Electronic Circular Dichroism Research Articles

Alliaceumolide A: A rare undescribed 17-membered macrolide from Indonesian Dysoxylum alliaceum

Alliaceumolide A (1), a new macrolide together with known ivorenolide B (2) were isolated from Dysoxylum alliaceum (Blume) Blume ex A.Juss. These compounds were classified as 17-membered macrolide, which is a rare structure for plant-derived natural products. The structures were elucidated by extensive spectroscopic analyses, and the absolute configuration of 1 was determined by electronic circular dichroism (ECD) using TDDFT method. Furthermore, compounds 1 and 2 were tested for cytotoxic activity against two cancer MCF-7 and HeLa cell lines.

Phytochemical and biological studies on rare and endangered plants endemic to China. Part XXXVI. Tsugaforrestiacids A–O: Structurally diverse C-18 carboxylated diterpenoids from the twigs and needles of the ‘vulnerable’ conifer Tsuga forrestii and their inhibitory effects on ATP-citrate lyase

An extensive phytochemical investigation on the EtOAc-soluble fraction of the 90% MeOH extract from the twigs and needles of the ‘vulnerable’ Chinese endemic conifer Tsuga forrestii (Forrest's hemlock) led to the isolation and characterization of 50 structurally diverse diterpenoids, including 15 unreported C-18 carboxylated ones (tsugaforrestiacids A−O, 1−15, resp.). Among them, compounds 1−7 are abieten-18-oic acids, compound 8 is an abieten-18-succinate, and compounds 10−12 are podocarpen-18-oic acids, whereas compounds 13−15 are pimarane-type, isopimarane-type, and totarane-type diterpenoid acids, respectively. Their structures and absolute configurations were determined by a combination of spectroscopic methods, GIAO NMR calculations and DP4+ probability analyses, electronic circular dichroism (ECD) data, and single crystal X-ray diffraction analyses. All the isolates were evaluated for their inhibitory activities against the ATP-citrate lyase (ACL), a key enzyme in cellular metabolism. Tsugaforrestiacids E (5) and H (8) were found to have significant inhibitory effects against ACL, with IC50 values of 5.3 and 6.2 μM, respectively. The interactions of the bioactive molecules with the ACL enzyme were examined by molecular docking studies. The isolated diterpenoids also provide chemotaxonomic evidence to support the delimitation of Tsuga from its closest sister group (Nothotsuga). The above findings highlight the importance of protecting plant species with unique and diverse secondary metabolites, which may be potential sources of new therapeutic agents for the treating ACL-associated diseases.

Phenolic Constituents with Glucose Uptake and GLUT4 Translocation Bioactivities from the Fruits of Cordia dichotoma.

From the fruits of Cordia dichotoma, 11 new phenolic compounds, dichotomins A-K, were isolated, together with 19 known compounds. Through the analysis of detailed NMR data and HRESIMS data, the planar structures of all compounds were confirmed. Using NMR calculations, the absolute configuration of dichotomins A-K was elucidated by comparing their observed and computed electronic circular dichroism (ECD) spectra. Dichotomin H (8) and dichotomin I (9) were determined as two pairs of enantiomers. The enantiomers of compounds 8 and 9 were separated using chiral-phase high-performance liquid chromatography (HPLC), and the stereostructure of each enantiomer was determined by similarly calculating the ECD. Compounds 3, 5, 7, 17, 18, 23-25, and 27-30 increased glucose uptake by 1.04- to 2.85-folds at concentrations of 30 μg/mL. Further studies revealed that compounds 3 and 5 had a moderate effect on glucose transporter 4 (GLUT4) translocation activity in L6 cells. At 30 μg/mL, compound 3 significantly enhanced AMPK phosphorylation and GLUT4 expression. As a whole, compound 3 has the potential to be a drug candidate for the treatment of type 2 diabetes mellitus (T2DM).

Phenolic Constituents with Glucose Uptake and GLUT4 Translocation Bioactivities from the Fruits of Cordia dichotoma.

