Xing-Cong Li

Determination of Absolute Configuration of Natural Products: Theoretical Calculation of Electronic Circular Dichroism as a Tool

Determination of absolute configuration (AC) is one of the most challenging features in the structure elucidation of chiral natural products, especially those with complex structures. With revolutionary advancements in the area of quantum chemical calculations of chiroptical spectroscopy over the past decade, the time dependent density functional theory (TDDFT) calculation of electronic circular dichroism (ECD) spectra has emerged as a very promising tool. The principle is simply based on the comparison of the calculated and experimental ECD spectra: the more closely they match, the more reliable conclusion for the AC assignment can be drawn. This review attempts to use several examples representing monomeric flavonoids, rotationally restricted biflavonoids, complex hexahydroxydiphenoyl-containing flavonoids, conformationally flexible and restrained sesquiterpenoids, cembrane-africanene terpenoids, dihydropyranocoumarins, alkaloids, and dihydroxanthones to illustrate the applicability of this approach in determining the AC of structurally diverse natural products. The findings clearly indicate that the TDDFT calculation of ECD spectra can quantify the contribution of individual conformers and the interaction of multiple chromophores, making it possible to determine the AC of complex chiral molecules. The calculated electronic transitions and molecular orbitals provide new insight into the interpretation of ECD spectra at the molecular level.

Antifungal Activity of C-27 Steroidal Saponins

ABSTRACT As part of our search for new antifungal agents from natural resources, 22 C-27 steroidal saponins and 6 steroidal sapogenins isolated from several monocotyledonous plants were tested for their antifungal activity against the opportunistic pathogens Candida albicans, Candida glabrata, Candida krusei, Cryptococcus neoformans, and Aspergillus fumigatus. The results showed that the antifungal activity of the steroidal saponins was associated with their aglycone moieties and the number and structure of monosaccharide units in their sugar chains. Within the 10 active saponins, four tigogenin saponins (compounds 1 to 4) with a sugar moiety of four or five monosaccharide units exhibited significant activity against C. neoformans and A. fumigatus, comparable to the positive control amphotericin B. The antifungal potency of these compounds was not associated with cytotoxicity to mammalian cells. This suggests that the C-27 steroidal saponins may be considered potential antifungal leads for further preclinical study.

Antioxidant activity of the dihydrochalcones Aspalathin and Nothofagin and their corresponding flavones in relation to other Rooibos ( Aspalathus linearis ) Flavonoids, Epigallocatechin Gallate, and Trolox.

The antioxidant activity of rooibos flavonoids, including the dihydrochalcones aspalathin and nothofagin and their corresponding flavone glycosides, was evaluated using the ABTS radical cation, metal chelating, and Fe(II)-induced microsomal lipid peroxidation assays. Epigallocatechin gallate (EGCG) and Trolox were used as reference standards. Optimized geometric conformers of aspalathin and nothofagin, in addition to calculated physicochemical properties, were considered to explain interaction with the microsomal membrane structure and thus relative potency of the dihydrochalcones. The most potent radical scavengers were aspalathin (IC50 = 3.33 microM) and EGCG (IC50 = 3.46 microM), followed by quercetin (IC50 = 3.60 microM) and nothofagin (IC50 = 4.04 microM). The least effective radical scavengers were isovitexin (IC50 = 1224 microM) and vitexin (IC50 > 2131 microM). Quercetin (IC50 = 17.5 microM) and EGCG (IC50 = 22.3 microM) were the most effective inhibitors of lipid peroxidation. Aspalathin (IC50 = 50.2 microM) and catechin (IC50 = 53.3 microM) displayed similar potencies. Nothofagin (IC50 = 1388 microM) was almost as ineffective as its flavone glycoside analogues.

NMR ASSIGNMENTS OF ELLAGIC ACID DERIVATIVES

HMBC spectroscopy optimized for small couplings was employed to determine the four‐bond and two‐bond proton carbon correlations on the aromatic rings of ellagic acid derivatives. Complete 13C NMR assignments of 3′‐O‐methyl‐3,4‐methylenedioxyellagic acid 4′‐O‐β‐D‐glucopyranoside (1), 3,3′‐di‐O‐methylellagic acid 4′‐O‐β‐D‐xylopyranoside (2), 3,3′,4‐tri‐O‐methylellagic acid 4′‐O‐β‐D‐glucopyranoside (3) and ellagic acid (4) were achieved using this technique. This study indicates that optimization of the delay time in the HMBC spectrum is crucial in assigning the 13C NMR signals of phenolic compounds with highly oxygenated quaternary carbons. Copyright

Oligomeric proanthocyanidins: naturally occurring O-heterocycles (January 1996 to December 1998)

This review covers the flavan-3-ols (catechins), flavan-4-ols/flavan-3,4-diols (leucoanthocyanidins), A-type proanthocyanidins, B-type proanthocyanidins including the procyanidins, prodelphinidins, propelargonidins, proteracacinidins, promelacacinidins, procassinidins, probutinidins, and non-proanthocyanidins with flavan-3-ol constituent units. Newly isolated proanthocyanidins, structure elucidation, syntheses, HPLC/MS analysis, NMR/ conformational analysis, and the effects of proanthocyanidins on human nutrition and health are reported. The literature from January 1999 to December 2001 is reviewed, and 130 references are cited.

Automated high-throughput system to fractionate plant natural products for drug discovery.

