Optical Rotation Calculations Research Articles

Sulfated Naphthopyrones and Anthraquinones from the Vietnamese Crinoid Comanthus delicata.

Three new sulfated naphthopyrone derivatives namely delicapyrons F-H (1-3) and two new sulfated anthraquinone derivatives namely delicaquinons A (4) and B (5), together with 6-methoxycomaparvin-5-methylether-8-O-sodium sulfate (6), 6-methoxycomaparvin-8-O-sodium sulfate (7), comaparvin-8-O-sodium sulfate (8), and 3-propyl-1,6,8-trihydroxy-9,10-anthraquinone-6-O-sodium sulfate (9) were isolated from the Vietnamese crinoid Comanthus delicata. Their chemical structures were elucidated by extensive analysis of the one dimensional (1D) and 2D-NMR, high resolution electrospray ionization quadrupole time-of-flight (HR-ESI-QTOF) mass spectra as well as calculation of optical rotation. In addition, significant cytotoxicity was observed for 6 against LNCaP (prostate cancer) cell line with IC50 value of 20.29 ± 2.43 µM, whereas moderate or weak cytotoxic effects were observed for 1-3 and 5-8 on SK-Mel-2 (melanoma) cell line and 7 and 8 against LNCaP cell line, with IC50 values ranging from 49.96 ± 1.74 to 76.92 ± 5.85 µM.

Polychlorinated cyclopentenes from a marine derived Periconia sp. (strain G1144)

Studies on an organic extract of a marine fungus, Periconia sp. (strain G1144), led to the isolation of three halogenated cyclopentenes along with the known and recently reported rhytidhyester D; a series of spectrometric and spectroscopic techniques were used to elucidate these structures. Interestingly, two of these compounds represent tri-halogenated cyclopentene derivatives, which have been observed only rarely from Nature. The relative and absolute configurations of the compounds were established via mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy, Mosher's esters method, optical rotation and GIAO NMR calculations, including correlation coefficient calculations and the use of both DP4+ and dJ DP4 analyses. Several of the isolated compounds were tested for activity in anti-parasitic, antimicrobial, quorum sensing inhibition, and cytotoxicity assays and were shown to be inactive.

Basis Set Dependence of Optical Rotation Calculations with Different Choices of Gauge.

In this work, the basis set dependence of optical rotation (OR) calculations is examined for various choices of gauge/level of theory. The OR is calculated for a set of 50 molecules using B3LYP and CAM-B3LYP and 17 molecules using coupled cluster with single and double excitations (CCSD). The calculations employ the correlation-consistent basis sets, aug-cc-pVζZ with ζ = D, T, Q. An inverse-power extrapolation formula is then utilized to obtain OR values at the complete basis set (CBS) limit. We investigate the basis set convergence for these methods and three choices of gauge: length gauge (with gauge-including atomic orbitals, LG(GIAOs), for DFT), the origin-invariant length gauge [LG(OI)], and the modified velocity gauge (MVG). The results show that all methods converge smoothly to the CBS limit and that the LG(OI) approach has a slightly faster convergence rate than the other choices of gauge. While the DFT methods reach gauge invariance at the CBS limit, CCSD does not. The significant difference between the MVG and LG(OI) results at the CBS limit, 26%, indicates that CCSD is not quite at convergence in the description of electron correlation for this property. On the other hand, gauge invariance at the CBS limit for DFT does not lead to the same OR values for the two density functionals, which is also due to electron correlation incompleteness. A limited comparison to gas-phase experimental OR values for the DFT methods shows that CAM-B3LYP seems more accurate than B3LYP. Overall, this study shows that the LG(OI) approach with the aug-cc-pVTZ basis set for DFT, and with the CBS(DT) extrapolation for CCSD, provides a good cost/accuracy balance.

Synthesis, structural analysis, vibrational properties, and chiral separation of Xanthine-Quinazoline diastereomers

Originating from the xanthine derivatives, a class of potent dipeptidyl peptidase IV (DPP-4) inhibitors for the treatment of type 2 diabetes have been discovered. These inhibitors play a vital role in maintaining the levels of endogenous GLP-1. In this study, Xanthine-Quinazoline derivatives have been designed and synthesized. R- and S-isomers of the target compound were separated by chiral column chromatography and the relative configurations were studied by means of NMR (nuclear magnetic resonance), ECD (electronic circular dichroism), FT-IR (fourier transform infrared spectroscopy), and DFT (density functional theory) calculations. In addition, the absolute configurations (ACs) of the title compound were confirmed by ECD, PES (Potential Energy Surface), optical rotation (OR), and theoretical calculations.