From the fruits of Cordia dichotoma, 11 new phenolic compounds, dichotomins A-K, were isolated, together with 19 known compounds. Through the analysis of detailed NMR data and HRESIMS data, the planar structures of all compounds were confirmed. Using NMR calculations, the absolute configuration of dichotomins A-K was elucidated by comparing their observed and computed electronic circular dichroism (ECD) spectra. Dichotomin H (8) and dichotomin I (9) were determined as two pairs of enantiomers. The enantiomers of compounds 8 and 9 were separated using chiral-phase high-performance liquid chromatography (HPLC), and the stereostructure of each enantiomer was determined by similarly calculating the ECD. Compounds 3, 5, 7, 17, 18, 23-25, and 27-30 increased glucose uptake by 1.04- to 2.85-folds at concentrations of 30 μg/mL. Further studies revealed that compounds 3 and 5 had a moderate effect on glucose transporter 4 (GLUT4) translocation activity in L6 cells. At 30 μg/mL, compound 3 significantly enhanced AMPK phosphorylation and GLUT4 expression. As a whole, compound 3 has the potential to be a drug candidate for the treatment of type 2 diabetes mellitus (T2DM).

Genome-Driven Discovery of Antiviral Atralabdans A-C from the Soil-Dwelling Streptomyces atratus.

Heterologous expression of an atr terpenoid gene cluster derived from Streptomyces atratus Gö66 in S. albus J1074 led to the discovery of three novel labdane diterpenoids featuring an unprecedented 6/6/5-fused tricyclic skeleton, designated as atralabdans A-C (1-3), along with a known compound, labdanmycin A. Compounds 1-3 were identified through extensive spectroscopic analysis, including NMR calculations with DP4+ probability analysis, and a comparative assessment of experimental and theoretical electronic circular dichroism (ECD) spectra. A plausible biosynthetic pathway for these compounds was proposed. Compounds 1-3 exhibited inhibitory activity against the human neurotropic coxsackievirus B3 (CVB3); 1 was the most potent, surpassing the positive control ribavirin with a higher therapeutic index.

Chromomycins from soil-derived Streptomyces sp. inhibit the growth of human non-small cell lung cancer cells by targeting c-FLIP

Three chromomycin derivatives, chromomycins A3 (1, CA3), A5 (2, CA5), and monodeacetylchromomycin A3 (3, MDA-CA3), were identified from the soil-derived Streptomyces sp. CGMCC 26516. A reinvestigation of the structure of CA5 is reported, of which the absolute configuration was unambiguously determined for the first time to be identical with that of CA3 based on nuclear magnetic resonance (NMR) data analysis as well as NMR and electronic circular dichroism calculations. Compounds 1–3 showed potent cytotoxicity against the non-small-cell lung cancer (NSCLC) cells (A549, H460, H157-c-FLIP, and H157-LacZ) and down-regulated the protein expression of c-FLIP in A549 cells. The IC50 values of chromomycins in H157-c-FLIP were higher than that in H157-LacZ. Furthermore, si-c-FLIP promoted anti-proliferation effect of chromomycins in NSCLC cells. In nude mice xenograft model, 1 and 2 both showed more potent inhibition on the growth of H157-lacZ xenografts than that of H157-c-FLIP xenografts. These results verify that c-FLIP mediates the anticancer effects of chromomycins in NSCLC.

A Joint Experimental and Theoretical Study on the Structural and Spectroscopic Properties of the Piv-Pro-d-Ser-NHMe Peptide.

In this paper, we investigate the secondary structure of the Piv-Pro-d-Ser-NHMe peptide by means of nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) experiments, in conjunction with theoretical simulations based on molecular dynamics and time-dependent density functional theory calculations including polarizable embedding to account for solvent effects. The various experimental and theoretical protocols are assessed and validated, and are shown to provide a consistent description of the turn structure adopted by this peptide in solution. In addition, a simple fitting procedure is proposed to make the simulated and experimental ECD almost perfectly match. This full methodology is finally tested on another small peptide, enlightening its efficiency and robustness.

Laburnicolamine: A Rare Penillic Acid Congener from the Nematode Cyst-Associated Fungus Laburnicola nematophila.

A chemical investigation of a methanol extract derived from a solid-state rice culture of the nematode-cyst associated fungus Laburnicola nematophila K01 led to the isolation and characterization of a previously undescribed penillic acid analogue named laburnicolamine (1). The chemical structure was elucidated through comprehensive 1D and 2D NMR spectroscopic analyses in methanol-d4 and DMSO-d6, alongside with HR-ESI-MS spectrometry. The absolute configuration of 1 was concluded through the electronic circular dichroism (ECD) and time-dependent density functional theory-ECD (TDDFT-ECD) computations compared to its acquired spectrum. Biological assays revealed that compound 1 exhibited no significant cytotoxic, antimicrobial, or nematicidal activity.

