Exciton Chirality Method Research Articles

The vibrational circular dichroism exciton coupling in single-bond C–O stretching vibrations of p-menthene derivatives

The exciton coupling (EC) phenomenon becomes a valuable tool for the absolute configuration (AC) determination of organic molecules when an interaction between two strategically located chromophores in a molecule is evidenced by circularly polarized radiation. Besides the widely used exciton chirality method in electronic circular dichroism, the technique has been also developed for vibrational circular dichroism (VCD). Notably, the information provided by CO stretching vibrations (1680−1800 cm−1) in VCD have demonstrated high applicability. However, reported theoretical approaches have warned about the adequate interpretations of the EC phenomenon since analyzed bisignate bands could be associated with other vibrations. The current paper experimentally addresses the problem to expand the criteria for using EC data in AC determinations. Herein, the VCD exciton coupling (VCDEC) methodology is extended to the analysis of C–O stretching vibrations (1100–1300 cm−1) to uncover their possible use in AC determinations, as well as to reveal the specific contribution of the EC related to C–O vibrations when experimental parameters are considered. To this aim, naturally occurring p-menthene alcohols 1–4 isolated from Ageratina glabrata were previously used to prepare acetates 5 and 6, and acetonides 7 and 8, and now, to prepare carbonates 9–11. Density functional theory (DFT) calculations, including the IR and VCD spectra of the seven derivatives (5–11), were carried out to reinforce the conformational and configurational analysis, while the experimental VCD spectra of 5–7, 9, and 11 demonstrated the presence of C–O couplets. A systematic analysis of these bands, including the Δε value at alpha and beta state (Δεα, Δεβ, respectively), the amplitude of EC (A = ∑ǀΔεǀ) value, the couplet period (L =v‾Δεβ − v‾Δεα) value, the specific area of C–O at couplet (S = Σf(x)(u2)), and the percentage of area related to EC from C–O (S%) were considered. These experimental results were directly related to dihedral angles (θ) from simplistic models to establish the AC. The results suggested that A, Cp, S, and S% parameters are deeply related to the nature of the chromophores. Thereby, adequate molecular structural moieties should be chosen for AC determination when using the EC methodology.

6-Methoxy-2-Naphthoate as a Standard Chromophore for Chiroptical Studies by Fluorescence-Detected Exciton-Coupled Circular Dichroism.

This study investigated the applicability of fluorescent chromophores for exciton-coupled circular dichroism (ECCD) exploiting fluorescence-detected circular dichroism (FDCD). FDCD had been previously reported useful in allowing the sensitive detection of ECCD in favorable conditions. However, fluorescence detection may prevent applications of the combined method especially when solutions are polarized in emission. Even without polarization of emission, FDCD deviates from circular dichroism (CD) in some cases when the fluorophore of interest interacts with nonfluorescent chromophore. Herein, it was confirmed that employing 6-methoxy-2-naphthoate always yielded interpretable exciton-coupled FDCD spectra even when coupling with nonfluorescent p-substituted benzoates. The 6-methoxy-2-naphthoate chromophore (6-MN) is prescribed in special cases when only a small amount of sample is available for determining the absolute stereochemistry by the CD exciton chirality method observed by FDCD.

Alstomaphylines A–K, monoterpenoid bisindole alkaloids from Alstonia macrophylla with AChE inhibitory activity and cytotoxicity

Eleven undescribed monoterpenoid bisindole alkaloids, alstomaphyines A−K (1−11), along with three known analogues were isolated from the leaves and stem bark of the Alstonia macrophylla. Compounds 1−3 were unprecedented dimerization alkaloids incorporating a macroline-type motif with an ajmaline-type motif via a C−C linkage. Their structures and absolute configurations were elucidated by extensive spectroscopic analysis, electronic circular dichroism (ECD) calculation, and CD exciton chirality method. Compounds 1−3 displayed potential inhibitory bioactivity against AChE with IC50 values of 4.44 ± 0.35, 3.59 ± 0.18, and 3.71 ± 0.23 μM, respectively. Enzyme kinetic study revealed compounds 1−3 as mixed competitive AChE inhibitors. Besides, compounds 8 and 12−14 exhibited better cytotoxicity against human cancer cell line HT-29 than cisplatin. Flow cytometry data revealed that compounds 8, 13, and 14 significantly induced the HT-29 cells arrest in G0/G1 phase in a concentration-dependent manner.

