Antileishmanial Carbasugars from Geosmithia langdonii - Journal of

Article Cite This: J. Nat. Prod. 2018, 81, 2222−2227

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Antileishmanial Carbasugars from Geosmithia langdonii Lourin G. Malak,†,‡ Mohamed Ali Ibrahim,†,§ Ahmed M. Moharram,¶ Pankaj Pandey,⊥,∥ Babu Tekwani,†,⊥,○ Robert J. Doerksen,†,⊥,∥ Daneel Ferreira,†,⊥,# and Samir A. Ross*,†,⊥,# †

National Center for Natural Products Research, ⊥Department of Biomolecular Sciences, #Divisions of Pharmacognosy, Pharmacology, and ∥Medicinal Chemistry, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677-1848, United States ‡ Department of Pharmacognosy, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt § Department of Chemistry of Natural Compounds, National Research Center, Dokki, 12622 Cairo, Egypt ¶ Assiut University Mycological Center, Assiut University, Assiut 71515, Egypt

J. Nat. Prod. 2018.81:2222-2227. Downloaded from pubs.acs.org by UNIV OF SUNDERLAND on 10/26/18. For personal use only.

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S Supporting Information *

ABSTRACT: Two new carbasugar-type metabolites, (1S,2R,3R,4R,5R)-2,3,4trihydroxy-5-methylcyclohexyl-2′,5′-dihydroxybenzoate (1) and (1S,2S,3S,4R,5R)4-[(2′,5′-dihydroxybenzyl)oxy]-5-methylcyclohexane-1,2,3-triol (2), were isolated from the filamentous fungus Geosmithia langdonii isolated from cotton textiles from Assiut, Egypt. The structures of 1 and 2 were elucidated based on comprehensive 1D and 2D NMR and MS data. Compounds 1 and 2 showed antileishmanial activity against Leishmania donovani with IC50 values of 100 and 57 μM, respectively. The (1S,2R,3R,4R,5R) absolute configuration of carbasugar 1 was assigned via 2D NMR and experimental and calculated electronic circular dichroism (ECD) data. Similarly, the tentative structure of compound 2 was shown to possess a (1S,2S,3S,4R,5R) absolute configuration via comparing its experimental ECD data and the specific rotation with 1 as well as examining the energy-minimized 3D computational models of compounds 1 and 2. Drugs used in the treatment of leishmaniasis, both first-line drugs such as pentavalent antimonials and second-line drugs such as amphotericin B and pentamidine, often display high toxicity, severe side effects, and high cost. In addition there is increased resistance of the parasite to the chemotherapeutic drugs.2,5 This serves as an impetus to discover and develop new and effective antileishmanial drugs. Natural products have played a vital role in the drug discovery field. Over one-third of U.S. FDA approved drugs are either of natural origin or are a modified version of a natural product.6 Many plant extracts and isolated compounds have been shown to exhibit antileishmanial activities. These effects may be attributed solely to direct action on the parasite or to a concomitant effect on the host immune response.7 A number of reports have shown the induction or inhibition of cytokine production as a crucial factor for the destruction of the parasite without causing significant host tissue damage. This, in turn, expands the window of discovery of antileishmanial drugs to include the immunomodulatory activities of the potential drug candidates. Geosmithia langdonii (Ascomycota: Hypocreales) is a filamentous fungus8 isolated from cotton textiles from Assiut, Egypt. The G. langdonii fungus was provided by Assiut University Mycological Center (Accession No. 6161). It was

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eishmaniasis is a group of diseases caused by at least 20 species of the protozoan parasite Leishmania.1 It is prominent in certain tropical and subtropical regions of the world and causes serious health problems.2 It is estimated by the World Health Organization (WHO) that leishmaniasis is endemic in 88 countries with 12 million infected people and 350 million people that are at risk, with about 1.5−2 million new cases annually.3 Leishmaniasis has three basic forms: cutaneous, mucosal, and visceral leishmaniasis, with the cutaneous and visceral forms found commonly in humans. Cutaneous leishmaniasis causes skin sores and chronic ulcers but is usually self-limiting, though it can progress in some cases. Visceral leishmaniasis affects a number of internal organs such as the spleen and liver, and this type can become fatal if untreated. According to the Center for Food Security and Public Health, College of Veterinary Medicine, Iowa State University, dogs play a key role in the epidemiology of this disease, acting as hosts of L. infantum, which is one of the two main organisms responsible for visceral leishmaniasis.4 According to the Centers for Disease Control and Prevention (CDC), the estimated number of cutaneous leishmaniasis cases ranges between 0.7 and 1.2 million, while the number of cases of visceral leishmaniasis ranges from 0.2 to 0.4 million. Leishmaniasis is widespread in Asia, the tropical regions of Africa, southern Europe, and South America and also occurs in parts of the United States, where a number of cutaneous leishmaniasis cases have been found in Texas and Oklahoma. © 2018 American Chemical Society and American Society of Pharmacognosy

