Polyacetylene Derivatives from the Polypore Fungus (Fistulina hepatica, Agaricomycetes) and Their Antimicrobial Activity.

Chemical investigation of the polypore fungus Fistulina hepatica resulted in the isolation of five compounds, including four new polyacetylenic fatty acid derivatives - isocinnatriacetin B (1), isocinnatriacetin A (2), cinna-triacetin C (3) and ethylcinnatriacetin A (4) together with one known polyacetylene fatty acid derivative - cinnatriacetin A (5). The structures were elucidated using spectroscopic methods (UV, NMR, HR-ESIMS) along with comparison to literature data. Antibacterial activity screening of compounds 1-5 against ESKAPE bacterial strains in vitro with zones of inhibition (ZOI) was performed and MIC values were established for the most active compounds (3 and 4). Together with that morphological and growth parameters under solid-phase cultivation were also researched.

In Vitro and In Silico Investigation of Polyacetylenes from Launaea capitata (Spreng.) Dandy as Potential COX-2, 5-LOX, and BchE Inhibitors.

Diverse secondary metabolites are biosynthesized by plants via various enzymatic cascades. These have the capacity to interact with various human receptors, particularly enzymes implicated in the etiology of several diseases. The n-hexane fraction of the whole plant extract of the wild edible plant, Launaea capitata (Spreng.) Dandy was purified by column chromatography. Five polyacetylene derivatives were identified, including (3S,8E)-deca-8-en-4,6-diyne-1,3-diol (1A), (3S)-deca-4,6,8-triyne-1,3-diol (1B), (3S)-(6E,12E)-tetradecadiene-8,10-diyne-1,3-diol (2), bidensyneoside (3), and (3S)-(6E,12E)-tetradecadiene-8,10-diyne-1-ol-3-O-ß-D-glucopyranoside (4). These compounds were investigated for their in vitro inhibitory activity against enzymes involved in neuroinflammatory disorders, including cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), and butyrylcholinesterase (BchE) enzymes. All isolates recorded weak-moderate activities against COX-2. However, the polyacetylene glycoside (4) showed dual inhibition against BchE (IC50 14.77 ± 1.55 µM) and 5-LOX (IC50 34.59 ± 4.26 µM). Molecular docking experiments were conducted to explain these results, which showed that compound 4 exhibited greater binding affinity to 5-LOX (-8.132 kcal/mol) compared to the cocrystallized ligand (-6.218 kcal/mol). Similarly, 4 showed a good binding affinity to BchE (-7.305 kcal/mol), which was comparable to the cocrystallized ligand (-8.049 kcal/mol). Simultaneous docking was used to study the combinatorial affinity of the unresolved mixture 1A/1B to the active sites of the tested enzymes. Generally, the individual molecules showed lower docking scores against all the investigated targets compared to their combination, which was consistent with the in vitro results. This study demonstrated that the presence of a sugar moiety (in 3 and 4) resulted in dual inhibition of 5-LOX and BchE enzymes compared to their free polyacetylenes analogs. Thus, polyacetylene glycosides could be suggested as potential leads for developing new inhibitors against the enzymes involved in neuroinflammation.

Polyacetylenes from the adventitious roots of Centella asiatica with glucose uptake stimulatory activity.

Centella asiatica (L.) Urban is an herbaceous perennial plant of the Apiaceae family that has diverse medicinal uses. Its active components are saponin, phenolics, and polyacetylenes. Plant cell cultures have been exploited for the efficient production of metabolites with pharmacological activity. In this work, we prepared adventitious root cultures of C. asiatica and analyzed their content and biological activity. Adventitious root extracts were found to increase glucose uptake by differentiated L6 skeletal muscle cells and to be more efficient than the extract of whole plants. Chromatographic fractionation of the extracts from adventitious roots of C. asiatica led to the isolation of two known polyacetylenes, araliadiol (1) and 8-acetoxy-1,9-pentadecadiene-4,6-diyn-3-ol (2), in addition to a new polyacetylene, which we have named centellidiol (3). All the three polyacetylenes stimulated glucose uptake in a dose-dependent manner. The methanol extract of adventitious roots contained 0.53% and 0.82% of compounds 1 and 2, respectively, which are values that were 15 and 21 times higher that are found in mother plants. We therefore suggest that the high content of these polyacetylenes contributes to the high efficacy of C. asiatica adventitious root cultures. Overall, adventitious root cultures of C. asiatica can be part of a secure supply of effective ingredients including polyacetylenes.