Induced Chirality in Sulfasalazine by Complexation With Albumins: Theoretical and Experimental Study.

Through molecular recognition, drugs can interact and complex with macromolecules circulating in the body. The serum albumin transport protein, found in several mammals, has several interaction sites where these molecules can be located. The drug sulfasalazine (SSZ) is known in the literature to complex at drug site 1 (DS1) in human serum (HSA) and bovine serum (BSA) proteins. This complexation can be studied using various spectroscopic techniques. With the techniques used in this work, absorption in the ultraviolet and visible regions (UV-Vis) and electronic circular dichroism (ECD), a significant difference was observed in the results involving HSA and BSA. The application of theoretical methodologies, such as TD-DFT and molecular docking, suggests that the conformation that SSZ assumes in DS1 of the two proteins is different, which exposes it to different amino acid residues and different hydrophobicities. This difference in conformation may be related to the location of DS1 where the drug interacts or to the possibility of SSZ moving in the BSA site, due to its larger size, and moving less freely in HSA.

Heteryunine A, an amidated tryptophan-catechin-spiroketal hybrid with antifibrotic activity from Heterosmilax yunnanensis

An unprecedented spiroC-glycoside adduct, heteryunine A (1), along with two uncommon alkaloids featuring a 2,3-diketopiperazine skeleton, heterpyrazines A (2) and B (3), were discovered in the roots of Heterosmilax yunnanensis. The detailed spectroscopic analysis helped to clarify the planar structures of these compounds. Compound 1, containing 7 chiral centers, features a catechin fused with a spiroketal and connects with a tryptophan derivative by a CC bond. Its complex absolute configuration was elucidated by rotating frame overhauser enhancement spectroscopy (ROESY), specific rotation, and the 13C nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculation. The possible biosynthetic routes for 1 were deduced. Compounds 1 and 2 showed significant antifibrotic effects and further research revealed that they inhibited the activation, migration and proliferation of hepatic stellate cells (HSCs) through suppressing the activity of Ras homolog family member A (RhoA).

Heteryunine A, an amidated tryptophan-catechin-spiroketal hybrid with antifibrotic activity from Heterosmilax yunnanensis

An unprecedented spiro-C-glycoside adduct, heteryunine A (1), along with two uncommon alkaloids featuring a 2,3-diketopiperazine skeleton, heterpyrazines A (2) and B (3), were discovered in the roots of Heterosmilax yunnanensis. The detailed spectroscopic analysis helped to clarify the planar structures of these compounds. Compound 1, containing 7 chiral centers, features a catechin fused with a spiroketal and connects with a tryptophan derivative by a CC bond. Its complex absolute configuration was elucidated by rotating frame overhauser enhancement spectroscopy (ROESY), specific rotation, and the 13C nuclear magnetic resonance (NMR) and electronic circular dichroism (ECD) calculation. The possible biosynthetic routes for 1 were deduced. Compounds 1 and 2 showed significant antifibrotic effects and further research revealed that they inhibited the activation, migration and proliferation of hepatic stellate cells (HSCs) through suppressing the activity of Ras homolog family member A (RhoA).

New polycyclic polyprenylated acylphloroglucinols with antidepressant activities from Hypericum perforatum L.

Six new polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperidiones A-F (1–6), were obtained from Hypericum perforatum L. Their structures were characterized via extensive spectroscopic analyses, the circular dichroism data of the in situ formed [Mo2(OCOCH3)4] complexes, the nuclear magnetic resonance calculation with DP4 + probability analysis, and the calculated electronic circular dichroism (ECD) spectra. Compounds 1–6 are bicyclic polyprenylated acylphloroglucinols with a major bicyclo[3.3.1]nonane-2,4,9-trione skeleton. Notably, compound 1 is a rare PPAP with a hydroperoxy group, and a plausible biosynthetic pathway for 1 was proposed. Compounds 4 and 6 exhibited significant neuroprotective effects under 10 μM against corticosterone (CORT)-injured SH-SY5Y cells. Furthermore, compound 4 demonstrated a noteworthy antidepressant effect at the dose of 5 mg/kg in the tail suspension test (TST), which was equivalent to 5 mg/kg of fluoxetine. And it potentially exerts an antidepressant effect through the hypothalamic–pituitary–adrenal (HPA) axis.

