This review covers conformational and configurational assignments in natural product molecules using chiroptical spectroscopy reported over the last 15 years. Special attention is given to vibrational optical activity methods associated with quantum mechanical calculations.

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The function of a protein is determined by its structure, which is intrinsically related to its solvent environment. Based on this paradigm, there has been a great deal of interest in the role that non-aqueous solvents play in regulating protein structure, with some debate in the literature regarding dimethyl sulfoxide (DMSO). Thus, in this work we have used Raman and Raman optical activity (ROA) spectroscopies to investigate conclusively the changes induced by DMSO in the secondary structure of an array of proteins including human serum albumin (highly α-helical), bovine α-lactalbumin (mainly α-helical), bovine ribonuclease A (containing both α-helix and β-sheet), bovine β-lactoglobulin (mainly β-sheet), and bovine α-casein (disordered). Our results clearly demonstrate that 100% DMSO solutions destabilize α-helices completely, converting them into the poly(L-proline) II (PPII) helix conformation. However, low concentrations of DMSO (10% v/v) were found to have little effect on the structure of even the most helical protein, human serum albumin. In the case of α-casein, the natively unfolded protein rich in PPII helix was converted into a further disordered structure when dissolved in pure DMSO. By contrast, β-sheets remained mostly unaffected regardless of DMSO concentration. While providing new insights into protein structure in organic solvents, this work reinforces the capability of vibrational optical activity to assess conformations of biomolecules in conditions not accessible to other techniques, such as X-ray crystallography and NMR.

A new orbitide named ribifolin was isolated and characterized from Jatropha ribifolia using mass spectrometry, NMR spectroscopy, quantitative amino acid analysis, molecular dynamics/simulated annealing, and Raman optical activity measurements and calculations. Ribifolin (1) and its linear form (1a) were synthesized by solid-phase peptide synthesis, followed by evaluation of its antiplasmodial and cytotoxicity activities. Compound 1 was moderately effective (IC50 = 42 μM) against the Plasmodium falciparum strain 3D7.

The flagellate protozoan Trypanosoma cruzi, the etiological agent of Chagas disease, affects more than 18 million people in Latin America and is responsible for approximately 400000 deaths per year.1) Only two drugs are commercially available for the treatment of this disease, namely, nifurtimox (a 2-nitrofuran derivative) and benznidazole (a 2-nitroimidazole acetamide). These drugs are, however, not consistently effective and, moreover, exhibit serious side effects including cardiac and/or renal toxicity.2) There is thus particular interest in the discovery of natural products that might be developed to generate safer and more efficient chemotherapeutic agents against T. cruzi. 3)A number of biologically-active chromenes have been isolated from species of the genus Piper, including the prenylated chromene 1 from Piper gaudichaudianum 4) and chromenes 2-5 ( Fig. 1) from P. aduncum. 5) Whilst these chromenes have been shown to exhibit anti-fungal 4) and antitumour properties, 5) no evaluation has yet been made with respect to their activity against T. cruzi. The object of the present study was to examine a range of natural chromenes and chromene derivatives in order to determine their potential for further development to treat Chagas disease. METHODS AND RESULTSGeneral All reagents were of analytical grade. For methylation reactions, an ethereal solution of diazomethane (30 ml) was prepared by dissolving 2.14 g of N-methyl-N-nitroso-p-toluenesulphonamide (Diazald; Aldrich, Steinheim, Germany) in 10.0 ml of ethanol containing 4.0% potassium hydroxide.6) Hydrogenation reactions were carried out under an atmosphere of hydrogen in the presence of palladium (3.0 or 10.0%) on activated charcoal (Acros Organics, New Jersey, U.S.A.) as catalyst.7) The acetylated chromene was prepared by treatment with acetic anhydride (20.0 ml) and pyridine (20.0 ml) overnight. 8) Benznidazole, employed as positive control in the assays of trypanocidal activity, was obtained from Roche (Rio de Janeiro, Brazil).Plant Material Specimens of P. gaudichaudianum and P. aduncum were cultivated from seed under greenhouse conditions at the Institute of Chemistry, UNESP, Araraquara-SP, Brazil. Plant material was authenticated by Dr. Guillermo E. D. Paredes (Universidad Pedro Ruiz Gallo, Lambayeque, Peru) and voucher specimens (with codes Kato 0093 and 0057, respectively) were deposited at the Herbarium of the The aim of the study was to investigate the anti-trypanocidal activities of natural chromene and chromene derivatives. Five chromenes were isolated from Piper gaudichaudianum and P. aduncum, and a further seven derivatives were prepared using standard reduction, methylation and acetylation procedures. These compounds were assayed in vitro against epimastigote forms of Trypanosoma cruzi, the causative agent of Chagas disease. The results showed that the most of the compounds, especially those possessing electron-donating groups as substituents on the aromatic ring, showed potent trypanocidal activity. The most active compound, [(2S)-methyl-2-m...

Chiral natural product molecules are generally assumed to be biosynthesized in an enantiomerically pure or enriched fashion. Nevertheless, a significant amount of racemates or enantiomerically enriched mixtures has been reported from natural sources. This number is estimated to be even larger since the enantiomeric purity of secondary metabolites is rarely checked in the natural product isolation pipeline. This latter fact may have drastic effects on the evaluation of the biological activity of chiral natural products. A second bottleneck is the determination of their absolute configurations. Despite the widespread use of optical rotation and electronic circular dichroism, most of the stereochemical assignments are based on empirical correlations with similar compounds reported in the literature. As an alternative, the combination of vibrational circular dichroism and quantum chemical calculations has emerged as a powerful and reliable tool for both conformational and configurational analysis of natural products, even for those lacking UV-Vis chromophores. In this review, we aim to provide the reader with a critical overview of the occurrence of enantiomeric mixtures of secondary metabolites in nature as well the best practices for their detection, enantioselective separation using liquid chromatography, and determination of absolute configuration by means of vibrational circular dichroism and density functional theory calculations.

Gaudichaudianic acid, a prenylated chromene isolated from Piper gaudichaudianum, has been described as a potent trypanocidal compound against the Y-strain of Trypanosoma cruzi. We herein describe its isolation as a racemic mixture followed by enantiomeric resolution using chiral HPLC and determination of the absolute configuration of the enantiomers as (+)-S and (-)-R by means of a combination of electronic and vibrational circular dichroism using density functional theory calculations. Investigation of the EtOAc extract of the roots, stems, and leaves from both adult specimens and seedlings of P. gaudichaudianum revealed that gaudichaudianic acid is biosynthesized as a racemic mixture from the seedling stage onward. Moreover, gaudichaudianic acid was found exclusively in the roots of seedlings, while it is present in all organs of the adult plant. Trypanocidal assays indicated that the (+)-enantiomer was more active than its antipode. Interestingly, mixtures of enantiomers showed a synergistic effect, with the racemic mixture being the most active.

When catechins are found in plant extracts, they are almost always identified as catechin and/or epicatechin probably due to stereoselectivity of the enzymes involved in the biosynthesis of these substances. However, the lack of reports regarding to ent-catechin as well as ent-epicatechin does not necessarily mean that these compounds have not been produced. In fact, most of the previous reports used chromatographic conditions not suitable for such separation. This article describes a simple and reliable analytical HPLC-PAD-CD method for simultaneous determination of catechin diastereomers both in infusions and extracts from the leaves of Byrsonima species. The direct separation of catechin, ent-catechin, epicatechin, and ent-epicatechin was obtained in normal phase by HPLC-PAD-CD using Chiralcel OD-H as chiral stationary phase and n-hexane/ethanol with 0.1% of TFA as mobile phase.