Six polyacetylenes from Atractylodes macrocephala Koidz and their anti-colon cancer activity.

Six undescribed polyacetylenes Atracetylenes A-F (1-6) and three known ones (7-9) were isolated from the rhizomes of Atractylodes macrocephala Koidz.. The comprehensive interpretation of NMR, HR-ESI-MS, DP4+ calculations, and electronic circular dichroism (ECD) calculations resulted in the elucidation of their structures and absolute configurations. The anti-colon cancer activities of (1-9) were evaluated by assaying the cytotoxicity and apoptosis on CT-26 cell lines. Notably, 5 (IC50 17.51 ± 1.41 µM) and 7 (IC50 18.58 ± 1.37 µM) exhibited significant cytotoxicity, and polyacetylenes 3-6 showed excellent abilities to promote apoptosis of CT-26 cell lines by Annexin V-FITC/PI assay. The results demonstrated that the polyacetylenes in A. macrocephala may be prospective for the treatment of colorectal cancer.

Dynamic helical cationic polyacetylenes for fast and highly efficient killing of bacteria.

The antimicrobial activity of native antimicrobial peptides (AMPs) is often attributed to their helical structure, but the effectiveness of synthetic mimics with dynamic helical conformations, such as antimicrobial cationic polymers (ACPs), has not been well studied. Herein we demonstrate the antimicrobial activity of pyrrolidinium-pendant polyacetylenes (PAs) with dynamic helical conformations. The PAs exhibit fast and efficient antimicrobial activity against a wide range of pathogens, with low toxicity to mammalian cells and minimal risk of antibiotic resistance. In addition, the full-thickness wound infection model in mice has demonstrated the favorable biocompatibility and effective in vivo antibacterial capabilities of these PAs. Our data suggest that the dynamic helical structure of these PAs allows them to adapt and form pores in the bacterial membrane upon interaction, leading to their potent antimicrobial activity. This work investigated the antibacterial mechanism of dynamic helical ACPs, which provides valuable guidance for the rational design of high-performance antimicrobial agents. STATEMENT OF SIGNIFICANCE: Our study represents a significant contribution to the literature on antimicrobial cationic polymers (ACPs) as alternatives to antibiotics. Through a systematic investigation of the role of dynamic helical conformation in polyacetylenes (PAs) and the use of PAs with adaptive structure for the first time, we have provided valuable insights into the bacterial membrane action and killing mechanisms of these polymers. The results of our study, including fast killing rates and minimum inhibitory concentrations as low as 4-16 µg/mL against a broad range of pathogens and strong in vivo antibacterial activity, demonstrate the potential of these ACPs as high-performance antimicrobials. Our findings may guide the design of future ACPs with enhanced antimicrobial activity.

Polyacetylenes from the roots of Cirsium japonicum var. ussuriense.

Eight previously undescribed polyacetylenes, cirussurynes A-H, were isolated from the methanolic extract of the roots of Cirsium japonicum var. ussuriense. Their structures were elucidated by interpretation of extensive 1D and 2D NMR spectroscopy and HRESIMS spectrometry data. The configuration of triols in cirussurynes A, B, and E-G was deduced by the J-value based configuration analysis together with specific rotation values. All compounds were evaluated for their inhibitory effects on nitric oxide production against LPS-induced RAW 264.7 macrophages, and exhibited IC50 values ranging from 5.5 to 68.7 µM.

Polyacetylenes from Codonopsis lanceolata Root Induced Apoptosis of Human Lung Adenocarcinoma Cells and Improved Lung Dysbiosis.

Codonopsis lanceolata is a perennial smelly herbaceous plant and widely employed for the treatment of various lung cancer and inflammation. However, the anticancer substances in C. lanceolata and their underlying mechanisms had not been well clarified. In this study, six compounds were obtained from the water extracts of C. lanceolata polyacetylenes (CLP) and then identified as syringin, codonopilodiynoside A, lobetyol, isolariciresinol, lobetyolin, and atractylenolide III. Treatment with CLP remarkably suppressed the cell proliferation, colony formation, migration, and invasion of A549 cells. Synergistic effects of lobetyolin and lobetyol were equivalent to the antiproliferative activities of CLP, while other compounds did not have any inhibition on the viabilities of A549 cells. CLP also reduced the expression of Ras, PI3K, p-AKT, Bcl-2, cyclin D1, and CDK4 but increased the expression of Bax, GSK-3ß, clv-caspase-3, and clv-caspase-9, which could be reversed by the PI3K activator 740YP. Furthermore, CLP retarded the growths of tumor and lung pathogenic bacteria in mice. It demonstrated that lobetyolin and lobetyol were the main antitumor compounds in C. lanceolata. CLP induced cell apoptosis of lung cancer cells via inactivation of the Ras/PI3K/AKT pathway and ameliorated lung dysbiosis, suggesting the therapeutic potentials for treating human lung cancer.