Anti-inflammatory and cytotoxicity nitrogenous merosesquiterpenoids from the sponge Pseudoceratina purpurea

Fourteen undescribed nitrogenous merosesquiterpenoids, purpurols A−D (1–4) and puraminones A−J (5–14), along with three known related compounds (15–17) were isolated from the sponge Pseudoceratina purpurea collected in the South China Sea. Their structures and absolute configurations were unambiguously elucidated by a combination of spectroscopic data, X-ray diffraction analysis, electronic circular dichroism calculations, and chemical derivatization. Purpurols A−D (1–4) incorporated nitrogenous heterocycles, compounds 1 and 2 feature an unusual benzothiazole ring, while 3 and 4 feature benzoxazole ring. Puraminones A−J (5–14) represent sesquiterpenoid aminoquinones with different amine and amino acid side chains at C-20. Additionally, twenty unreported sesquiterpenoid aminoquinone analogues were obtained through chemical derivatization. It is worth noting that all compounds are featured with unusual rearranged 4,9-friedodrimane subunit. In the bioassays, purpurols A and B showed weak anti-inflammation in zebrafish, as well as some compounds showed activities against tumor cells, therefore, preliminary structure–cytotoxicity relationships are also discussed.

13,14-seco withaphysalins from Physalis minima and their inhibitory effects on NLRP3 inflammasome activation

Seven new 13,14-seco withaphysalins including two new skeletons (1 and 9) were isolated from the whole plants of Physalis minima, together with three known analogues (6–8). Among them, compound 1 was an extremely rare steroid with a 6, 8-cyclo ring. Their structures were established by extensive analysis of spectroscopic data, experimental electronic circular dichroism measurements, and single-crystal X-ray crystallographic analysis. In Raw264.7 cells, compounds 1–3, 5, 6, and 8 demonstrated potent ability to reduce the NLRP3-dependent caspase-1 activation. Among these compounds, 1 and 2 showed a superior potential, consistently concentration-dependent downregulating NLRP3-dependent proinflammatory cytokine IL-1β production in macrophage. Mechanistically, compounds 1 and 2 reduced the cleavage of caspase-1 and GSDMD, and exhibited no obvious impact both on the NF-κB activation and the expression of NLRP3 and IL-1β, suggesting that the compounds target the activation of the NLRP3 pathway mainly by inhibiting the NLRP3 inflammasome activation step rather than the priming step.

Short Oligourea Foldamers as N‐ or C‐Caps for Promoting α‐Helix Formation in Water

While foldamers have been extensively studied as protein mimics and especially as α‐helix mimics, their use as capping motif to enhance α‐helix propensity remains comparatively much limited. In this study, we leverage the structural similarities between urea‐based helical foldamers and α‐helix to investigate the efficacy of oligoureas as N‐ or C‐caps for reinforcing α‐helical structures in water. Short oligoureas, comprising 3 to 4 residues, were strategically introduced at the N‐ or C‐terminus of two peptide sequences (S‐peptide and an Ala‐rich model sequence). The impact of these foldamer insertions on peptide conformation was examined using electronic circular dichroism (ECD) and solution NMR. This research identifies specific foldamer sequences capable of promoting a‐helicity when incorporated at either terminus of the peptides. Not only does this work broaden the application scope of foldamers, but it also provides valuable insights into novel strategies for modulating peptide conformation in aqueous environments. The findings presented in this study may have implications for peptide design and the development of bioactive foldamer‐based peptide mimics.

New Monoterpenoid Glycosides from the Fruits of Hypericum patulum Thunb.

The whole Hypericum patulum Thunb. plant is utilized in traditional medicine for its properties of clearing heat, detoxifying, soothing meridians, relaxing the liver, and stopping bleeding. In folk medicine, it is frequently used to treat hepatitis, colds, tonsillitis, and bruises. Phytochemical investigation of a 30% ethanol extract of the fresh ripe fruits of H. patulum has resulted in the isolation of two new pinane-type monoterpenoid glycosides 1-2, named patulumside E-F, and three new chain-shaped monoterpenoid glycosides 3-5, named patulumside G-H, J. Their structures were determined using extensive spectroscopic techniques, such as HR-ESI-MS, 1D and 2D NMR spectroscopy, and electronic circular dichroism (ECD) calculation. The anti-inflammatory activities of these compounds were evaluated in the LPS-induced RAW264.7 cells. This research represents the inaugural comprehensive phytochemical study of H. patulum, paving the way for further exploration of monoterpenoid glycosides.

