Computer-assisted Structure Elucidation Software Research Articles

Trichopsistides A and B: Two Highly Oxygenated Pentacyclic Polyketides with Promising Inhibitory Effects on the NF-κB Signaling Pathway from the Fungus Trichoderma koningiopsis WZ-196.

Two highly oxygenated pentacyclic polyketides with two new carbon skeletons, trichopsistide A (1) and trichopsistide B (2), were isolated from the plant endophyte Trichoderma koningiopsis WZ-196 derived from the leaf of Rubia podantha Diels. The structures of these polyketides with full configurations were determined by comprehensive spectroscopic analysis, computer-assisted structure elucidation software, computational calculation, and X-ray crystal diffraction. Among them, 1 represented the first example of an unprecedented 5/6/6/6/5 pentacyclic ketal-containing polyketide pyridine alkaloid, and 2 possessed a novel 6/6/6/6/5 pentacyclic ketal-containing polyketide scaffold fused with an α-pyrone. The plausible biosynthetic route for 1 and 2 was also proposed. Moreover, biological activity assays showed that 1 and 2 possessed inhibitory effects on the NF-κB signaling pathway with IC50 values of 14.77 and 8.58 μM, respectively. Furthermore, 1 and 2 could also inhibit the expression of IκBα and p65 phosphorylation, decrease the expression of MCP-1, E-selectin, and IL-8 at the mRNA level, and inhibit the TNF-α-induced nuclear translocation of p65.

Two new seco-polycyclic polyprenylated acylphloroglucinol from Hypericum sampsonii.

Hypsampsone A (1) and hyperhexanone F (2), two novel seco-polycyclic polyprenylated acylphloroglucinols, were isolated from Hypericum sampsonii. Hypsampsone A (1) features the first spirocyclic system fused with 5/6/5/5 tetracyclic skeleton. Hyperhexanone F (2) represents the second novel 1,2-seco-bicyclo[3.3.1]-PPAP skeleton. Their structures were established by extensive spectroscopic analysis, computer-assisted structure elucidation software, and calculated electronic circular dichroism spectra. A plausible biogenetic pathway of 1 was also proposed. Compounds 1 and 2 showed moderate multidrug resistance reversal activity to adriamycin (ADR) resistant cancer cell lines, HepG2/ADR and MCF-7/ADR, with the fold-reversals ranging from 16 to 38 at noncytotoxic concentration of 10 μM.

Hyperfols A and B: Two Highly Modified Polycyclic Polyprenylated Acylphloroglucinols from Hypericum perforatum.

Two novel polycyclic polyprenylated acylphloroglucinols (PPAPs), hyperfols A (1) and B (2), and two known biosynthetically related precursors (3 and 4) were isolated from Hypericum perforatum. Compound 1 possesses an unprecedented 2,3-seco-PPAP with a fused 5/5/9/5 tetracyclic skeleton, and 2 features a 30-norPPAP. Their structures were established by spectroscopic analysis, computer-assisted structure elucidation software, and electronic circular dichroism calculations. Moreover, compounds 1 and 4 exhibit significant cytotoxicity against human erythroleukemia cells by inducing cell apoptosis.

Phenolics from Archidendron clypearia (Jack) I.C.Nielsen protect SH-SY5Y cells against H2O2-induced oxidative stress

Five undescribed phenolics named pithecellobiumin C-G, along with thirteen known ones were isolated from the twigs and leaves of Archidendron clypearia (Jack) I.C.Nielsen. Their structures were elucidated based on comprehensive spectroscopic analyses, combined with computer-assisted structure elucidation software (ACD/Structure Elucidator) and gauge-independent atomic orbitals (GIAO) NMR chemical shift calculations. The absolute configurations were determined by comparison of experimental and calculated specific rotation and ECD curves. These compounds were tested for their neuroprotective activities against H2O2-induced injury in human neuroblastoma SH-SY5Y cells by MTT assay. Pithecellobiumin C-E exhibited noticeable neuroprotective effect. Further pharmacological study demonstrated that they could prevent cell death through inhibiting the apoptosis induction. Flow cytometry assays also proved that these compounds could attenuate reactive oxygen species (ROS) level and mitochondrial dysfunction in SH-SY5Y cells.

The identification of alkaloids from the stems of Picrasma quassioides via computer-assisted structure elucidation and quantum chemical calculations

Four new alkaloids (1-4) and one known alkaloid were isolated from the stems of Picrasma quassioides. The structures of these isolated compounds were elucidated by spectroscopic analyses, a combination of computer-assisted structure elucidation software (ACD/Structure Elucidator) and gauge-including atomic orbital (GIAO) calculation of 1 D NMR data. All compounds were evaluated for their cytotoxic activities against hepatocellular carcinoma HepG2 and Hep3B cells. However, they did not show obvious inhibitory activities.