Benchmarking study on calculation of specific optical rotation of rigid chiral molecules in solution: 1:1 solute-solvent complex with PCM solvation model

We carried out DFT calculations of the specific optical rotation (OR) of six rigid chiral molecules in gas and solution phases. To examine the explicit solvent effect, multiple conformers of a 1:1 solute–solvent complex were considered. The most accurate results in the gas phase were obtained using cam-B3LYP/aug-cc-PVTZ. The specific ORs of chiral solutes were computed using cam-B3LYP/aug-cc-PVTZ in conjunction with the PCM solvation model. The calculated ORs of the six chiral molecules in hexane at 633 nm agreed overall with experimental measurements, but the explicit addition of hexane produced more accurate results. Applying the PCM model alone to (R)-methyloxirane did not reproduce experimentally observed distinct OR values for three different nonpolar solvents with similar dielectric constants. Using a 1:1 solute–solvent complex with the PCM model produced OR values for (R)-methyloxirane in cyclohexane, carbon tetrachloride, and benzene that were in considerably better agreement with the experimental solution values.

Streptoindoles A–D, novel antimicrobial indole alkaloids from the marine-associated actinomycete Streptomyces sp. ZZ1118

Six indole alkaloids, including the new streptoindoles A–D (1–4) and the known N-acetyltryptamine (5) and (3S)-bacilsubteramide A (6), were isolated from a culture of the marine-sourced actinomycete Streptomyces sp. ZZ1118 in rice medium. Streptoindoles A (1) and B (2) were enantiomers and separated by using a chiral HPLC column. Structures of the isolated compounds were determined based on their HRESIMS data, extensive NMR spectroscopic analyses, ECD calculations, optical rotation calculations, and a single crystal X-ray diffraction experiment. Streptoindoles A (1) and B (2) showed antimicrobial activities in inhibiting the growth of methicillin-resistant Staphylococcus aureus (MRSA), Escherichia coli, and Candida albicans with MIC values in a range from 7 to 25 μg/mL. Streptoindole C (3) had antimicrobial activities against E. coli and C. albicans with a MIC value of 7 μg/mL, while streptoindole D (4) showed antibacterial activity (MIC: 25 μg/mL) against MRSA.

Automated Quantum Chemistry-Based Calculation of Optical Rotation for Large Flexible Molecules.

The calculation of optical rotation (OR, [α]D) for nonrigid molecules was limited to small systems due to the challenging problem of generating reliable conformer ensembles, calculating accurate Boltzmann populations and the extreme sensitivity of the OR to the molecules' three-dimensional structure. Herein, we describe and release the crenso workflow for the automated computation of conformer ensembles in solution and corresponding [α]D values for flexible molecules. A comprehensive set of 28 organic drug molecules (28-144 atoms) with experimentally determined values is used in our assessment. In all cases, the correct OR sign is obtained with an overall mean relative deviation of 72% (mean absolute deviation of 82 °[dm(g/cm3)]-1 for experimental values in the range -160 to 287 °[dm(g/cm3)]-1). We show that routine [α]D computations for very flexible, biologically active molecules are both feasible and reproducible in about a day of computation time on a standard workstation computer. Furthermore, we observed that the effect of energetically higher-lying structures in the ensemble on the OR is often averaged out and that in 23 out of 28 cases, the correct OR sign is obtained by just considering only the lowest free energy conformer. In four example cases, we show that the approach can also describe the OR of pairs of flexible diastereomers properly. In summary, even very sensitive, multifactorial physicochemical properties appear reliably predictable with minimal user input from efficiently automated quantum chemical methods.

Alkaloids From the Marine Fungus Lecanicillium fusisporum Using an Amino Acid-Directed Strategy

An amino acid-directed strategy has been developed to explore the potential of marine fungi to produce alkaloids. The marine fungus Lecanicillium fusisporum was cultured in glucose-peptone-yeast (GPY) medium to which were added L-tryptophan, L-phenylalanine, L-threonine, D, L-methionine, L-serine, L-lysine and L-valine. A new indole alkaloid, lecasporinoid (1), along with five known alkaloids (2−6) were discovered from the culture broth. The planar structure of lecasporinoid (1) was determined by HR-ESIMS, and 1D and 2D NMR spectroscopic data. The absolute configuration was established by optical rotation and 13C NMR calculations combining with a chemical synthetic approach.

