Pentacyclic Ring Research Articles

Yonarolide A, an unprecedented furanobutenolide-containing norcembranoid derivative formed by photoinduced intramolecular [2+2] cycloaddition

Eight polycyclic furanobutenolide-containing norcembrane diterpenoids featuring C19 frameworks (1–8) were rapidly recognized and isolated from the Hainan soft coral Sinularia sp. by the HSQC-based small molecule accurate recognition technology. Yonarolide A (1a), featuring an unprecedented 5/6/4/4/7 pentacyclic ring skeleton, was surprisingly obtained as a transformed product by leaving compound 1 under indoor natural light, and was further proved to be a [2 + 2] cycloaddition product of 1 by photochemical reaction. The absolute stereochemistry of 1a and the three known norcembrane diterpenoids 1, 4, and 7 were determined by using X-ray diffraction (XRD) analyses. Further, with the aid of XRD analysis, the structure of scabrolide B (2), which was previously reported of possessing 5/6/7 tricyclic skeleton, was firmly revised as 2a with the rare inelegane skeleton featured by the highly oxygenated 5/7/6 tricyclic carbocycle.

Norprzewalsone A, a Rearranged Polycyclic Polyprenylated Acylphloroglucinol with a Spiro[cyclopentane-1,3'-tricyclo[7.4.0.01,6]tridecane] Core from Hypericum przewalskii.

Norprzewalsone A (1), a rearranged polyprenylated polycyclic acylphloroglucinol (PPAP) with a new carbon skeleton, along with a new congener, norprzewalsone B (2), were isolated from Hypericum przewalskii. Compound 1 possessed a new 5/6/5/6/6 pentacyclic ring system based on a spiro[cyclopentane-1,3'-tricyclo[7.4.0.01,6]tridecane] core, which might be derived from the common [3.3.1]-type bicyclic polyprenylated acylphloroglucinol (BPAP) via the key retro-Claisen, intramolecular cyclization, and Diels-Alder cyclization reactions. Their structures and absolute configurations were confirmed by spectroscopic data, calculated 1D NMR data with DP4+ probability analyses, and electronic circular dichroism calculations and comparison. More significantly, compound 1 exhibited a moderate inhibitory effect on NO production in lipopolysaccharide-stimulated RAW264.7 cells.

Cytochalasan Alkaloids as TRAIL Sensitizers from an Endophytic Fungus Chaetomium sp.

Two new cytochalasans with a rare 6/6/5/5/7 pentacyclic ring system, named chaetoconvosins C-D (1: -2: ), together with two known congeners (3: -4: ), were isolated from the fermentation of an endophytic fungus, Chaetomium sp. SG-01, harbored in the fibrous roots of Schisandra glaucescens Diels. Their structures including the absolute configuration were elucidated by extensive spectroscopic (HRESIMS, NMR, and ECD) and X-ray crystallographic analyses. The TRAIL-resistance-overcoming activity of 1: -4: in a TRAIL-resistant HT29 colorectal cancer cell line was evaluated, which revealed that co-treatment of 1: -4: at 50 µM with TRAIL (150 ng/mL) reduced the HT29 cell viability by 19.0%, 24.1%, 17.9%, and 15.5%, respectively, compared to treatment with 1: -4: alone.

Towards Tianeptine Analogues: Synthesis of New Ring Systems Containing a Dibenzo[c,f][1,2]thiazepine S,S-Dioxide Core

AbstractIn the course of the synthesis of fused-ring analogues of the antidepressant drug tianeptine, representatives of three new heterocyclic ring systems, indolo[1,7-bc][1,2]benzothiazepines (and their 4,5-dihydro analogues), 5,6-dihydroquino[1,8-bc][1,2]benzothiazepines, and [1,2]benzothiazepino[4,3,2-jk]carbazoles, as well as their intermediates, have been prepared. The tetracyclic and pentacyclic ring systems containing either an oxo or a hydroxy functional group are suitable for introducing various side chains, including potential pharmacophores. For this latter transformation, examples are demonstrated by conversion of the hydroxy group into a chloro moiety and subsequent reaction with amines or with primary alcohols bearing a tertiary amino side chain. Two fused-ring derivatives exhibiting the side-chain characteristics of tianeptine have also been synthesized. Altogether 40 compounds are described in the present manuscript, eight of them are also characterized by single-crystal X-ray diffraction.