Bioactive polyacetylenes from Bidens pilosa L and their anti-inflammatory activity.

A new polyacetylenic glucoside together with three known compounds were isolated from the whole herb of Bidens pilosa L. The structure elucidation of these four compounds was employed by combining NMR and HR-MS data as 4-O-ß-D-glucopyranosyloxy-1-hydroxy- 6-(E)-tetradecene-8,10,12-triyne (1), 3-O-ß-D-glucopyranosyloxy-1-hydroxy-6-(E)-tetradec- ene-8,10,12-triyne (2), 2-O-ß-D-glucopyranosyloxy-1-hydroxy-5-(E)-tetradecene-7,9,11-triy- ne (3) and icthyothereol acetate (4). Additionally, bioactivity study showed that these compounds have potential anti-inflammatory activity. This study has certain guiding significance for the development and utilisation of polyacetylene compounds in Bidens pilosa L.

UV-guided isolation of enantiomeric polyacetylenes from Bupleurum scorzonerifolium Willd. with inhibitory effects against LPS-induced NO release in BV-2 microglial cells.

UV-guided fractionation led to the isolation of thirteen new polyacetylenes (1-13) from the roots of Bupleurum scorzonerifolium Willd. All polyacetylenes were analyzed as racemates since the lack of optical activity and Cotton effects in the ECD spectra. The sequent chiral-phase HPLC resolution successfully gave twelve pairs of enantiomers 1a/1b and 3a/3b-13a/13b. Their structures were elucidated based on the HRESIMS and NMR data analyses. The absolute configurations were determined by the combination of Snatzke's method, electronic circular dichroism calculations, and single-crystal X-ray diffraction. Using Griess methods and MTT assays, polyacetylenes 1a, 3a, 4a/4b-12a/12b, and 13a displayed inhibitory activities against LPS-induced NO release in BV-2 microglial cells.

Secondary Metabolites from the Marine Sponges of the Genus Petrosia: A Literature Review of 43 Years of Research.

Sponges are prolific sources of various natural products that have provided the chemical scaffolds for new drugs. The sponges of the genus Petrosia inhabit various regions and contain a variety of biologically active natural products such as polyacetylenes, sterols, meroterpenoids, and alkaloids. This review aims to provide a comprehensive summary of the chemical structures and biological activities of Petrosia metabolites covering a period of more than four decades (between 1978 and 2020). It is also described in this review that the major groups of metabolites from members of the genus Petrosia differed with latitude. The polyacetylenes were identified to be the most predominant metabolites in Petrosia sponges in temperate regions, while tropical Petrosia species were sources of a greater variety of metabolites, such as meroterpenoids, sterols, polyacetylenes, and alkaloids.

A new polyacetylene and other constituents with anti-inflammatory activity from Artemisia halodendron.

A new polyacetylene, (3 R,8S)-heptadeca-1,16-dien-4,6-diyne-3,8-diol (1), together with 10 known compounds (2-11) were isolated from an ethanol extract of Artemisia halodendron Turcz. ex Bess. (Asteraceae). The chemical structures of these compounds were elucidated by NMR and HR-ESI-MS analysis, and by comparing these results with data reported in literatures. Compounds 1-11 were evaluated for their inhibitory activity against NO, TNF-α and IL-6 production. Compounds 1-11 significantly inhibited the levels of NO, TNF-α and IL-6 in LPS-induced RAW264.7 cells in a dose-dependent manner, with IC50 values ranging from 15.12 to 66.97 µM.

Osirisynes G-I, New Long-Chain Highly Oxygenated Polyacetylenes from the Mayotte Marine Sponge Haliclona sp.