Streptonaphthyridine A, a new naphthyridine analogue with antiproliferative activity against human glioma cells from mariana trench-associated actinomycete Streptomyces sp. SY2111

A new naphthyridine analogue, named streptonaphthyridine A (1), together with eight previously reported compounds (2–9), were isolated from a Mariana Trench sediment-associated actinomycete Streptomyces sp. SY2111. Planar structure of streptonaphthyridine A was established by analyses of its HRESIMS data and extensive NMR spectra and its absolute configuration was determined by a combination of single crystal X-ray diffraction analysis and optical rotation calculations. Streptonaphthyridine A (1) had antiproliferative activity against human glioma U87MG and U251 cells with IC50 values of 7.9 ± 1.3 and 13.4 ± 2.7 µM, respectively, and the known compound monomethylsulochrin (7) showed more potent activity with IC50 values of 0.6 ± 0.1 µM for U87MG cells and 0.1 ± 0.0 µM for U251 cells.

Phomaligols F–I, polyoxygenated cyclohexenone derivatives from marine-derived fungus Aspergillus flavus BB1

By tracing the 13C NMR resonances for carbonyls and enols, four new oxidized phomaligol derivatives, phomaligols F–I (1–4), along with seven known compounds (5–11) were isolated from the culture of the fungus Aspergillus flavus BB1 isolated from the marine shellfish Meretrix meretrix collected on Hailing Island, Yangjiang, China. The chemical structures and the absolute configurations of the new compounds were elucidated by MS, NMR, ECD, optical rotation, and 13C NMR calculations. Compounds 1 and 2 represent the first examples of phomaligol derivatives that contain an unusual bicyclic skeleton. All isolated compounds were tested for their cytotoxic activity. Among them, sporogen-AO 1 (8) showed potent inhibitory activity against the cancer cell lines A549, H1299, SK-BR-3, and HCT116 with IC50 values of 0.13, 0.78, 1.19, and 1.32 μM, respectively. Phomaligol G (2) displayed cytotoxic activity against the A549 and H1299 cell lines with IC50 values of 46.86 and 51.87 μM respectively. Additionally, phomaligol H (3) demonstrated cytotoxic activity against the A549 cell line with an IC50 value of 65.53 μM. Mechanistic studies of compound 8 showed that it induced apoptosis of HCT116 cells in a dose-dependent manner.

Polycyclic polyprenylated acylphloroglucinols with immunosuppressive activity from Hypericum perforatum and absolute configurations assignment of previously reported analogues

Hyperformitins A–I (1–9), nine undescribed polycyclic polyprenylated acylphloroglucinols (PPAPs) with double-bond migration, along with four new isomers hyperformitins J–M (10–13), were isolated from Hypericum perforatum. Their structures and absolute configurations were determined by spectroscopic analyses including HRESIMS, IR, UV, NMR, and ECD, as well as optical rotation (OR) calculations. The absolute configurations of previously reported analogues, garsubellins D and C as well as garcinielliptones L and M, were assigned for the first time by NMR spectra and specific rotations analyses assisting with OR calculations. Selected compounds were tested for their immunosuppressive activities against lipopolysaccharide (LPS)-induced B lymphocyte proliferation. Compounds 1, 3, 4, 5, 7, and 11 showed inhibition activities against the proliferation of B lymphocyte with IC50 values ranging from 4.1 to 9.7 μM. Furthermore, the neuroprotective activities of the isolates against corticosterone (CORT)-induced injury in PC12 cells were also tested, and compounds 1, 12, and 13 exhibited neuroprotective effects with cell viabilities of 68.0%, 71.3%, and 68.4%, respectively under the concentration of 10 μM.

Tyrosinase Inhibitors from the Stems of Streblus Ilicifolius.