Albifimbrins A and B, a pair of epimeric tetrahydrofuran-containing linear polyketide derivatives from the marine-derived fungus Albifimbria verrucaria CD1-4

A pair of new epimeric polyketides, named albifimbrins A and B (1 and 2), were isolated from the cultures of the shellfish-derived fungus Albifimbria verrucaria CD1–4. Their structures were determined by extensive spectroscopic analysis including HR-MS, 1D and 2D NMR data, together with the CD exciton chirality method. Compounds 1 and 2 possess unusual tetrahydrofuran moiety in their linear molecule structures. The antimicroalgal assay indicated that compounds 1 and 2 shown moderate inhibitory activities against marine harmful microalgae, Prorocentrum donghaiense, Amphidinium carterae and Heterocapsa circulariaquama.

Hinokione: an abietene diterpene with pancreatic β cells regeneration and hypoglycemic activity, and other derivatives with novel structures from the woods of Agathis dammara.

In this study, 14 abietene and pimarene diterpenoids were isolated from the woods of Agathis dammara. Among them, 4 new compounds, dammarone A-C and dammaric acid A (1-4), were firstly reported, respectively. The structure of the new compounds was determined by HR ESI-MS and 1D/2D NMR spectroscopy, and their absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. The hypoglycemic effect of all compounds was evaluated by transgenic zebrafish model, and the structure-activity relationship was discussed. Hinokione (7, HO) has low toxicity and significant hypoglycemic effects on zebrafish, the mechanism is mainly by promoting the differentiation of zebrafish pancreatic endocrine precursor cells (PEP cells) into β cells, thereby promoting the regeneration of pancreatic β cells.

Compounds from Agathisdammara exert hypoglycaemic activity by enhancing glucose uptake: lignans, terpenes and others

In this study, two new kaurane diterpenes (16, 17), together with 12 lignans (1–12), a triterpene (15), and two other compounds (13, 14) were isolated from the woods of Agathisdammara. The structure of the new compound was determined by HR ESIMS and 1D/2D NMR spectroscopy, and its absolute configuration was determined by electronic circular dichroism (ECD) exciton chirality method. Compounds 5, 11, 14 exhibit significant hypoglycaemic activity in zebrafish, and their mechanism of action is to enhance glucose uptake in zebrafish.Graphical

D-chiro-Inositol Derivatives with Multidrug Resistance Reversal Activities from the Fruits of Chisocheton siamensis.

Chisosiamols A-K (1-11), 11 new d-chiro-inositol derivatives, along with a known analogue (12) were isolated from the fruits of Chisocheton siamensis. Their planar structures and relative configurations were elucidated by the comprehensive application of spectroscopic methods, especially from the characteristic coupling constants, and 1H-1H COSY spectra. The absolute configurations of the d-chiro-inositol core were determined using the ECD exciton chirality and X-ray diffraction crystallographic analytical methods. This is the first crystallographic data reported for the d-chiro-inositol derivatives. A structural elucidation strategy mainly combining 1H-1H COSY correlations and ECD exciton chirality for determining the structure of d-chiro-inositol derivatives was developed, which also led to the revisions of previously reported structures. Bioactivity evaluation indicated that chisosiamols A, B, and J can reverse multidrug resistance in MCF-7/DOX cells in the IC50 range of 3.4-6.5 μM (RF: 3.6-7.0).

Rare noreudesmane sesquiterpenoids from the fruits of Dysoxylum densiflorum

Seven rare noreudesmane sesquiterpenoids (dysoxydenones M-S, 1–7), including three 11,12,13-trinoreudesmanes, three 13-noreudesmanes and one spirovetivane-type sesquiterpenoid, along with two known analogues were isolated from the fruits of Dysoxylum densiflorum. The planar structures were elucidated by a combination of 1D, 2D NMR and HRESIMS analyses. Their absolute configurations were determined by combination of single-crystal X-ray diffraction, CD exciton chirality method and ECD calculation. All compounds were screened for anti-inflammatory activity on LPS-induced RAW 264.7 cells and IL-1β inhibitory activity.