Chemical study of the CH2Cl2-MeOH (1:1) extract from the sponge Haliclona sp. collected in Mayotte highlighted three new long-chain highly oxygenated polyacetylenes, osirisynes G-I (1-3) together with the known osirisynes A (4), B (5), and E (6). Their structures were elucidated by 1D and 2D NMR spectra and HRESIMS and MS/MS data. All compounds were evaluated on catalase and sirtuin 1 activation and on CDK7, proteasome, Fyn kinase, tyrosinase, and elastase inhibition. Five compounds (1; 3-6) inhibited proteasome kinase and two compounds (5-6) inhibited CDK7 and Fyn kinase. Osirisyne B (5) was the most active compound with IC50 on FYNB kinase, CDK7 kinase, and proteasome inhibition of 18.44 µM, 9.13 µM, and 0.26 µM, respectively.

Toonasindiynes A-F, new polyacetylenes from Toona sinensis with cytotoxic and anti-inflammatory activities.

The plants of genus Toona are well known for diverse limonoid secondary metabolites, while polyacetylenes are rarely found from Toona species. In this work, six new polyacetylenes toonasindiynes A-F (1-6) and six known analogues (7-12) were isolated from the root bark of Toona sinensis. Their structures and absolute configurations were elucidated by HRESIMS, 1D and 2D NMR spectroscopic analysis, modified Mosher's method, and biosynthetic consideration. These polyacetylenes share the same 4,6-diyne moiety with different side chain length and different oxidation degree. Bioactivity screening revealed the cytotoxic activity of 3, 5, 9, and 11 against U2OS cells, and the inhibitory effects on nitric oxide (NO) production of 1, 2, 5, 8, 9, and 11 in lipopolysaccharide-induced RAW 264.7 cells.

Three new polyacetylene glycosides (PAGs) from the aerial part of Launaea capitata (Asteraceae) with anti-biofilm activity against Staphylococcus aureus.

Four polyacetylenic glycosides, three of which are new, together with two known flavonoids were isolated from the methanol extract of the aerial parts of Launaea capitate, designated bidensyneoside A1 (1), 6´-O-acetyl-bidensyneoside A1 (2), bidensyneoside E (3), bidensyneoside F (4), luteolin (5) and luteolin-7-glucoside (6) also known as cynaroside. Their structures were elucidated by comprehensive analysis of 1D, 2D-NMR and HR-MS data. The absolute configuration of the bidensyneosides was determined by Mosher ester analysis and the optical rotation values. The isolated compounds were tested against biofilm formation of Staphylococcus aureus as well as against several pathogens including Gram-positive bacteria, Gram-negative bacteria, fungi and yeasts. Furthermore, they were tested for their cytotoxicity against two cancer cell lines L929 and KB-3-1. Compound 4 showed moderate inhibition of S. aureus biofilm formation with 30% and 25% at 256 and 128 µg/mL, respectively, while compounds 1 and 5 showed weak inhibition with 20% at 256 µg/mL. Compound 5 showed moderate cytotoxicity against both cell lines L929 and KB-3-1, with IC50 values of 18 µg/mL.

Enantioselective Synthesis and Antifungal Activity of C18 Polyacetylenes.

Fungal pathogens cause serious crop diseases and decrease crop yields and quality. Polyacetylene alcohols are plant secondary metabolites and bioactive against various pathogenic fungi. They are, however, difficult to synthesize. In the present study, an efficient and highly enantioselective method (>98% ee) was established and employed to achieve the synthesis of the natural C18 polyacetylenes (S,E)-octadeca-1,9-dien-4,6-diyn-3-ol 1, (3R,10R,E)-octadeca-1,8-dien-4,6-diyne-3,10-diol 2, and their analogs. The title compounds were structurally characterized and biologically evaluated for fungicidal activities. The compounds exhibited high potencies against eight pathogenic fungal species tested, such as Colletotrichum gloeosporioiles, Bipolaris sorokiniana, Fusarium graminearum, and Fusarium pseudograminearum, with half-maximum effective concentrations ranging from 8 to 425 µg/mL, being similar to those of the fungicide thiophanate-methyl (3-408 µg/mL). These compounds are potential natural fungicides and fungicide lead candidates for further structural and property improvements.

Albanitriles A-G: Antiprotozoal Polyacetylene Nitriles from a Mycale Marine Sponge.

Seven new nitrile-bearing polyacetylenes, named albanitriles A-G, were isolated from a marine sponge of the Mycale genus (Order: Poecilosclerida, Family: Mycalidae) collected near Albany, Western Australia. Structural elucidation was achieved using a combination of high-resolution mass spectrometry and ultraviolet/visible, infrared, and nuclear magnetic resonance spectroscopy. The compounds were found to possess moderate activity against Giardia duodenalis when compared to a metronidazole positive control.