Two new stilbene derivatives, named strebluses C and D, were isolated from the EtOAc-soluble fraction of the stems of Streblus ilicifolius (Moraceae). Its absolute configuration was elucidated based on NMR spectroscopic data interpretation and optical rotation calculation. Streblus C possesses strong tyrosinase inhibitory activity with an IC50 value of 0.01 μM. Docking studies of 1 and 2 with oxy-tyrosinase were carried out to analyze their interactions. The analysis of the docked poses confirmed that 1 showed better binding affinity for oxy-tyrosinase than that of 2.

A Density Functional Theory Study of Optical Rotation in Some Aziridine and Oxirane Derivatives.

We present time-dependent density functional theory (TDDFT) calculations of the electronic optical rotation (ORP) for seven oxirane and two aziridine derivatives in the gas phase and in solution and compare the results with the available experimental values. For seven of the studied molecules it is the first time that their optical rotation was studied theoretically and we have therefore investigated the influence of several settings in the TDDFT calculations on the results. This includes the choice of the one-electron basis set, the exchange-correlation functional or the particular polarizable continuum model (PCM). We can confirm that polarized quadruple zeta basis sets augmented with diffuse functions are necessary for converged results and find that the aug-pc-3 basis set is a viable alternative to the frequently employed aug-cc-pVQZ basis set. Based on our study, we cannot recommend the generalized gradient functional KT3 for calculations of the ORP in these compounds, whereas the hybrid functional PBE0 gives results quite similar to the long-range correct CAM-B3LYP functional. Finally, we observe large differences in the solvent effects predicted by the integral equation formalism of PCM and the SMD variant of PCM. For the majority of solute/solvent combinations in this study, we find that the SMD model in combination with the PBE0 functional and the aug-pc-3 basis set gives the best agreement with the experimental values.

Opportunities and Limitations for Assigning Relative Configurations of Antibacterial Bislactones using GIAO NMR Shift Calculations.

Four new bislactones, dihydroacremonol (1), clonostachyone (2), acremodiol B (3), and acremodiol C (4), along with one known compound, hymeglusin (5), were isolated from cultures of two fungal strains (MSX59876 and MSX59260). Both strains were identified based on phylogenetic analysis of molecular data as Clonostachys spp.; yet, they biosynthesized a suite of related, but different, secondary metabolites. Given the challenges associated with elucidating the structures and configurations of bislactones, GIAO NMR calculations were tested as a complement to traditional NMR and HRESIMS experiments. Fortuitously, the enantiomer of the new natural product (4) was known as a synthetic compound, and the predicted configuration from GIAO NMR calculations (i.e., for the relative configuration) and optical rotation calculations (i.e., for the absolute configuration) matched those of the synthesis product. These results engendered confidence in using similar procedures, particularly the mixture of GIAO NMR shift calculations coupled with an orthogonal technique, to predict the configuration of 1-3; however, there were important limitations, which are discussed for each of these. The metabolites displayed antimicrobial activities, with compounds 1 and 4 being the most potent against Staphylococcus aureus with MICs of 1 and 4 μg/mL, respectively.

Bioactive Polyketides From the Potato Endophytic Fungus Aspergillus carneus

A previously undescribed polyketide (1) and 3 known analogs (2-4) were obtained from cultures of the potato endophytic fungus Aspergillus carneus. The structures were elucidated on the basis of extensive nuclear magnetic resonance spectroscopic data. The absolute configuration of 1 was further determined by electronic circular dichroism and optical rotation calculations. Compounds 1-4 showed moderate antifungal activity against plant pathogens. Compounds 1, 2, and 4 inhibited nitric oxide production in lipopolysaccharide-stimulated RAW264.7 cells, with half-maximal inhibitory concentration values of 13.36, 30.16, and 51.47 µM, respectively. Compound 4 showed effective antioxidant activity.

L-Tryptophan Induces a Marine-Derived Fusarium sp. to Produce Indole Alkaloids with Activity against the Zika Virus.