Tricyclic or Pentacyclic D Units: Design of D-π-A-Type Copolymers for High VOC Organic Photovoltaic Cells.

Although there are several electron-donating (D) units, only the classic benzo[1,2-b:4,5-b']dithiophenes (BDT) unit was utilized to develop D-π-A-type copolymers for high-voltage organic photovoltaic (OPV) cells. Hence, in this work, we chose two tricyclic D units, BDT and benzo[1,2-b:4,5-b']difurans (BDF), together with one pentacyclic ring, dithieno[2,3-d;2',3'-d']benzo[1,2-b;4,5-b']dithiophenes (DTBDT), to comprehensively study the effect of different D units on the optoelectronic properties and photovoltaic performance. By copolymerized with the benzo[1,2,3]triazole (BTA) electron-accepting unit, the final copolymers J52-Cl, F11, and PE52 were combined with a nonfullerene acceptor (NFA) F-BTA3 according to the "Same-A-Strategy." As we preconceived, all the three single-junction OPV cells can obtain high open-circuit voltage (VOC) over 1.10 V. Although the tricyclic D unit of BDF exhibits a slightly lower VOC of 1.12 V because of its mildly larger energy loss of 0.698 eV, its higher carrier mobilities and exciton dissociation efficiency strikingly boost the short-circuit current (JSC) and fill factor, which contribute to a comparable PCE of 10.04% with J52-Cl (10.10%). However, the DTBDT-based polymer PE52 shows the worst performance with a PCE of 6.78% and a VOC of 1.14 V, owing to the higher bimolecular recombination and disordered molecular stacking. Our results indicate that tricyclic D units should be a better choice for constructing D-π-A-type polymers for high-voltage photovoltaic materials than the pentacyclic analogues.

Interaction of new tri-, tetra-, and pentacyclic azaphenothiazine derivatives with calf thymus DNA: Spectroscopic and molecular docking studies

Azaphenothiazines (AZA), modified phenothiazine derivatives, have been reported to exhibit a wide spectrum of biological activities, including anticancer activities, but the mechanisms of their interactions with biomolecules are not fully recognized. In this work, the mode of interaction of selected AZA with calf thymus DNA was investigated using UV–Vis absorption, fluorescence spectroscopy (competition experiment with ethidium bromide, quenching of fluorescence) and molecular docking. The investigated AZA represent dipyrido[3,4-b;3′4′-e][1,4]thiazine, quino[3,2-b]benzo[1,4]thiazine and diquino[3,2-b;2′,3′-e][1,4]thiazine possessing tricyclic, tetracyclic and pentacyclic ring system with the additional N,N-dimethylaminopropyl group at the nitrogen atom in the 1,4 thiazine ring. The results obtained from spectroscopic studies showed that AZA bind to DNA by insertion of a fragment of the fused rings system between the base pair stack in the double helix of DNA. In addition, the number of rings in the AZA structures seemed to be related to the strength of the interaction, because pentacyclic AZA (binding constant Kb = 6.31 × 106 L/mol) demonstrated 10-fold higher affinity towards DNA than the tetracyclic AZA and about 100-fold higher affinity than that of tricyclic AZA. The molecular docking results showed that the binding mode of AZA to DNA helix was an intercalation mode with the partial insertion of one planar part of the AZA structure (the pyridine or quinoline ring) into the neighboring bases of one of the DNA chains with additional hydrogen bonding with the minor groove through the positively charged N,N-dimethylaminopropyl group. Chemical potential (μ), chemical hardness (ƞ), electronegativity (χ) and the value of electrons transferred from one system to another (ΔN) calculated from the HOMO and LUMO energies by the density functional theory method indicated that AZA acted as the electron acceptors to the DNA bases.

Synthesis, structural characterization, and optical properties of benzo[f]naphtho[2,3-b]phosphoindoles.

