Chromene Skeleton Research Articles

Shikimate-Derived Meroterpenoids from the Ascidian-Derived Fungus Amphichorda felina SYSU-MS7908 and Their Anti-Glioma Activity.

Glioma is a clinically heterogeneous type of brain tumor with a poor prognosis. Current treatment approaches have limited effectiveness in treating glioma, highlighting the need for novel drugs. One approach is to explore marine natural products for their therapeutic potential. In this study, we isolated nine shikimate-derived diisoprenyl-cyclohexene/ane-type meroterpenoids (1-9), including four new ones, amphicordins A-D (1-4) from the ascidian-derived fungus Amphichorda felina SYSU-MS7908, and further semisynthesized four derivatives (10-13). Their structures were extensively characterized using 1D and 2D NMR, modified Mosher's method, HR-ESIMS, NMR and ECD calculations, and X-ray crystallography. Notably, amphicordin C (3) possesses a unique benzo[g]chromene (6/6/6) skeleton in this meroterpenoid family. In an anti-glioma assay, oxirapentyn A (7) effectively inhibited the proliferation, migration, and invasion of glioma cells and induced their apoptosis. Furthermore, an in silico analysis suggested that oxirapentyn A has the potential to penetrate the blood-brain barrier. These findings highlight the potential of oxirapentyn A as a candidate for the development of novel anti-glioma drugs.

Identification of new bisabosqual-type meroterpenoids reveals non-enzymatic conversion of bisabosquals into seco-bisabosquals.

Bisabosqual-type meroterpenoids are fungi-derived polyketide-terpenoid hybrids bearing a 2,3,3a,3a1,9,9a-hexahydro-1H-benzofuro[4,3,2-cde]chromene skeleton (6/6/6/5 ring system) or its seco-C-ring structure, and exhibit diverse bioactivities. Their unique structural architecture and impressive biological activities have led to considerable interest in discovering new analogues. However, to date, only nine analogues have been identified. Herein, we reported the isolation and identification of six new bisabosqual-type meroterpenoids stachybisbins C-H (1-6), together with one known compound bisabosqual C (7), from Stachybotrys bisbyi PYH05-7. Intriguingly, we found that 7, which contains the intact tetracyclic skeleton, can be non-enzymatically converted into its seco derivative stachybisbin I (8), unveiling the biosynthetic relationship between bisabosquals and seco-bisabosquals. Moreover, based on CRISPR/Cas9-mediated gene disruption, we revealed that the three-gene cluster responsible for the formation of LL-Z1272β is associated with the biosynthesis of bisabosqual-type meroterpenoids, and then proposed a plausible route to 1-8.

Rhodium(III)-catalyzed intermolecular [3+3] annulation of benzoxazines with quinone compounds: access to spiro-heterocyclic scaffolds.

A rhodium(III)-catalyzed redox-neutral spiroannulation approach to access the spiro[benzo[b][1,4]oxazine-benzo[c]chromene skeleton is described in this contribution. A variety of spiro[5.5]-heterocyclic scaffolds were obtained in moderate to excellent yields under mild conditions. Key features of this protocol are good substrate scope, silver-free conditions, low catalyst loadings, easy handling under air and 100% atom economy. Furthermore, scale-up reactions and late-stage derivatizations highlight the potential synthetic utility of this methodology.

Isolation of new compounds related to xyloketals biosynthesis implies an alternative pathway for furan-fused-chromene formation.

In fungi, there is a rare group of natural products harboring the 2,3,3a,9a-tetrahydro-4H-furo[2,3-b]chromene skeleton, represented by xyloketal B, which display a wide range of biological activities and have drawn significant attention. In this work, four new analogues simpliketals A-D (1-4), as well as two other new compounds simplilactones A and B (5 and 6), were isolated from Simplicillium sp. AHK071-01. Their structures were elucidated by extensive NMR spectroscopic methods, 13C NMR calculation, single-crystal X-ray diffraction, and ECD calculation. In addition, five known compounds (7-11) including alboatrin (7) were also obtained. Based on the structural similarity of the above compounds, we inferred that compounds 5, 6, and 8-11 might be biosynthetically related with 1-4 and 7, which allowed us to propose an alternative biosynthetic route to generate the furan-fused chromene skeleton of this class of compounds, instead of a previously presumed polyketide-terpenoid hybrid pathway. Finally, cytotoxicity assays showed that 1-4 exhibited weak inhibitory activity on PANC-1 cells and that 2 and 3 possessed moderate activity against SH-SY5Y cells.