Received: June 8, 2018 Published: October 9, 2018 2222

DOI: 10.1021/acs.jnatprod.8b00473 J. Nat. Prod. 2018, 81, 2222−2227

Journal of Natural Products

Article

Table 2. 1H and 13C NMR Spectroscopic Data of 1 and 2.a

cultivated using potato dextrose broth (PDB) medium. Previously, 12 compounds were isolated from this fungus.9 The genus Geosmithia Pitt (Ascomycota: Hypocreales) consists of cosmopolitan fungi living in a platform constructed by phloeophagous insects.10 During the course of a search for natural antileishmanial drugs via screening fungal extracts, the ethyl acetate extract of G. langdonii was found to show promising antileishmanial activity. The current chemical and biological investigations of the ethyl acetate fraction of this fungus led to the isolation of the new compounds 1 and 2. The structures of the new carbasugars were elucidated via interpretation of comprehensive 1D and 2D NMR and MS data. Carbasugars, particular kinds of cyclitols, are analogues of carbohydrates in which the endocyclic oxygen atom is replaced by a methylene group. They are rare among natural products, and the first natural carbasugar was isolated from Streptomyces sp. Cyclitols are chemically stable and are usually present as subunits of naturally isolated compounds.11,12 Cyclitol-containing compounds possess interesting biological activities such as αglucosidase inhibition, antibiotic, antifungal, antiviral, and antimalarial activities.13,14 Herein, we report the structure elucidation of compounds 1 and 2 and assignment of their absolute configurations by comparison of their experimental and calculated ECD spectra, as well as their antileishmanial properties.

1 position

Leishmania donovani 1 2 pentamidine amphotericin B

100 57 9 0.2

>134 119 17 0.4

CH CH CH CH CH CH2

7 1′ 2′ 3′ 4′

16.8, CH3 113.4, C 155.7, C 118.8, CH 124.8, CH

5′ 6′ 7′ 2-OH

150.1, C 115.6, CH 170.3, C

5.35, m 3.98, brs 4.05, d (4.8) 3.63, brs 1.68, d (13.2) α, 1.94, dd (9.6, 13.2) β, 2.13, brs 1.06, d (6.8)

6.76, d (8.8) 6.96, dd (2.8, 8.8)

7.32, d (2.8)

68.5, 70.0, 74.9, 82.4, 31.8, 32.7,

CH CH CH CH CH CH2

17.2, CH3 125.8, C 149.7, C 116.8, CH 117.3, CH 150.8, C 117.6, CH 71.2, CH2

δH (J in Hz) 3.96, 4.06, 3.45, 3.64, 1.94, 1.49,

m t (4.4, 3.6) t (3.6, 3.2) m m m

1.60, m 0.94, d (6.8)

6.60, d (8.8) 6.55, dd (2.8, 8.8) 6.64, d (2.8) 4.62, d (3.2)