Phosphole-fused π-conjugated acenes have been attracting interest because of the attractive features of the phosphole moiety, such as fluorescence and chemically modifiable properties. Herein, 6-phenyl-6H-benzo[f]naphtho[2,3-b]phosphoindole was prepared by reacting dichlorophenylphosphine with a dilithium intermediate derived from 3,3′-dibromo-2,2′-binaphthyl. Various derivatives, such as a phospholium salt and a borane–phosphole complex with functional groups on the phosphorus atom were synthesized using the obtained phosphole as a common starting material. Single-crystal X-ray analysis of the parent benzo[f]naphtho[2,3-b]phosphoindole revealed that the pentacyclic ring is almost planar. Fluorescence spectroscopy data showed that the phosphole derivatives, such as phosphine oxide and the phospholium salt and borane complex exhibited photoluminescence in chloroform.

Ascandinines A-D, Indole Diterpenoids, from the Sponge-Derived Fungus Aspergillus candidus HDN15-152.

Four new indole diterpenoids, ascandinines A-D (1-4), were isolated from an Antarctic sponge-derived fungus Aspergillus candidus HDN15-152. Their structures, including absolute configurations, were established based on NMR data, computational calculations, and biosynthetic considerations. Ascandinine A (1) possesses an unprecedented 2-oxabicyclo[2.2.2]octan-3-ol motif embedded in a pentacyclic ring system, while compounds 2-4 represent a rare type of indole diterpenoid featuring the 6/5/5/6/6/6/6-fused ring system. Compound 3 displayed anti-influenza virus A (H1N1) activity with an IC50 value of 26 μM, while compound 4 showed cytotoxicity against HL-60 cells with an IC50 value of 7.8 μM.

Coordination Methods of Thioligands in Trinuclear Complexes of Platinum (II)

The trinuclear complexes with simple and mixed ligands of platinum (II) with mercaptoethanol and mercaptoethylamine have been generated and their contents and structures investigated by numerous physicochemical methods. Mercaptoethanol (SHCH2CH2OH) is coordinated monodentally with just sulfur atom and forms pentacyclic metalchelate ring, where as mercaptoethylamine (HSCH2CH2NH2) is coordinated monodentally as well as bidentally and forms an identical ring (pentacyclic metalchelate). The sulfur atom of ligands plays a bridge role between the metals in the trinuclear platinum complexes. The hydroxyl group of mercaptoethanol does not participate in the coordination

Citronamine A, an Antiplasmodial Isoquinoline Alkaloid from the Australian Marine Sponge Citronia astra.

Citronamine A (1), an isoquinoline alkaloid containing an unprecedented pentacyclic ring system, was isolated from the Australian marine sponge Citronia astra. Based on the combination of MS and NMR analyses and comparison of experimental and TDDFT calculated ECD spectra, the absolute structure of 1 was determined. Compound 1 displayed moderate activity against drug sensitive (3D7) and drug resistant (Dd2) strains of the parasite, Plasmodium falciparum, responsible for malaria.

Penispirozines A-H, Three Classes of Dioxopiperazine Alkaloids with Spirocyclic Skeletons Isolated from the Mangrove-Derived Penicillium janthinellum.

Eight new dioxopiperazine alkaloids, penispirozines A-H (1-8), were discovered from the mangrove-derived fungus Penicillium janthinellum HDN13-309. Their structures were elucidated by spectroscopic analysis, TDDFT-ECD calculations, and X-ray diffraction. Compound 1 had an unusual pyrazino[1,2]oxazadecaline coupled with a thiophane ring system, and compound 2 possessed a 6/5/6/5/6 pentacyclic ring system with two rare spirocyclic centers. Interestingly, compounds 3-8 were distinguished by not only the existence of a spiro-thiophane or spiro-furan ring system but also the chirality of the pentacyclic moiety. Compounds 3 and 4 increased the expression of the two relevant phase II detoxifying enzymes SOD2 and HO-1 at 10 μM.

A four-protein metabolon assembled by a small peptide protein creates the pentacyclic carbonate ring of aldgamycins

Organic carbonates (OCs) are a class of compounds featured by a carbonyl flanked by two alkoxy/aryloxy groups. They exist in either linear or cyclic forms, of which the majority encountered in nature adopt a pentacyclic structure. However, the enzymatic basis for pentacyclic carbonate ring formation remains elusive. Here, we reported that a four-protein metabolon (AlmUII–UV) assembled by a small peptide protein (AlmUV) appends a reactive N-hydroxylcarbamoyl moiety to the decarboxylated aldgamycins followed by a non-enzymatic condensation to give the pentacyclic carbonate ring. Our results have documented an unprecedent mechanism for carbonate formation.