Dendropanax morbifera Branch Water Extract Increases the Immunostimulatory Activity of RAW264.7 Macrophages and Primary Mouse Splenocytes.

Polyacetylenes in the bark of Dendropanax morbifera trees have been reported to promote immune cell proliferation and to strengthen the innate immune system. The immunomodulatory potential of D. morbifera branch water extract (DBW) was evaluated by determining its effect on cell viability and the expression of cytokines and immune effector molecules in mouse RAW264.7 macrophages and splenocytes. Production of nitric oxide (NO), inducible nitric oxide synthase (iNOS), and cytokines (interleukin [IL]-1ß, IL-2, and IFN-γ) in RAW264.7 macrophages increased after treatment with DBW. The activation of components of the NF-κB signaling pathway, including the phospho-IκBα and the expression and translocation of p65, a subunit of NF-κB, were also increased in RAW264.7 mouse macrophage cells after treatment with DBW. In addition, when mice were orally administered DBW, splenocyte cytokines and NO production were increased in a dose-dependent manner relative to control-treated mice. Furthermore, natural killer cell activity in DBW-treated mice was determined by lactate dehydrogenase (LDH) release assay. LDH release also increased in response to DBW treatment. Taken together, these results indicate that D. morbifera extract enhances innate immunity by promoting NF-κB signaling, leading to increased expression of proinflammatory cytokines and effector molecules. DBW therefore has potential therapeutic use in the context of immune stimulation.

Oxygenated C17 polyacetylene metabolites from Algerian Eryngium tricuspidatum L. roots: Structure and biological activity.

The secondary metabolite pattern of Eryngium tricuspidatum has been found to be dominated by C17 acetylene oxylipins, according to the chemistry reported in the literature for the genus Eryngium. Two new oxylipins, 11-acetoxy-falcarindiol (4) and 1,2-dihydro-11-acetoxy-falcarindiol (5) have been isolated, along with main related polyacetylenes 1-3 and the already known monoterpene aldehydes 6-10, from the petroleum ether extract of roots. The structure and the absolute configuration of compounds 4 and 5 have been determined by spectroscopic methods as well as by comparison with related known compounds. Polyacetylenes 1-4 inhibited significantly the in vitro growth of a series of cancer cell lines, ranging from 0.3 to 29 µM, whereas 5 was inactive.

Anti-Inflammatory Compounds from Atractylodes macrocephala.

In relation to anti-inflammatory agents from medicinal plants, we have isolated three compounds from Atractylodes macrocephala; 1, 2-[(2E)-3,7-dimethyl-2,6-octadienyl]-6-methyl-2, 5-cyclohexadiene-1, 4-dione; 2, 1-acetoxy-tetradeca-6E,12E-diene-8, 10-diyne-3-ol; 3, 1,3-diacetoxy-tetradeca-6E, 12E-diene-8, 10-diyne. Compounds 1-3 showed concentration-dependent inhibitory effects on production of nitric oxide (NO) and prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. Western blotting and RT-PCR analyses demonstrated that compounds 1-3 suppressed the protein and mRNA levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Furthermore, compounds 1-3 inhibited transcriptional activity of nuclear factor-κB (NF-κB) and nuclear translocation of NF-κB in LPS-activated RAW 264.7 cells. The most active compound among them, compound 1, could reduce the mRNA levels of pro-inflammatory cytokines (IL-1ß, IL-6 and TNF-α) and suppress the phosphorylation of MAPK including p38, JNK, and ERK1/2. Taken together, these results suggest that compounds 1-3 from A. macrocephala can be therapeutic candidates to treat inflammatory diseases.

Polyacetylenes from the Roots of Swietenia macrophylla King.

A phytochemical investigation of the roots of Swietenia macrophylla led to the isolation of seven polyacetylenes, including five new compounds (1-5) and two known ones (6-7). Their structures were elucidated by extensive spectroscopic analysis and detailed comparison with reported data. All the isolates were tested for their cytotoxicity against the human hepatocellular carcinoma cell line BEL-7402, human myeloid leukemia cell line K562, and human gastric carcinoma cell line SGC-7901. Compounds 1 and 6 showed moderate cytotoxicity against the above three human cancer cell lines with IC50 values ranging from 14.3 to 45.4 µM. Compound 4 displayed cytotoxicity against the K562 and SGC-7901 cancer cell lines with IC50 values of 26.2 ± 0.4 and 21.9 ± 0.3 µM, respectively.