Diterpenoids with Antibacterial Activities from the Fungus Trichoderma harzianum.

A new fusicoccane diterpenoid, harziaderma A (1), two novel harziane diterpenoids, harzianones G and H (2 and 3), one revised harziane diterpenoid (4), and two known diterpenoids (5 and 6) were isolated from the fungus Trichoderma harzianum and established via NMR, HRESIMS, Mo2(OAc)4-induced circular dichroism (ICD) and electronic circular dichroism (ECD) calculations. It is worth noting that compound 1 represents the first instance of a fusicoccane-type diterpenoid derived from T. harzianum. The structure of furanharzianone B was revised to 4 via careful spectroscopic analyses. Additionally, compounds 2 and 5 could suppress the overall growth of the foodborne bacterial pathogen Bacillus cereus. Compound 4 showed a moderate suppressive impact on NO generation in lipopolysaccharide (LPS)-treated RAW 264.7 cells. The discoveries from the current study not only expanded the structural variety of diterpenoids isolated from T. harzianum but also laid a robust foundation for the development of harziane diterpenoids as anti-foodborne pathogen agents.

Rogersonins C-F, 9H-Imidazo[2,1-i]purine-Incorporating Adenine-Polyketide Hybrids from an Ophiocordyceps-Associated Clonostachys rogersoniana.

Rogersonins C-F (1-4), four unprecedented adenine-polyketide hybrids featuring a rare 9H-imidazo[2,1-i]purine (1,N6-ethenoadenine) moiety, were isolated from an Ophiocordyceps-associated fungus, Clonostachys rogersoniana. Their structures were elucidated primarily by NMR experiments. The absolute configurations of 1-4 were assigned by a combination of the modified Mosher method, chemical degradation, electronic circular dichroism (ECD) calculations, and X-ray crystallography using Cu Kα radiation. Compound 3 downregulated the expression of PD-L1 protein in MDA-MB-231 and A549 cells, but did not show detectable effect on mRNA transcription of the PD-L1-encoding gene CD274.

Cytotoxic Pentaketide-Sesquiterpenes from the Marine-Derived Fungus Talaromyces variabilis M22734.

Talaromyces, a filamentous fungus widely distributed across terrestrial and marine environments, can produce a diverse array of natural products, including alkaloids, polyketones, and polyketide-terpenoids. Among these, chrodrimanins represented a typical class of natural products. In this study, we isolated three previously undescribed pentaketide-sesquiterpenes, 8,9-epi-chrodrimanins (1-3), along with eight known compounds (4-11). The structures of compounds 1-3 were elucidated using nuclear magnetic resonance (NMR) and mass spectrometry (MS), while their absolute configurations were determined through X-ray crystallography and electronic circular dichroism (ECD) computations. The biosynthetic pathways of compounds 1-3 initiate with 6-hydroxymellein and involve multiple stages of isoprenylation, cyclization, oxidation, and acetylation. We selected four strains of gastrointestinal cancer cells for activity evaluation. We found that compound 3 selectively inhibited MKN-45, whereas compounds 1 and 2 exhibited no significant inhibitory activity against the four cell lines. These findings suggested that 8,9-epi-chrodrimanins could serve as scaffold compounds for further structural modifications, potentially leading to the development of targeted therapies for gastric cancer.

Testing the Simplified Molecular Dynamics Approach to Improve the Reproduction of ECD Spectra and Monitor Aggregation.

A simplified molecular-dynamics-based electronic circular dichroism (ECD) approach was tested on three condensed derivatives with limited conformational flexibility and an isochroman-2H-chromene hybrid, the ECD spectra of which could not be precisely reproduced by the conventional ECD calculation protocol. Application of explicit solvent molecules at the molecular mechanics (MD) level in the dynamics simulations and subsequent TDDFT-ECD calculation for the unoptimized MD structures was able to improve the agreements between experimental and computed spectra. Since enhancements were achieved even for molecules with limited conformational flexibility, deformations caused by the solvent molecules and multitudes of conformers produced with unoptimized geometries seem to be key factors for better agreement. The MD approach could confirm that aggregation of the phenanthrene natural product luzulin A had a significant contribution to a specific wavelength range of the experimental ECD. The MD approach has proved that dimer formation occurred in solution and this was responsible for the anomalous ECD spectrum. The scope and limitations of the method have also been discussed.