10.26, s

H-6α (δH 1.94, dd) with C-7 (δC 16.8), C-1 (δC 74.3), and C-5 (δC 31.9); and H3-7 (δH 1.06, d) with C-4 (δC 74.8). In addition, 1H−1H COSY correlations were observed between H-3 (δH 4.05, d) and H-4 (δH 3.63, brs), H-1 (δH 5.35, m), and H-6α (δH 1.94, dd) and between H-5 (δH 1.68, d) and H6α (δH 1.94, dd). Compound 2 had a molecular formula of C14H20O6 as revealed by HRESIMS data and was obtained as a white residue. The 1H and 13C NMR data (Table 2) showed similarities to those of 1. The resonances of a carbasugar moiety were characterized by the presence of four oxymethines at δH 3.45 (t, J = 3.6, 3.2 Hz)/δC 74.9, δH 3.64 (m)/δC 82.4, δH 3.96 (m)/δC 68.5, and δH 4.06 (t, J = 4.4, 3.6 Hz)/δC 70.0; an sp3 methine at δH 1.94 (m)/δC 31.8; a methylene at δH 1.49 (m), 1.60 (m)/δC 32.7; and a secondary methyl at δH 0.94 (d, J = 6.8 Hz)/δC 17.2. The NMR spectra also revealed the presence of a 2,5-dihydroxybenzyl alcohol moiety, which was confirmed by the presence of an oxygenated methylene resonance at δH 4.62 (d, J = 3.2 Hz)/δC 71.2, the protons of which showed HMBC correlations to C-4 (δC 82.4), C-1′ (δC 125.8), C-2′ (δC 149.5), and C-6′ (δC 117.6) of the dihydroxybenzyl alcohol moiety. The structure was further confirmed by the HMBC correlations of H-6′ (δH 6.64, d) to C-2′ (δC 149.5), C-4′ (δC 117.3), and C-7′ (δC 71.2). In addition, 1H−1H COSY correlations were evident between H5 (δH 1.94, m) and H-6 (δH 1.49, m), H2-6 (δH 1.486, m) and H-1 (δH 3.96, m), H-1 (δH 3.96, m) and H-2 (δH 4.06, t), and H-2 (δH 4.06, t) and H-3 (δH 3.45, t). The absolute configurations of 1 and 2 were assessed via electronic circular dichroism (ECD), NOESY, and specific rotation data. The NOESY spectrum of compound 1 showed correlations between H-1, H-2, H-3, H-4, and H-5 and hence an all-cis configuration of the carbasugar moiety. This limited the number of possible stereoisomers for the two enantiomers, i.e., (1S,2R,3R,4R,5R)-1 and (1R,2S,3S,4S,5S)-1. The ECD spectrum of the (1S,2R,3R,4R,5R)-1 enantiomer was calculated using time-dependent density functional theory (TDDFT)15 at the B3LYP/6-311++G(2d,p) level with the polarizable

Table 1. Antileishmanial Activities of Compounds 1 and 2 IC90 (μM)b

74.3, 72.7, 72.3, 74.8, 31.9, 29.3,

2 δC, type

Data for 1 and 2 are obtained in methanol-d4 (400 MHz for 1H, 100 MHz for 13C, δ in ppm).

RESULTS AND DISCUSSION Compound 1 was obtained as a white solid and exhibited a molecular formula of C14H18O7 as revealed by HRESIMS data. The 1H and 13C NMR data (Table 2) were characterized by

IC50 (μM)a

1 2 3 4 5 6

δH (J in Hz)

a

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compound

δC, type

a

IC50 is the concentration that affords 50% inhibition of cell growth. IC90 is the concentration that affords 90% inhibition of cell growth.

b

the presence of four oxymethines at δH 3.63 (brs)/δC 74.8, δH 3.98 (brs)/δC 72.7, δH 5.35 (m)/δC 74.3 and δH 4.05 (d, J = 4.8 Hz)/δC 72.3; an sp3 methine at δH 1.68 (d, J = 13.2 Hz)/δC 31.9; a methylene at δH 1.94 (dd, J = 9.6, 13.2 Hz), 2.13 (brs)/ δC 29.3; and a secondary methyl at δH 1.06 (d, J = 6.8 Hz)/δC 16.8. These features suggested the presence of a carbasugar unit in the molecule. The presence of three aromatic signals at δH 6.76 (d, J = 8.8 Hz)/δC 118.8, δH 6.96 (dd, J = 2.8, 8.8 Hz)/ δC 124.8, and δH 7.32 (d, J = 2.8 Hz)/δC 115.6 is attributed to H-3′, H-4′, and H-6′, characteristic of the ABX spin pattern of a trisubstituted aromatic system. The deshielded carbon resonance at δC 170.3 suggested the presence of an ester carbonyl carbon, and the location of the ester moiety was confirmed by the HMBC correlation (Figure S5, Supporting Information) of H-1 of the carbasugar moiety (δH 5.35, m) with the ester carbonyl carbon. The structure was further confirmed by the two- and three-bond HMBC correlations of H-1 (δH 5.35, m) with C-5 (δC 31.9); H-3 (δH 4.05, d) with C2 (δC 72.7); H-4 (δH 3.63, brs) with C-6 (δC 29.3), C-7 (δC 16.8), and C-3 (δC 72.3); H-5 (δH 1.68, d) with C-1 (δC 74.3); 2223



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Figure 1. Structures of compounds 1 and 2.