The identification of phenylpropanoids isolated from the root bark of Ailanthus altissima (Mill.) Swingle

Chemical investigation of 75% EtOH exact of the root bark of Ailanthus altissima (Mill.) Swingle led to the isolation and identification of two new phenylpropanoids (1–2), along with six known compounds (3–8). Their chemical structures were elucidated by extensive spectroscopic data analyses including NMR experiments and HRESIMS analyses, as well as computer-assisted structure elucidation software (ACD/Spectrus Processor). All compounds were evaluated for cytotoxic activities against Hep 3B and Hep G2 cells. Compound 1 and 7 displayed weak cytotoxic activities against the Hep 3B cell line.

Characterization and Synthesis of Eudistidine C, a Bioactive Marine Alkaloid with an Intriguing Molecular Scaffold.

An extract of Eudistoma sp. provided eudistidine C (1), a heterocyclic alkaloid with a novel molecular framework. Eudistidine C (1) is a racemic natural product composed of a tetracyclic core structure further elaborated with a p-methoxyphenyl group and a phenol-substituted aminoimidazole moiety. This compound presented significant structure elucidation challenges due to the large number of heteroatoms and fully substituted carbons. These issues were mitigated by application of a new NMR pulse sequence (LR-HSQMBC) optimized to detect four- and five-bond heteronuclear correlations and the use of computer-assisted structure elucidation software. Synthesis of eudistidine C (1) was accomplished in high yield by treating eudistidine A (2) with 4(2-amino-1H-imidazol-5-yl)phenol (4) in DMSO. Synthesis of eudistidine C (1) confirmed the proposed structure and provided material for further biological characterization. Treatment of 2 with various nitrogen heterocycles and electron-rich arenes provided a series of analogues (5-10) of eudistidine C. Chiral-phase HPLC resolution of epimeric eudistidine C provided (+)-(R)-eudistidine C (1a) and (-)-(S)-eudistidine C (1b). The absolute configuration of these enantiomers was assigned by ECD analysis. (-)-(S)-Eudistidine C (1b) modestly inhibited interaction between the protein binding domains of HIF-1α and p300. Compounds 1, 2, and 6-10 exhibited significant antimalarial activity against Plasmodium falciparum.

Macleayine, a new alkaloid from Macleaya cordata

Macleayine (1), a new natural occurring alkaloid with a unique spiro [furanone-piperidinedione] framework, was isolated from the aerial parts of Macleaya cordata. Its unusual structure was established by extensive spectroscopic analyses, computer-assisted structure elucidation software (ACD/Structure Elucidator), quantum chemistry calculations and ECD calculation. The result of virtual molecular docking predicted the compound can enhance the effects of insulin, and may be used to treat type II diabetes.

Self-Sensitized Photooxygenation of 2H-Pyrans: Characterization of Unexpected Products Assisted by Computed Structural Elucidation and Residual Dipolar Couplings.

The UVA (350 nm) irradiation of an α-pyran in the presence of oxygen led to the unexpected formation of a tetraoxygenated compound whose structure could not be unambiguously determined on the basis of conventional (1)H-(13)C correlated experiments. 1,1-ADEQUATE (adequate double quantum transfer experiment) and 1,n-ADEQUATE combined with computer-assisted structure elucidation software led to two structural possibilities involving the formation of either an epoxide or an oxetane. Residual dipolar couplings allowed not only the identification of the compound as a spiroepoxide but also the determination of its relative configuration. To account for its formation, we propose a bisepoxide intermediate that, as opposed to most α,β-epoxyketones under irradiation, undergoes O-Cβ cleavage probably due to the presence of an extra oxygen substituent in the β position. 1,2-Acyl migration would then proceed stereoselectively to the final product obtained as a single diastereomer.

Computer-Assisted Structure Elucidation of Black Chokeberry (Aronia melanocarpa) Fruit Juice Isolates with a New Fused Pentacyclic Flavonoid Skeleton.

Melanodiol 4″-O-protocatechuate (1) and melanodiol (2) represent novel flavonoid derivatives isolated from a botanical dietary supplement ingredient, dried black chokeberry (Aronia melanocarpa) fruit juice. These noncrystalline compounds possess an unprecedented fused pentacyclic core with two contiguous hemiketals. Due to having significant hydrogen deficiency indices, their structures were determined using computer-assisted structure elucidation software. The in vitro hydroxyl radical-scavenging and quinone reductase-inducing activity of each compound are reported, and a plausible biogenetic scheme is proposed.