Pyrenosetin D, a New Pentacyclic Decalinoyltetramic Acid Derivative from the Algicolous Fungus Pyrenochaetopsis sp. FVE-087.

The fungal genus Pyrenochaetopsis is commonly found in soil, terrestrial, and marine environments, however, has received little attention as a source of bioactive secondary metabolites so far. In a recent work, we reported the isolation and characterization of three new anticancer decalinoyltetramic acid derivatives, pyrenosetins A–C, from the Baltic Fucus vesiculosus-derived endophytic fungus Pyrenochaetopsis sp. FVE-001. Herein we report a new pentacyclic decalinoylspirotetramic acid derivative, pyrenosetin D (1), along with two known decalin derivatives wakodecalines A (2) and B (3) from another endophytic strain Pyrenochaetopsis FVE-087 isolated from the same seaweed and showed anticancer activity in initial screenings. The chemical structures of the purified compounds were elucidated by comprehensive analysis of HR-ESIMS, FT-IR, [α]D, 1D and 2D NMR data coupled with DFT calculations of NMR parameters and optical rotation. Compounds 1–3 were evaluated for their anticancer and toxic potentials against the human malignant melanoma cell line (A-375) and the non-cancerous keratinocyte cell line (HaCaT). Pyrenosetin D (1) showed toxicity towards both A-375 and HaCaT cells with IC50 values of 77.5 and 39.3 μM, respectively, while 2 and 3 were inactive. This is the third chemical study performed on the fungal genus Pyrenochaetopsis and the first report of a pentacyclic decalin ring system from the fungal genus Pyrenochaetopsis.

Synthesis of the 8,19-Epoxysteroid Eurysterol A.

We report the first chemical synthesis of eurysterol A, a cytotoxic and antifungal marine steroidal sulfate with a unique C8−C19 oxy‐bridged cholestane skeleton. After C19 hydroxylation of cholesteryl acetate, used as an inexpensive commercial starting material, the challenging oxidative functionalization of ring B was achieved by two different routes to set up a 5α‐hydroxy‐7‐en‐6‐one moiety. As a key step, an intramolecular oxa‐Michael addition was exploited to close the oxy‐bridge (8β,19‐epoxy unit). DFT calculations show this reversible transformation being exergonic by about −30 kJ mol−1. Along the optimized (scalable) synthetic sequence, the target natural product was obtained in only 11 steps in 5 % overall yield. In addition, an access to (isomeric) 7β,19‐epoxy steroids with a previously unknown pentacyclic ring system was discovered.

Arene Trifunctionalization with Highly Fused Ring Systems through a Domino Aryne Nucleophilic and Diels–Alder Cascade

AbstractA convenient and efficient domino aryne process was developed under transition‐metal‐free conditions to generate a range of tetra‐ and pentacyclic ring systems. This transformation was realized via a 1,2‐benzdiyne through a nucleophilic and Diels–Alder reaction cascade using styrene as the diene moiety. Three new chemical bonds, namely one C−N and two C−C bonds, and two benzofused rings could be constructed concomitantly, which was made possible by distinct chemoselective control at both the 1,2‐aryne and 2,3‐aryne stages. Moreover, in‐depth studies were carried out on the domino aryne precursors and controlling the diastereoselectivity.

Arene Trifunctionalization with Highly Fused Ring Systems through a Domino Aryne Nucleophilic and Diels-Alder Cascade.

A convenient and efficient domino aryne process was developed under transition-metal-free conditions to generate a range of tetra- and pentacyclic ring systems. This transformation was realized via a 1,2-benzdiyne through a nucleophilic and Diels-Alder reaction cascade using styrene as the diene moiety. Three new chemical bonds, namely one C-N and two C-C bonds, and two benzofused rings could be constructed concomitantly, which was made possible by distinct chemoselective control at both the 1,2-aryne and 2,3-aryne stages. Moreover, in-depth studies were carried out on the domino aryne precursors and controlling the diastereoselectivity.