Figure 2. 3D structures of lowest-energy conformers (A) 1a and (B) 1f of compound 1 in methanol at the B3LYP/6-311++G(2d,p) level.

continuum (PCM)16 solvation model with MeOH as the solvent. Only two conformers, 1a and 1f, with significantly different root mean square deviation (RMSD) were obtained for (1S,2R,3R,4R,5R)-1 in MeOH at the B3LYP/6-311+ +G(2d,p) level. The conformers are shown in Figure 2, and their relative binding free energies (kcal/mol) and % Boltzmann populations are listed in Table 3.

Compounds 1 and 2 were found to have weak antileishmanial activities against Leishmania donovani, with IC50 values of 100 and 57 μM, respectively, compared to the controls, pentamidine (IC50 9 μM) and amphotericin B (IC50 0.2 μM), (Table 1). These compounds complement the relatively rare series of natural products that possess carbasugar (cyclitol) constituent units.

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Table 3. Major Conformers of (1S,2R,3R,4R,5R)-1 and Their Relative Binding Free Energies (kcal/mol) and % Boltzmann Populations (1S,2R,3R,4R,5R)-1 conformer

relative binding free energies (kcal/mol)

Boltzmann population distribution (%)

1a 1f

0 0.062

52.59 47.61

EXPERIMENTAL SECTION

General Experimental Procedures. Optical rotations were measured with an Autopol IV automatic polarimeter. UV data were acquired on a Cary-50 Bio spectrophotometer, and ECD data on a JASCO J-715 spectrometer. HRESIMS data were acquired using a Bruker BioApex-FTMS with electrospray ionization (ESI). 1D and 2D NMR spectra were recorded on a Varian AS 400 MHz spectrometer. Incubator shakers (New Brunswick Scientific, Innova 4430) were used for incubating fungi. Sephadex LH-20 (Mitsubishi Kagaku, Tokyo, Japan) and silica gel (60−120 mesh, Merck, Darmstadt, Germany) were used for column chromatography (CC). Fractions from CC were monitored using precoated aluminum sheets [silica 60 F254, 0.25 mm (Merck, Darmstadt, Germany)], with detection provided by UV light (254 and 366 nm) and by spraying with 1% vanillin−H2SO4 reagent followed by heating for 5−10 min (105 °C). Diaion HP-20 (250 μm, Sigma-Aldrich, St. Louis, MO, USA) was used for the separation of metabolites from the liquid media. Fungal Material. G. langdonii (Ascomycota: Hypocreales) was provided by the Assiut University Mycological Center, Assiut, Egypt. The fungus has been identified by one of the coauthors (A.M.M.) at Assiut University Mycological Center based on its morphological character and comparison with the literature (accession no. 6161).8 The fungus was isolated from cotton from Assiut, Egypt. The textiles were rinsed with water followed by surface sterilization using 70% EtOH for 1 min, rinsed with sterilized water, cut into small pieces (2 cm in length and width), deposited in a Petri dish containing potato dextrose agar (PDA) medium (200 g potato infusion, 20 g glucose, and 15 g agar in 1 L distilled water, supplemented with 100 mg/L chloramphenicol), and cultivated at 28 °C for 3 days. The hyphal tips

The absolute configuration of 1 was assigned by comparison of the calculated and experimental ECD data. The calculated spectra of (1S,2R,3R,4R,5R)-1 in MeOH is in accordance with the experimental spectrum for 1, hence confirming its absolute configuration. Figure 3 depicts overlays of the experimental spectrum of 1 and the Boltzmann-weighted calculated spectrum of (1S,2R,3R,4R,5R)-1 and (1R,2S,3S,4S,5S)-1 at the B3LYP/6-311++G(2d,p) level. These results matched well with the experimental ECD spectrum (Figure 3) and hence permitted assignment of the (1S,2R,3R,4R,5R) absolute configuration of 1. Comparison of the ECD spectra and specific rotations of compounds 1 and 2 permitted assignment of the (1S,2S,3S,4R,5R) absolute configuration of compound 2 (Figure 4). The absence of the ester carbonyl group in 2, thus, has a negligible influence on the preferred conformations of 2. 2224



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Figure 3. Experimental ECD spectrum of (1S,2R,3R,4R,5R)-1 (black), calculated averaged Boltzmann-weighted ECD spectrum of (1S,2R,3R,4R,5R)-1 [conformers; 1a and 1f (red)], and calculated ECD spectrum of (1R,2S,3S,4S,5S)-1 enantiomer in MeOH (blue). The σvalue (artificial line broadening) was set to 0.29 eV.