The development of an automated, high-throughput fractionation procedure to prepare and analyze natural product libraries for drug discovery screening is described. Natural products obtained from plant materials worldwide were extracted and first prefractionated on polyamide solid-phase extraction cartridges to remove polyphenols, followed by high-throughput automated fractionation, drying, weighing, and reformatting for screening and storage. The analysis of fractions with UPLC coupled with MS, PDA, and ELSD detectors provides information that facilitates characterization of compounds in active fractions. Screening of a portion of fractions yielded multiple assay-specific hits in several high-throughput cellular screening assays. This procedure modernizes the traditional natural product fractionation paradigm by seamlessly integrating automation, informatics, and multimodal analytical interrogation capabilities.

Cycloartane Glycosides from Sutherlandia frutescens

Four new cycloartane glycosides, sutherlandiosides A-D (1-4), were isolated from the South African folk medicine Sutherlandia frutescens and their structures established by spectroscopic methods and X-ray crystallography as 1 S,3 R,24S,25-tetrahydroxy-7S,10S-epoxy-9,10- seco-9,19-cyclolanost-9(11)-ene 25-O-beta-D-glucopyranoside (1), 3R,7S,24S,25-tetrahydroxycycloartan-1-one 25-O-beta-D-glucopyranoside (2), 3R,24S,25-trihydroxycycloartane-1,11-dione 25-O-beta-D-glucopyranoside (3), and 7S,24S,25-trihydroxycycloart-2-en-1-one 25-O-beta-D-glucoyranoside (4). Compound 1 represents the first secocycloartane skeleton possessing a 7,10-oxygen bridge. Compounds 2- 4 are also the first examples of naturally occurring cycloartanes with a C-1 ketone functionality. Biosynthetic considerations and chemical evidence suggest that the presence of the C-1 ketone in 2 may facilitate the ring opening of the strained cyclopropane system.

Reversal of Fluconazole Resistance by Sulfated Sterols from the Marine Sponge Topsentia sp.

Bioassay-guided fractionation of the extract of Topsentia sp. led to the identification of two new sulfated sterols, geodisterol-3-O-sulfite (1) and 29-demethylgeodisterol-3-O-sulfite (2), the active constituents reversing efflux pump-mediated fluconazole resistance. Both compounds enhanced the activity of fluconazole in a Saccharomyces cerevisiae strain overexpressing the Candida albicans efflux pump MDR1, as well as in a fluconazole-resistant Candida albicans clinical isolate known to overexpress MDR1. These results provide insight into the clinical utility of combining efflux pump inhibitors with current antifungals to combat the resistance associated with opportunistic fungal infections caused by C. albicans.

Potent in vitro antifungal activities of naturally occurring acetylenic acids.

ABSTRACT Our continuing effort in antifungal natural product discovery has led to the identification of five 6-acetylenic acids with chain lengths from C16 to C20: 6-hexadecynoic acid (compound 1), 6-heptadecynoic acid (compound 2), 6-octadecynoic acid (compound 3), 6-nonadecynoic acid (compound 4), and 6-icosynoic acid (compound 5) from the plant Sommera sabiceoides. Compounds 2 and 5 represent newly isolated fatty acids. The five acetylenic acids were evaluated for their in vitro antifungal activities against Candida albicans, Candida glabrata, Candida krusei, Candida tropicalis, Candida parapsilosis, Cryptococcus neoformans, Aspergillus fumigatus, Aspergillus flavus, Aspergillus niger, Trichophyton mentagrophytes, and Trichophyton rubrum by comparison with the positive control drugs amphotericin B, fluconazole, ketoconazole, caspofungin, terbinafine, and undecylenic acid. The compounds showed various degrees of antifungal activity against the 21 tested strains. Compound 4 was the most active, in particular against the dermatophytes T. mentagrophytes and T. rubrum and the opportunistic pathogens C. albicans and A. fumigatus, with MICs comparable to several control drugs. Inclusion of two commercially available acetylenic acids, 9-octadecynoic acid (compound 6) and 5,8,11,14-eicosatetraynoic acid (compound 7), in the in vitro antifungal testing further demonstrated that the antifungal activities of the acetylenic acids were associated with their chain lengths and positional triple bonds. In vitro toxicity testing against mammalian cell lines indicated that compounds 1 to 5 were not toxic at concentrations up to 32 μM. Furthermore, compounds 3 and 4 did not produce obvious toxic effects in mice at a dose of 34 μmol/kg of body weight when administered intraperitoneally. Taking into account the low in vitro and in vivo toxicities and significant antifungal potencies, these 6-acetylenic acids may be excellent leads for further preclinical studies.

Anti-infective Discorhabdins from a Deep-Water Alaskan Sponge of the Genus Latrunculia

Bioassay- and LC-MS-guided fractionation of a methanol extract from a new deep-water Alaskan sponge species of the genus Latrunculia resulted in the isolation of two new brominated pyrroloiminoquinones, dihydrodiscorhabdin B and discorhabdin Y (2), along with six known pyrroloiminoquinone alkaloids, discorhabdins A (3), C (4), E (5), and L (6), dihydrodiscorhabdin C (7), and the benzene derivative 8. Compounds 3, 4, and 7 exhibited anti-HCV activity, antimalarial activity, and selective antimicrobial activity. Although compounds 3 and 7 displayed potent and selective in vitro antiprotozoal activity, Plasmodium berghei-infected mice did not respond to these metabolites due to their toxicity in vivo.