Ru(II)-Catalyzed Regioselective Annulation of 2-Hydroxystyrenes with Allenyl Acetates via Vinylic C-H Activation.

Herein, we disclose an unprecedented and robust Ru(II)-catalyzed non-oxidative [5+1] annulation of 2-hydroxystyrenes with allenyl acetates to access biologically relevant chromene skeletons. The heteroatom on allene plays a pivotal role in controlling the regioselectivity of migratory insertion, and the reaction proceeds through a Ru-σ-allyl pathway, which has been elusive so far in C-H activation reactions with allenes. The protocol is sustainable in nature as it proceeds at room temperature and avoids the use of any toxic metal oxidants. In addition, the synthetic utility of the protocol was also demonstrated by late stage functionalization and modular synthesis of various natural product conjugates.

Synthesis of Dihydrobenzofuro[3,2-b]chromenes as Potential 3CLpro Inhibitors of SARS-CoV-2: A Molecular Docking and Molecular Dynamics Study.

The recent emergence of pandemic of coronavirus (COVID‐19) caused by SARS‐CoV‐2 has raised significant global health concerns. More importantly, there is no specific therapeutics currently available to combat against this deadly infection. The enzyme 3‐chymotrypsin‐like cysteine protease (3CLpro) is known to be essential for viral life cycle as it controls the coronavirus replication. 3CLpro could be a potential drug target as established before in the case of severe acute respiratory syndrome coronavirus (SARS‐CoV) and Middle East respiratory syndrome coronavirus (MERS‐CoV). In the current study, we wanted to explore the potential of fused flavonoids as 3CLpro inhibitors. Fused flavonoids (5a,10a‐dihydro‐11H‐benzofuro[3,2‐b]chromene) are unexplored for their potential bioactivities due to their low natural occurrences. Their synthetic congeners are also rare due to unavailability of general synthetic methodology. Here we designed a simple strategy to synthesize 5a,10a‐dihydro‐11H‐benzofuro[3,2‐b]chromene skeleton and it's four novel derivatives. Our structural bioinformatics study clearly shows excellent potential of the synthesized compounds in comparison to experimentally validated inhibitor N3. Moreover, in‐silico ADMET study displays excellent druggability and extremely low level of toxicity of the synthesized molecules. Further, for better understanding, the molecular dynamic approach was implemented to study the change in dynamicity after the compounds bind to the protein. A detailed investigation through clustering analysis and distance calculation gave us sound comprehensive data about their molecular interaction. In summary, we anticipate that the currently synthesized molecules could not only be a potential set of inhibitors against 3CLpro but also the insights acquired from the current study would be instrumental in further developing novel natural flavonoid based anti‐COVID therapeutic spectrums.

Total syntheses of hyperaspidinols A and B enabled by a bioinspired diastereoselective cascade sequence

A bioinspired acid-triggered hemiacetalization/dehydration/[3 + 3]-type cycloaddition cascade process was disclosed, diastereoselectively furnishing furo[2,3-b]chromene skeleton under mild conditions. The viability of this approach was demonstrated by syntheses of a series of furo[2,3-b]chromene and pyrano[2,3-b]chromene derivatives. The successful total syntheses of two lignan-phloroglucinol hybrids, hyperaspidinols A and B, exemplified the synthetic utility of our biomimetic methodology.

Biowaste-Derived Heterogeneous Catalyst for the One-Pot Multicomponent Synthesis of Diverse and Densely Functionalized 2-Amino-4H-Chromenes

Chromene skeletons are crucial structural motifs existing in abundant natural products and drug molecules.1 These oxygen-containing heterocyclic compounds have a broad range of biological propertie...