Figure 4. Experimental ECD spectra of 1 and 2. extract (2 g) was subjected to silica gel CC (50 g, 65 × 5 cm) and eluted with n-hexane/EtOAc in a ratio of increasing polarity (100:0− 0:100, 2 L/fraction) to afford 10 fractions [A−J]. Fraction G (eluted with n-hexane/EtOAc ratio 13:7, 120 mg) was further purified using Sephadex LH-20 CC (15 g, 65 × 1.5 cm) and eluted with MeOH/ CHCl3 (50:50), yielding 1 (30 mg). Fraction H (eluted with nhexane/EtOAc ratio 3:2, 80 mg) was further purified using CC over silica gel (1.5 g, 25 × 1.5 cm) using CHCl3/MeOH in a ratio of increasing polarity (70:30−30:70, 50 mL/fraction) to yield three subfractions [H1−H3], of which subfraction H3 yielded 2 (2.1 mg). The remaining fractions have been shown to be composed of our previously reported metabolites: 4-[2′,4′-dihydroxy-6′(hydroxymethyl)benzyl]benzene-1,2-diol, (4R,5R,6R)-4,5-dihydroxy6-(6′-methylsalicyloxy)-2-methyl-2-cyclohexen-1-one, (+)-epiepoformin, (−)-dihydroepiepoformin, (4S,5S)-4,5-dihydroxy-2-methylcyclohex-2-enone, 6-methylsalicylic acid, gentisylquinone, 3,4-dihydroxytoluene, 2,5-dihydroxybenzaldehyde, 3-hydroxybenzyl alcohol, 2,5dihydroxybenzyl alcohol, and 3-hydroxytoluene.9 (1S,2R,3R,4R,5R)-2,3,4-Trihydroxy-5-methylcyclohexyl-2′,5′-dihydroxybenzoate (1): white solid (MeOH); UV (MeOH) λmax (log ε) 335 (3.59) and 341 (3.57) nm; [α]20D +13.3 (c 0.02, MeOH); 1H NMR (methanol-d4, 400 MHz) see Table 2; 13C NMR (methanol-d4, 400 MHz) see Table 2; HRESIMS m/z 297.1008 [M − H]− (calcd

were examined and transferred to new PDA plates and subcultured until pure culture was obtained. Culture Media. Fungi were grown on PDA plates at 28 °C for 14 days. Plates were kept in a refrigerator and used when needed. The fungus was grown on tryptic soy, malt extract, and PDB media. Extraction and Isolation of Bioactive Metabolites. G. langdonii was grown in 2.8 L Erlenmeyer flasks containing 1 L of PDB medium (36 flasks). PDB medium was prepared by dissolving 24 g of PDB in 1 L of distilled water and autoclaved. Each flask was seeded with small fragments (≈ 2−5 mm) of the mycelium. The fungi were incubated at 30 °C, using shakers (160 rpm) for 2 weeks. After the incubation period, the mycelia were filtered through sterile cotton using vacuum filtration, and the filtrates (40 L) were extracted with activated ion-exchange resin (Diaion HP-20) by adding 100 g of resin to each 1 L of the filtrate before being returned to the shakers and left overnight. The contents of the flasks were filtered, and the HP-20 was washed with distilled water to remove salts and sugars. The resin was eluted with MeOH and acetone. The MeOH and acetone eluates were combined and dried under vacuum to yield a viscous residue, which was dissolved in water and successively extracted with nhexane, CH2Cl2, and EtOAc (each 4 × 1 L). Each fraction was separately concentrated under vacuum to afford 2 g (n-hexane), 10 g (DCM), and 2 g (EtOAc) extracts, respectively. The EtOAc crude 2225



