the roots of Euphorbia kansui. The chemical structure and absolute stereochemistry were elucidated on the basis of extensive spectroscopic methods and single-crystal X-ray diffraction analysis. Compound 1 exhibited moderate cytotoxicity against two human tumor cell lines HeLa and NCI-446. A proposed biosynthetic pathway of compound 1 is also described.

Montecrinanes A-C: Triterpenes with an Unprecedented Rearranged Tetracyclic Skeleton from Celastrus vulcanicola. Insights into Triterpenoid Biosynthesis Based on DFT Calculations.

Three new triterpenoids with an unprecedented 6/6/6/6-fused tetracyclic carbon skeleton, montecrinanes A-C (1-3), were isolated from the root bark of Celastrus vulcanicola, along with known D:B-friedobaccharanes (4-6), and lupane-type triterpenes (7-12). The stereostructures of the new metabolites were elucidated based on spectroscopic (1D and 2D NMR) and spectrometric (HR-EIMS and HR-ESIMS) techniques. Their absolute configurations were determined by both NMR spectroscopy, with (R)-(-)-α-methoxyphenylacetic acid as a chiral derivatizing agent, and biogenetic considerations. Biogenetic pathways for montecrinane and D:B-friedobaccharane skeletons were proposed and studied by DFT methods. The theoretical results support the energetic feasibility of the putative biogenetic pathways, in which the 1,2-methyl shift from the secondary baccharenyl cation represents a novel and key reaction step for a new montecrinane skeleton.