Kojicone C, new anti-inflammatory polyketide from insect-associated fungus Aspergillus versicolor

The chemical study of EtOAc extracts of the insect-associated fungus Aspergillus versicolor led to the isolation of a new polyketide kojicone C ( 1 ) and its precursor (2 R ,4 R )−4-hydroxy-5-methoxy-2,4-dimethyl-2-[(2 R )−2-methylbutyryloxy]−5-cyclohexen-1,3-dione ( 2 ). Kojicone C belongs to the rare tricycle cyclohexen-1,3-dione adduct class. The structures of 1 and 2 were determined by HRESIMS (high resolution electrospray ionization mass spectroscopy) data, 1D and 2 D NMR (nuclear magnetic resonance) spectroscopic analysis, ECD (electronic circular dichroism) calculations, and CD exciton chirality method. Compound 1 exhibited moderate anti-inflammatory activities that reduced LPS-induced NO production of RAW 264.7 cells (IC 50 = 35.8 μ Μ). It could also significantly inhibit LPS-induced mRNA expression of TNF- α , IL-1 β , and IL-6 of this cell line at a concentration of 20 μ Μ. • One new polyketide was isolated from Aspergillus versicolor . • The new compound is a rare tricycle cyclohexen-1,3-dione adduct. • The new compound exhibited potent anti-inflammatory activities.

Cucurbitane-type triterpenoids from the fruits of Citrullus colocynthis

A phytochemical investigation of the fruits of Citrullus colocynthis resulted in the isolation of 21 structurally diverse cucurbitane triterpenoids, including 9 previously undescribed ones, colocynins A-I (1–9). Their absolute configurations were elucidated by means of quantum chemical electronic circular dichroism (ECD) calculations, CD exciton chirality method, and single-crystal X-ray crystallography. Colocynins A-C (1–3) represent the first examples of nonanorcucurbitane-type triterpenoids. An anti-acetylcholinesterase activity assay showed that 6, 10, 13, 18, and 20 exhibited inhibitory activities, with IC50 values ranging from 5.0 to 21.7 μM. In addition, 18 and 21 showed significant cytotoxicity against PACA, A431, and HepG2 cells, with IC50 values ranging from 0.042 to 0.60 and 3.6–14.4 μM, respectively.

Steroid glycosides from the roots of Marsdenia tenacissima

Eleven undescribed glycosylated C21 steroids and nine known homologous glycosides with diverse acyl substituents, as well as their common steroid aglycone, have been obtained from the roots of Marsdenia tenacissima. Their structures were elucidated mainly by comprehensive spectroscopic analyses and comparison with previously reported analogues, with the absolute configuration assignment being supported by chemical degradation, X-ray crystallography and ECD exciton chirality method. Among them, two pairs of regioisomers were found to exist as inseparable equilibrium mixtures due to an interesting intramolecular transesterification, and nicotinoyl substitution was first reported for metabolites from the title plant. Screening of these compounds in a panel of bioassays revealed that two glycosides displayed mild inhibition against butyrylcholinesterase.

Astramalabaricosides A-T, Highly Oxygenated Malabaricane Triterpenoids with Migratory Inhibitory Activity from Astragalus membranaceus var. mongholicus.

Twenty new malabaricane triterpenoids, astramalabaricosides A-T (1-20), were isolated from the roots of Astragalus membranaceus var. mongholicus (Astragali Radix). Their structures were determined by spectroscopic analysis, and the use of the circular dichroism exciton chirality method, quantum chemical calculations, and chemical methods. Malabaricane triterpenoids, an unusual group with the 6-6-5-tricyclic core, are distributed in plants (e.g., Simaroubaceae, Polypodiaceae, and Fabaceae), a marine sponge, and fungi, and their number obtained to date is limited. Compounds 1-20 were characterized as glycosides with a highly oxygenated side chain, and 13-20 were the first cyclic carbonate derivatives among the malabaricane triterpenoids. The stereocluster formed from the continuous hydroxylated chiral carbons in each highly oxygenated side chain and the 6-6-5-tricyclic core system were entirely segregated, and the independent identification of their stereoconfigurations required considerable effort. The migratory inhibitory and antiproliferative activities of 1-20 were evaluated by wound-healing and cell-viability assays, respectively. Most compounds showed significant migratory inhibitory activity, and a preliminary structure-activity relationship was developed. Malabaricane triterpenoids are being reported in the genus Astragalus for the first time.