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for C14H17O7, 297.09741) and m/z 595.2073 [2M − H]− (calcd for C28H35O14, 595.20265). (1S,2S,3S,4R,5R)-4-[(2′,5′-Dihydroxybenzyl)oxy]-5-methylcyclohexane-1,2,3-triol (2): white residue (MeOH); UV (MeOH) λmax (log ε) 297 (3.21) and 289 (3.19) nm; [α]20D +13.3 (c 0.02, MeOH); 1 H NMR (methanol-d4, 400 MHz) see Table 2; 13C NMR (methanold4, 400 MHz) see Table 2; HRESIMS m/z 307.1183 [M + Na]+ (calcd for C14H20O6Na, 307.1158) and m/z 591.2433 [2M + Na]+ (calcd for C28H40O12Na, 591.2418). Antileishmanial Bioassay. The antileishmanial activity was evaluated against a culture of L. donovani promastigotes grown in RPMI 1640 medium supplemented with 10% GIBCO fetal calf serum at 26 °C. Growth of L. promastigotes was determined by the Alamar Blue assay (BioSource International, Camarillo, CA, USA). Standard fluorescence was measured by a FLUOstar Galaxy plate reader (excitation wavelength, 544 nm; emission wavelength, 590 nm).17,18 Pentamidine (IC50 9 μM and IC90 17 μM) and amphotericin B (IC50 0.2 μM and IC90 0.4 μM) were used as controls. Computational Methods. The structure of (1S,2R,3R,4R,5R)-1 was drawn in Maestro19 and energy-minimized using the LigPrep20 module of the Schrödinger suite. Conformational search for 1 was carried out using the optimized potentials for liquid simulations (OPLS3)21 force field and mixed torsional/low-mode sampling using the MacroModel22 program implemented in the Schrö dinger software. An energy window cutoff of 10.0 kcal/mol was used during the conformational search. Similar settings and methods for molecular mechanics and quantum mechanics calculations were used as reported.23,24 Redundant conformers were eliminated using an RMSD cutoff of 0.5 Å. The resulting six lowest-energy conformers were further optimized at the hybrid density-functional B3LYP level of theory using the 6-31G(d,p) basis set, with tight geometry convergence. The resulting geometries were further optimized using B3LYP/6-311++G(2d,p), to get more accurate geometries. Frequency calculations were performed subsequent to geometry optimizations to ensure that all conformers were minima on the potential energy surface. Geometry optimizations were performed in MeOH, for which the polarizable continuum solvation model16 implemented in Gaussian 09 Rev. B0.125 was used. All the optimized conformers were used for ECD calculations using TDDFT15 at the B3LYP/6311++G(2d,p) level in MeOH. ECD curves were generated with SpecDis26 software (version 1.70.1) using a half-bandwidth of 0.29 eV. The relative populations of each conformer were calculated on the basis of the Boltzmann weighting factor at 298 K, using the Gibbs free energy. To generate the final ECD spectrum, the calculated spectra of all the lowest energy conformations which showed >1% Boltzmann population were averaged using Boltzmann weighting. The computed ECD spectra generated at 0.29 eV using a Gaussian function, within the SpecDis26 software, were used for comparison to experimental data.

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Samir A. Ross: 0000-0002-3807-1299 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the Egyptian Government and the National Center for Natural Products Research, University of Mississippi, USA, for their financial support. This work was supported in part by the USDA Agricultural Research Service Specific Cooperaive Agreement No. 58-6060-6-015. P.P. and R.J.D. were supported in part by grant P20GM104932 from the U.S. National Institutes of Health and the National Science Foundation Major Research Infrastructure grant no. 1338056; their research was conducted in part at the Mississippi Center for Supercomputing Research and in part in a facility constructed with support from the Research Facilities Improvement Program C06RR14503 from the NIH.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jnatprod.8b00473. 1 H NMR, 13C NMR, HMBC, HMQC, 1H−1H COSY, DEPT, NOESY, and HRESIMS data for compounds 1 and 2 and computational details (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] (S. A. Ross). Tel: +1 662 915 1031. Fax: +1 662 915 7989. ORCID

Pankaj Pandey: 0000-0001-9128-8254 Robert J. Doerksen: 0000-0002-3789-1842 Daneel Ferreira: 0000-0002-9375-7920 2226



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