Formation of epoxychromeno[4,3-c]isoquinolines through diastereoselective one-pot IMDA reaction of 4-chloro-3-[(1E)-3-oxo-3-phenyl-1-propen-1-yl]-2H-chromen-2-one and furfurylamine

An intramolecular Diels–Alder mediated reaction of (2E)-3-(4-chloro-2-methylene-2H-chromen-3-yl)-1-phenyl-2-propen-1-one, which was obtained in situ from the reaction of 4-chloro-2-oxo-2H-chromene-3-carbaldehyde and Wittig reagent, with furfurylamine leads to fused epoxychromeno[4,3-c]isoquinolines. Reaction performed in one-pot condition and only one diastereomer was obtained. In this method, the key step for the formation of the final product is IMDA reaction. A series of fused epoxychromeno[4,3-c]isoquinoline compounds containing chromene skeleton have been synthesized through the cyclization strategy, from 4-chloro-2-oxo-2H-chromene-3-carbaldehyde, Wittig reagent, and furfurylamine. The reactions were carried out under reflux condition in DCM/toluene.

Deep Eutectic Solvent Mediated Alkyne‐Carbonyl Metathesis (ACM) Reaction for the Synthesis of 2H‐Chromene Derivatives

Abstract2H‐Chromene is an important structural motif present in many biologically active compounds, natural products and showed many other properties. Deep Eutectic Solvent (DES) an environmentally benign and alternative to the conventional organic volatile solvents has been utilized first time for the synthesis of the 2H‐chromene derivatives in moderated to excellent yields. The DES is recycled for 5 times for the synthesis of 2H‐chromene derivatives. Based on the stability of ring size, we justified the regio‐selectivity on the formation of cyclization product. Based on the control experiments, we ruled out the free radical mechanism and propose the ACM mechanistic path to construct chromene skeleton.

Capillasterin A, a Novel Pyrano[2,3-f]chromene from the Australian Crinoid Capillaster multiradiatus.

Capillasterin A (1), a novel pyrano[2,3-f]chromene, together with seven known naphthopyrones including comaparvin (2), TMC-256C1 (3), 6-methoxycomaparvin-5- methyl ether (4), 5,8-dihydroxy-6-methoxy-2-propyl-4H-naphtho[2,3-b]pyran-4-one (5), 5,8-dihydroxy-6,10-dimethoxy-2-propyl-4H-naphtho[2,3-b]pyran-4-one (6), TMC-256A1 (7) and 6-methoxycomaparvin (8) were isolated from an EtOH/H2O extract from the Australian crinoid Capillaster multiradiatus. The structures of all the compounds were determined by detailed spectroscopic (1D/2D NMR and MS) data analysis. This is the first report of a natural product that contains the pyrano[2,3-f]chromene skeleton. Compounds 2–6 were observed to display moderate inhibition of in vitro HIV-1 replication in a T cell line with EC50 values ranging from 7.5 to 25.5 µM without concomitant cytotoxicity.

Microwave assisted synthesis of novel tetrazole/sulfonamide derivatives based on octahydroacridine, xanthene and chromene skeletons as inhibitors of the carbonic anhydrases isoforms I, II, IV and VII

The synthesis of novel tetrazole/sulfonamide derivatives based on octahydroacridine, xanthene and chromene scaffold by using microwave (MW) assisted techniques is reported in this study. These synthesized hybrid compounds were assayed for the inhibition of carbonic anhydrase (CA, EC 4.2.1.1). The inhibitory activities were determined against three cytosolic human isoforms (hCA I, II and VII) and one membrane-associated (hCA IV) isoform. Some of the newly synthesized sulfonamides showed micromolar to nanomolar inhibitory activity against these enzymes.

Erecricins A–E, prenylated acylphloroglucinols from the roots of Hypericum erectum

Six new prenylated acylphloroglucinols, erecricins A–E (1–5) and adotogirin (6), were isolated from the roots of Hypericum erectum (Hypericaceae). Their structures were assigned on the basis of spectroscopic evidences. Erecricins A–E (1–5) are bicyclic prenylated acylphloroglucinols possessing a chromane or a chromene skeleton. Adotogirin (6) is a simple achylphloroglucinol with an O-geranyl moiety. Antimicrobial activities of these acylphloroglucinols were also evaluated.

ChemInform Abstract: Tandem Prins Cyclization for the Stereoselective Synthesis of the 4,5‐Diaryl‐hexahydropyrano[3,4‐c]chromene Skeleton of Calyxins I and J.