The effects of l-tryptophan supplementation on secondary metabolite production in the marine-derived fungus Fusarium sp. L1 were investigated by culturing the fungus in GPY medium with and without the amino acid. HPLC analysis of the products showed distinct metabolite profiles between the two cultures. The 1H NMR spectrum of the EtOAc extract of the culture supplemented with l-tryptophan displayed a series of characteristic aromatic proton signals (δH 6.50-8.50) and NH signals (δH 10.50-11.50) that were not observed in those from cultures not supplemented with l-tryptophan. Subsequently, 23 distinct indole alkaloids, including six new compounds, fusaindoterpenes A and B (1 and 2), fusariumindoles A-C (3-5), and (±)-isoalternatine A (6), together with 17 known compounds, were obtained from this culture. Fusaindoterpene A (1) contains a 6/9/6/6/5 heterocyclic system. Their chemical structures were determined by analysis of HRMS, NMR spectroscopy, optical rotation calculation, ECD calculation, and single-crystal X-ray diffraction data. Compounds 2, 9, and 15 displayed inhibitory activity against the Zika virus (ZIKV) in a standard plaque assay with EC50 values of 7.5, 4.2, and 5.0 μM, respectively, while not showing significant cell cytotoxicity against the A549 adenocarcinomic human alveolar basal epithelial cell line.

Cytochalasins from Xylaria sp. CFL5, an Endophytic Fungus of Cephalotaxus fortunei

Three previously undescribed cytochalasins, named xylariasins A‒C (1‒3), together with six known ones (4‒9) were isolated from Xylaria sp. CFL5, an endophytic fungus of Cephalotaxus fortunei. The chemical structures of all new compounds were elucidated on the basis of extensive spectroscopic data analyses and electronic circular dichroism calculation, as well as optical rotation calculation. Biological activities of compounds 1, 4‒9 were evaluated, including cytotoxic, LAG3/MHC II binding inhibition and LAG3/FGL1 binding inhibition activities. Compounds 6 and 9 possessed cytotoxicity against AGS cells at 5 μM, with inhibition rates of 94% and 64%, respectively. In addition, all tested isolates, except compound 6, exhibited obvious inhibitory activity against the interaction of both LAG3/MHC II and LAG3/FGL1. Compounds 1, 5, 7, and 8 inhibited LAG3/MHC II with IC50 values ranging from 2.37 to 4.74 μM. Meanwhile, the IC50 values of compounds 1, 7, and 8 against LAG3/FGL1 were 11.78, 4.39, and 7.45 μM, respectively.Graphic

Four new pyrrole alkaloids from the rhizomes of Amomum koenigii

Four new pyrrole alkaloids, named amokoens A-D (1-4), together with three known compounds (5-7) were isolated from the rhizomes of Amomum koenigii. Their structures and absolute configurations were established by spectroscopic data, including 1D and 2D NMR, and the optical rotation calculations. All the isolates were evaluated for their effects on nitric oxide (NO) production in lipopolysaccharide-induced RAW264.7 macrophages. Compounds 1-7 inhibited NO production ranging from 27.1 to 82.4% at a concentration of 100μM, and compounds 5 and 6 showed efficacious inhibitory activities with IC50 values of 42.2 and 69.3µM, respectively.

Origin invariant optical rotation in the length dipole gauge without London atomic orbitals.

We present an approach to perform origin invariant optical rotation calculations in the length dipole gauge without recourse to London atomic orbitals, called origin invariant length gauge [LG(OI)]. The LG(OI) approach works with any approximate wave function or density functional method, but here we focus on the implementation with the coupled cluster (CC) with single and double excitations method because of the lack of production-level alternatives. Preliminary numerical tests show the efficacy of the LG(OI) procedure and indicate that putting the origin in the center of mass of a molecule may not be an optimal choice for conventional CC-LG calculations.

Cytospyrone and Cytospomarin: Two New Polyketides Isolated from Mangrove Endophytic Fungus, Cytospora sp.

Two new polyketides, cytospyrone (1), cytospomarin (2), together with three known metabolites dimethoxyphtalide (3), integracin A (4) and integracin B (5), were isolated from the culture of Cytospora sp. from the Chinese mangrove Ceriops tagal. Their structures were elucidated by extensive spectroscopic analyses and time dependent density functional theory (TDDFT), calculation of electronic circular dichroism (ECD) and optical rotation (OR) data. Compound 2 displayed weak inhibitory activity against Escherichia coli GIM1.201 (minimum inhibitory concentration (MIC) value of 0.35 mM). Compounds 4 and 5 displayed significant cytotoxicity against human cancer cell line HepG2 (IC50 values of 5.98 ± 0.12 µM and 9.97 ± 0.06 µM, respectively), more potent than the positive control 5-fluorouracil (IC50 value of 43.50 ± 3.69 µM).