Diverse dihydroagarofuran sesquiterpene derivatives from the stem and branch of Tripterygium wilfordii

Ten new dihydroagarofuran sesquiterpene polyol esters, tripterdines A-J (1−10) were isolated from the stem and branch of Tripterygium wilfordii. The structures of new compounds were elucidated on the basis of extensive spectroscopic analyses, including UV, IR, HRESIMS, NMR, and CD exciton chirality method. The structures of compounds 1, 3, and 6 were confirmed by X-ray crystallographic analyses. The anti-inflammatory and cytotoxic activities were assessed for all the compounds (1–10). Compounds 3, 5 and 10 exhibited potent anti-inflammatory activities with the secretion level of TNF-α ranging from 43.86% to 51.27%, and the IL-6 ranging from 32.44% to 50.64%. In addition, compounds 1, 3, 7 and 9 showed weak cytotoxicities against three human tumor cell lines (Huh7, MCF-7 and HCT-116).

Sarglafuran A, a lindenane-type sesquiterpene dimers with unique furan ring from the leaves of Sarcandra glabra

Sarglafuran A (1), a new [4 + 2] type lindenane sesquiterpene dimer with an unique furan ring moiety, and a pair of new [2 + 2] type dimeric lindenane epimers, sarglalactones N and O (2 and 3), were isolated from the leaves of Sarcandra glabra. Their structures were elucidated by comprehensive spectroscopic analyses, and the absolute configurations of these compounds were determined by single crystal X-ray diffraction or CD exciton chirality method. In addition, a possible biosynthetic pathway of the unique furan ring moiety in 1 had been proposed. Their cytotoxicity against MCF-7 and MDA-MB-231, together with the inhibitory activity against nitric oxide (NO) production of LPS-induced RAW264.7 macrophages were evaluated.

A/D-rings-seco limonoids from the fruits of Aglaia edulis and their bioactivities

Agledulines A-K, eleven previously undescribed limonoids, including eight biogenic A/D-rings-seco limonoid analogs (agledulines A-H), one D-ring-seco limonoid (agleduline I) and two A-ring-seco limonoids with a rare Δ4,28 moiety (agledulines J-K), together with twelve reported limonoids, were isolated from the fruits of Aglaia edulis. Their structures were determined by NMR data, HRESIMS, X-ray diffraction, ECD spectra and the CD exciton chirality method. Observably, the absolute configurations of agleduline A, agleduline C and nymania 2 were unambiguously elucidated by single-crystal X-ray diffraction analyses. The biological evaluation showed that agleduline C exhibited significant cytotoxic activities with IC50 values of 10.05 μM, and 11α-acetoxygedunin showed notable anti-inflammatory activity (IC50: 4.70 μM). In addition, agleduline I and 11α-acetoxygedunin reversed the multidrug resistance with IC50 values of 5.05 and 1.49 μM (RI: 4.64 and 15.77) in the MCF-7/Dox cells.

ECD exciton chirality method today: a modern tool for determining absolute configurations.

The application of the exciton chirality method (ECM) to interpret electronic circular dichroism (ECD) spectra is a well‐established and still popular approach to assign the absolute configuration (AC) of natural products, chiral organic compounds, and organometallic species. The method applies to compounds containing at least two chromophores with electric dipole allowed transitions (e.g., π–π* transitions). The exciton chirality rule correlates the sign of an exciton couplet (two ECD bands with opposite sign and similar intensity) with the overall molecular stereochemistry, including the AC. A correct application of the ECM requires three main prerequisites: (a) the knowledge of the molecular conformation, (b) the knowledge of the directions of the electric transition moments (TDMs), and (c) the assumption that the exciton coupling mechanism must be the major source of the observed ECD signals. All these prerequisites can be easily verified by means of quantum‐mechanical (QM) calculations. In the present review, we shortly introduce the general principles that underpin the use of the ECM for configurational assignments and survey its applications, both classic ones and some reported in the recent literature. Based on these examples, we will stress the advantages of the ECM but also the key requisites for its correct application. Additionally, we will discuss the dependence of the couplet sign on geometrical parameters (angles α,β,γ between TDMs), which can be helpful for discerning the sign of exciton chirality in ambiguous situations. Finally, we will present a molecular orbital (MO) description of the exciton coupling phenomenon.