AbstractThis novel Prins bicyclization strategy allows the stereoselective synthesis of various trans‐fused chromene derivatives (III) and product (V) possessing the core structure of calyxins I and J.

Tandem Prins Cyclization for the Stereoselective Synthesis of the 4,5‐Diaryl‐hexahydropyrano[3,4‐c]chromene Skeleton of Calyxins I and J

AbstractA Prins bicyclization strategy for the stereoselective synthesis of trans‐fused hexahydropyrano[3,4‐c]chromene derivatives in good to excellent yields has been developed. The synthetic versatility of this approach has been demonstrated in the synthesis of calyxin I and J analogues. This is the first example of the synthesis of hexahydropyrano[3,4‐c]chromene derivatives from (E)‐3‐[2‐(benzyloxy)phenyl]‐5‐phenylpent‐4‐en‐1‐ol (4b) and aldehydes.

Stereoselective synthesis of a highly oxygenated decahydrocyclopenta[g]chromene derivative: the common tricyclic framework of leucosceptrine and leucosesterterpenone.

Stereoselective construction of the highly oxygenated decahydrocyclopenta[g]chromene skeleton, which is the tricyclic core of leucosceptrine, which possesses prolylendopeptidase inhibitory activity, and leucosesterterpenone, which exhibits anti-angiogenic activity, from Leucosceptrum canum, was achieved.

Stereochemistry of Methoxylated Flavonoids from Artemisia semiarida

The aerial part of Artemisia semiarida (Krasch. et Lavr.) Filat. was collected in May 2009 in Betpak-Dala desert in Zhanaarka District, Karagandy Province, during the vegetative phase in order to study its chemical composition. Finely ground aerial part was extracted with CHCl3. The resulting extract was worked up with EtOH:H2O (2:1) at 70–75°C. The filtrate was extracted with CHCl3. Total extracted substances were mixed with KSK silica gel and transferred to a chromatography column (total:sorbent, 1:19) and eluted with petroleum ether:EtOAc (13:7) to afford yellow crystalline 1, mp 234–237°C (EtOAc), C18H16O7, Rf 2.25 (EtOAc:petroleum ether, 1:1). Elution by petroleum ether:EtOAc (63:37) isolated yellow crystalline 2, mp 244–247°C (EtOH), C18H16O8, Rf 0.19 (EtOAc:petroleum ether, 2:1). Compound 1 was identified by its spectral properties as 5,7-dihydroxy-6,3 ,4 -trimethoxyflavone or eupatilin, which was previously isolated from Eupatorium semiserratum DC. [1]; compound 2, as 5,7,3 -trihydroxy-6,4 ,5 -trimethoxyflavone, which was previously isolated from Artemisia frigida Willd. [2]. The molecular structure of 2 (Fig. 1) was determined by an x-ray crystal structure analysis. Flavones are the flavonoids with the least conformational flexibility because of many factors that hinder movement of the atoms in the molecule. Thus, the chromene skeleton of 2 was flat within ±0.01 A° . The closest hydroxyl and methoxyl O atoms lay practically in the plane of the main framework. The phenyl ring was planar within ±0.010 A° . The methoxyl C8 was also located in the plane of the phenyl ring (torsion angle C4 C5 O3 C8 , –175.5°). The other two methoxyls were twisted by significant angles (torsion angles C5C6O4C11, 87.5°; C3 C4 O2 C7 , 121.3°). The phenyl ring was rotated insignificantly by 6.0° relative to the chromene skeleton, like in the majority of flavones, e.g., 5-hydroxy-6,7,4 -trimethoxyflavone [3] and 5,6,7-trihydroxyflavone [4]. Organic molecules in the crystal may not be situated in the most energetically favorable conformation if it is advantageous to change because of packing-density effects [5]. Therefore, quantum-chemical calculations by the semi-empirical AM1 method [6] with rotation of the phenyl ring around the C2–C1 bond were performed in order to determine the possible conformations of 1 and 2. Possible orientations of the methoxyl relative to the main skeleton were determined. Because the chromene skeleton in flavones is rigid, the various conformations can be realized primarily by rotating the phenyl ring around the C2–C1 bond. The calculations indicated that four conformations with different rotations of the phenyl ring and torsion angles (O1C2C1 C2 ) = 30 and 20, 140 and 140, 210 and 200, and 320 and 310°, respectively, with small energy barriers (~2 kcal/mol) were possible for isolated 1 and 2. Similar rotations of a phenyl ring relative to a chromene skeleton were observed, e.g., in 6-hydroxy-1 ,2,3 -trimethoxyflavone [ (O1C2C1 C2 ) = 161.3°] [7]; 5,4 -dihydroxy-6,7dimethoxyflavone [ (O1C2C1 C2 ) = 337.8°] [8]; 6,1 -dihydroxyflavone [ (O1C2C1 C2 ) = 142.4°] [9], and 5,6,7,4 tetramethoxyflavone [ (O1C2C1 C2 ) = 18.3°] [10]. Furthermore, possible orientations of the methoxyl relative to the main skeleton were determined. The orientations of the methoxyl on the chromene skeletons of 1 and 2 were analogous and gave methoxyl positions with torsion angles (C5C6O4C11) of 70 and 270°. The methoxyls of the phenyl ring of 1 adopted a favorable position with (C2 C3 O2 C7 ) and (C3 C4 O3 C8 ) in the range from –80 to 180°. The methoxyls of the phenyl ring of 2 adopted a favorable position with (C3 C4 O2 C7 ) of 40, 70, 140, 240, and 290° and (C4 C5 O3 C8 ) in the range from –80 to 180°. This difference in the conformational behavior of the methoxyls in the different positions was explained by the different closest environment of these groups. In fact, the methoxyls could adopt any conformation over broad limits if there was no bulky neighboring substituent.