Blind trials of computer-assisted structure elucidation software

BackgroundOne of the largest challenges in chemistry today remains that of efficiently mining through vast amounts of data in order to elucidate the chemical structure for an unknown compound. The elucidated candidate compound must be fully consistent with the data and any other competing candidates efficiently eliminated without doubt by using additional data if necessary. It has become increasingly necessary to incorporate an in silico structure generation and verification tool to facilitate this elucidation process. An effective structure elucidation software technology aims to mimic the skills of a human in interpreting the complex nature of spectral data while producing a solution within a reasonable amount of time. This type of software is known as computer-assisted structure elucidation or CASE software. A systematic trial of the ACD/Structure Elucidator CASE software was conducted over an extended period of time by analysing a set of single and double-blind trials submitted by a global audience of scientists. The purpose of the blind trials was to reduce subjective bias. Double-blind trials comprised of data where the candidate compound was unknown to both the submitting scientist and the analyst. The level of expertise of the submitting scientist ranged from novice to expert structure elucidation specialists with experience in pharmaceutical, industrial, government and academic environments.ResultsBeginning in 2003, and for the following nine years, the algorithms and software technology contained within ACD/Structure Elucidator have been tested against 112 data sets; many of these were unique challenges. Of these challenges 9% were double-blind trials. The results of eighteen of the single-blind trials were investigated in detail and included problems of a diverse nature with many of the specific challenges associated with algorithmic structure elucidation such as deficiency in protons, structure symmetry, a large number of heteroatoms and poor quality spectral data.ConclusionWhen applied to a complex set of blind trials, ACD/Structure Elucidator was shown to be a very useful tool in advancing the computer's contribution to elucidating a candidate structure from a set of spectral data (NMR and MS) for an unknown. The synergistic interaction between humans and computers can be highly beneficial in terms of less biased approaches to elucidation as well as dramatic improvements in speed and throughput. In those cases where multiple candidate structures exist, ACD/Structure Elucidator is equipped to validate the correct structure and eliminate inconsistent candidates. Full elucidation can generally be performed in less than two hours; this includes the average spectral data processing time and data input.

Approaches to the Assessment of Stable and Chemically Reactive Drug Metabolites in Early Clinical Trials

The recommendations of the FDA's final Guidance document on Safety Testing of Drug Metabolites provide a framework for devising preclinical toxicology assessment paradigms, where necessary, for human metabolites of small molecule drug candidates. Importantly, these recommendations carry implications for the qualitative and quantitative analysis of circulating drug metabolites in early human trials, which typically are performed without the benefit of a radiolabeled tracer. In this perspective, an approach to these goals is outlined based on recent work at Merck Research Laboratories involving the use of ultraperformance liquid chromatography-mass spectrometry analysis, performed on a high-resolution time-of-flight mass spectrometer, of first-in-human study plasma samples. With the aid of a fractional mass filtering algorithm, drug metabolites are distinguished from endogeneous background materials and subsequently identified on the basis of their accurate masses, product ion mass spectra, and computer-assisted structure elucidation software routines. Semiquantitative analysis then is based on calibration of the MS response to each analyte with reference to radioactivity data from in vitro metabolic profiles. In the case of chemically reactive drug metabolites, which are excluded from consideration in the Guidance, a proactive approach is advocated whereby potent (low dose) drug candidates with only a limited propensity to form electrophilic intermediates are advanced into development. Overall, a decision on the need to conduct separate evaluation of the safety profile of a human drug metabolite(s) should take into consideration all of the available information on the compound of interest and be based on a case-by-case approach employing sound scientific principles.

Thermodynamic Properties of Asphaltenes Through Computer Assisted Structure Elucidation and Atomistic Simulations. 1. Bulk Arabian Light Asphaltenes

This article describes a new method for estimating the thermodynamic properties of asphaltenes. To illustrate this methodology, we used a computer assisted structure elucidation software (SIGNATURE) to generate an ensemble of 10 isomers for Arabian Light (AL) asphaltenes compatible with (i) analytical data from elemental analysis, FT-IR spectroscopy, 1-D 1H/13C solution NMR and vapor pressure osmometry and (ii) literature data on the molecular composition of asphaltenes. The 10 model isomers were packed into a 3-D periodic cell to form the condensed phase model for the fraction of bulk AL asphaltenes with a number average molar mass (M n) approximately equal to 1280 Dalton. This cell was subsequently used in molecular dynamics (MD) simulations to estimate the molar volume, density, enthalpy, specific heat at constant pressure, solubility parameter, and isothermal compressibility of the AL asphaltene fraction. The results of the MD simulations compare favorably with the available experimental data.