Guaianolide Sesquiterpenes With Significant Antiproliferative Activities From the Leaves of Artemisia argyi.

Four new guaiane-type sesquiterpenes, argyin H–K (1–4), and two known analogues (5 and 6) were isolated from the leaves of Artemisia argyi Lévl et Vant. The new compounds were characterized by the basic analysis of the spectroscopic data obtained (1H NMR, 13C NMR, HMBC, and NOESY experiments), and their absolute configurations were determined by empirical approaches, combined with the exciton chirality method and electronic circular dichroism calculations. To further understand the antitumor effects of A. argyi, the antiproliferative activities of these compounds against A549, MCF-7, and HepG2 cell lines were tested in vitro using CCK-8 assays. The results showed that these compounds had significant antiproliferative effects on MCF-7, with IC50 values of 15.13–18.63 μM, which were superior to that of oxaliplatin (i.e., IC50 22.20 μM).

Humulane-type and germacrane-type sesquiterpenoids from the fruits of Xanthium spinosum Linn.

Eight undescribed humulane-type sesquiterpenoids (xanthspinol A-E, I, J and N), three undescribed germacrane-type sesquiterpenoids (xanthspinol F, G and O) and twelve known compounds were isolated from the fruits of Xanthium spinosum. The structures of the undescribed compounds were elucidated by analyses of spectroscopic data, electronic circular dichroism (ECD) calculations, dimolybdenum tetraacetate [Mo2(OAc)4]-induced circular dichroism (ICD) spectra, a CD exciton chirality method and the modified Mosher's method. Xanthspinol A and B featured a humulane skeleton containing a 2,5-dihydrofuran fragment. Putative biosynthetic pathways for the undescribed compounds are proposed. Xanthspinol N, 8-epi-isoxanthanol and deacetyl-4-epixanthanol showed moderate activity against Coxsackie virus B3 (CVB3) with IC50 values of 8.70, 3.70 and 3.70 μM, respectively.

Diverse Polycyclic Polyprenylated Acylphloroglucinol Congeners with Anti-Nonalcoholic Steatohepatitis Activity from Hypericum forrestii.

The new polycyclic polyprenylated acylphloroglucinols, hyperforcinols A-J (1-10), were isolated from the fruits of Hypericum forrestii, together with 30 biogenetic congeners of known structures. The structures of hyperforcinols A-J were determined by HRESIMS and 1D/2D NMR spectroscopic analysis, and their absolute configurations were determined by a combination of the electronic circular dichroism (ECD) exciton chirality method, ECD calculations, and X-ray diffraction analysis. A selection of 25 isolates, possessing seven types of carbon skeletons, were assessed for their in vitro effects against nonalcoholic steatohepatitis (NASH) using a free fatty acid-induced L02 cell model. Compounds 20 and 40 significantly decreased intracellular lipid accumulation. QRT-PCR analyses revealed that compounds 20 and 40 regulate the expression of lipid metabolism-related genes, including CD36, FASN, PPARα, and ACOX1.

Phthalide-derived oxaspiroangelioic acids A–C with an unprecedented carbon skeleton from an aqueous extract of the Angelica sinensis root head

Three phthalide-derived analogues, oxaspiroangelioic acids A–C (1–3), were isolated as minor components of an aqueous extract of the Angelica sinensis root heads (guitou). Oxaspiroangelioic acids A and B were racemates separated into enantiomers by chiral HPLC. Their structures including absolute configurations were determined by spectroscopic data analysis, single crystal X-ray diffraction, exciton chirality method and electronic circular dichroism (ECD) calculation. These compounds share an undescribed carbon skeleton, for which biosynthetic pathways are proposed. Compound 1 and its enantiomers showed almost identical activity inhibiting Tandem of P domains in a weak inwardly rectifying K+ channel 1 (TREK-1).