Synthesis, reactions and antineoplastic activity of 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromene derivatives

Abstract The key 3-(2-oxo-2H-chromen-3-yl)-2-oxo-2H,5H-pyrano[3,2-c]chromen-5-yl acetates 3 were synthesized in high yields by cyclocondensation of 4-oxo-4H-chromen-3-carbaldehydes 1 with coumarin-3-acetic acids 2 under mild conditions. The reaction pathway involves aldol condensation and subsequent intramolecular lactonization to afford 2-oxo-2H,5H-pyrano[3,2-c]chromene skeleton 3. Further treatment of acetates 3 with alcohols, water or nitrogen containing compounds led to 5-alkoxy-, 5-hydroxy- or 5-acylamino-2H,5H-pyrano[3,2-c]chromen-2-ones 4-6 via nucleophilic substitution of acetyloxy group at C-5. Acetates and hydroxyl derivatives 3 and 5 undergo facile rearrangement in an acid medium yielding 5-hydroxypyrano[2,3-b]chromen-2(10aH)-ones 7. Twelve prepared compounds were evaluated on their antineoplastic activities on 60 human tumour cell line panels in NCI USA. The obtained biological results confirmed that 3-(2-oxo-2H-chromen-3-yl)-2H,5H-pyrano[3,2-c]chromen-2-one represents a new leading skeleton suitable for further antitumour activity study.

Intramolecular Cascade Hydroarylation/Cycloisomerization Strategy for the Synthesis of Polycyclic Aromatic and Heteroaromatic Systems

AbstractA new PtCl2/PtCl4‐catalyzed hydroarylation/cycloisomerization cascade reaction leading to the formation of two aromatic or heteroaromatic rings in one step is reported. The strategy developed is exemplified by the synthesis of the 5,6‐dihydrobenzo[c]phenanthrene and 6H‐naphtho[2,1‐c]chromene skeletons. Attempts to prepare [8]helicene‐like molecules are also discussed.

ChemInform Abstract: Lewis Acid‐Catalyzed Intramolecular [3 + 2] Cycloaddition of Cyclopropane 1,1‐Diesters with Alkynes for the Synthesis of Cyclopenta[c]chromene Skeletons.

An efficient method to construct cyclopenta[c]chromene skeletons by Lewis acid-catalyzed intramolecular [3+2] cycloaddition of cyclopropane 1,1-diesters with alkynes is presented. Two new fused cycles can be formed in one step in moderate to excellent yields (up to 94 %), and the products can be converted into bioactive barbituric acid derivatives (1) under simple reaction conditions.