Betulin-Based Thermoplastics and Thermosets through Sustainable and Industrially Viable Approaches: New Insights for the Valorization of an Underutilized Resource

The use of naturally available building blocks for the preparation of high-performance polymers is attracting increasing interest. Betulin (or betulinol) is a naturally occurring, large, nonaromatic diol with a pentacyclic ring structure that can be extracted in high percentages from the bark of birch trees. Here we demonstrate that betulin can be used to prepare polyesters with exceptional thermal attributes through industrially viable and scalable melt polycondensation reactions. Specifically, betulin-based thermoplastics were synthesized using succinic acid, adipic acid, 1,12-dodecanedioic acid, and 1,18-octadecanedioic acid as comonomers and showed good solubility in common industrial solvents. Additionally, betulin-based polyester thermosets were formulated via the incorporation of glycerol as a cross-linker. A systematic study evaluating the effect of various comonomers on the structure–property relationships of these betulin-derived thermoplastics (Mws ranging from 7500 g mol–1 to about 60,000 g mo...

Effect of Alkyl Chain Length and Linker Atom on the Crystal Packing in 6,12-Dialkoxy- and 6,12-Dialkylsulfanyl-Benzo[1,2-b:4,5-b′]bis[b]benzothiophenes

The effect of varying the chain length on the solid state conformation and packing of 6,12-dialkoxy- and 6,12-dialkylsulfanyl-benzo[1,2-b:4,5-b’]bis[b]benzothiophenes has been studied. The compounds were prepared by SNAr reaction of 6,12-difluorbenzo[1,2-b:4,5-b’]bis[b]benzothiophene with alkoxides or alkanethiolates derived from C7-C10 alcohols and alkanethiols. Single crystal X-ray diffraction analysis revealed all but two compounds to crystallise in the triclinic space group P1. Two compounds were obtained as monoclinic crystals with space group P21/c. The alkoxy substituted compounds adopted a molecular conformation with a step from the core and a gauche conformation about the C1’-C2’ bond placing the alkyl chains close to parallel with the pentacyclic arene ring system, whereas in the alkylsufanyl derivatives, the alkyl chains were arranged strongly deviated from the plane of the ring, with the sulfur atom anti-periplanar to C3’ of the alkyl chain. NMR measurement of T1 relaxation in CDCl3 showed both the alkoxy and alkylsulfanyl substituents to be freely rotating at ambient temperature in solution indicating the orientation of the chains in the solid state was due to packing interactions during crystallization.

Grayanane Diterpenoids from the Leaves of Rhododendron auriculatum and Their Analgesic Activities.

Twenty-four grayanane diterpenoids (1-24) including 12 new ones (1-12) were isolated from Rhododendron auriculatum. The structures of the new grayanane diterpenoids (1-12) were defined via extensive spectroscopic data analysis. The absolute configurations of compounds 2-4, 10-12, 14, and 16 were established by single-crystal X-ray diffraction analysis, and electronic circular dichroism data were used to define the absolute configurations of auriculatols D (8) and E (9). Auriculatol A (1) is the first example of a 5,20-epoxygrayanane diterpenoid bearing a 7-oxabicyclo[4.2.1]nonane motif and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring system. Auriculatol B (2) is the first example of a 3α,5α-dihydroxy-1-βH-grayanane diterpenoid. 19-Hydroxy-3-epi-auriculatol B (6) and auriculatol C (7) represent the first examples of 19-hydroxygrayanane and grayan-5(6)-ene diterpenoids, respectively. Diterpenoids 1-24 showed analgesic activities in the writhing test induced by HOAc, and 2, 6, 10, 13, 19, and 24 at a dose of 5.0 mg/kg exhibited significant analgesic effects (inhibition rates >50%). Grayanane diterpenoids grayanotoxins I (19) and IV (24) at doses of 0.2 and 0.04 mg/kg showed more potent analgesic activities than morphine.

Linderalides A–D, Disesquiterpenoid–Geranylbenzofuranone Conjugates from Lindera aggregata

Four disesquiterpenoid-geranylbenzofuranone conjugates, linderalides A-D (1-4), were isolated from Lindera aggregata. Compounds 1-3 represent the first examples of disesquiterpenoid-geranylbenzofuranone hybrids directly linked by two C-C bonds. Linderalide D (4) bears an unprecedented carbon skeleton featuring an unusual linearly 6/6/5/6/6 pentacyclic ring system fused by a sesquiterpenoid unit and a geranylbenzofuranone moiety. Their structures and absolute configurations were elucidated by extensive spectroscopic data and electronic circular dichroism analysis. Their biosynthetic pathways were also proposed.