Phthalides: Distribution in Nature, Chemical Reactivity, Synthesis, and Biological Activity.

Phthalides are a relatively small group of natural compounds confined to several plant families and some genera of fungi and liverworts. They are divided into two structural groups, the monomeric and dimeric phthalides, and known mainly as bioactive constituents of different plant species used traditionally for medicinal purposes in Asia, Europe, and North America.The first reports on the chemistry of phthalides appeared at the end of the nineteenth century, in which they were identified as the odor constituents of the essential oil of celery (Apium graveolens) by Ciamician and Silber (1897). In the first half of the last century, phthalides were isolated from Cnidium officinale and Ligusticum acutilobum, species widely used in Asian traditional medicine, and from Levisticum officinale, a species used as food and condiment. Throughout the second part of the twentieth century, phthalides have been characterized from several plant families, namely Asteraceae, Leguminosae, Orchidaceae and Rutaceae, among others, but mainly from the Umbelliferae (syn Apiaceae) family, and the major contributors have been the following species used in traditional medicine: Ligusticum chuanxiong (Chinese name: Chuanxiong), Angelica sinensis (Chinese name: Danggui), Cnidium officinale (Japanese name: Senkyu), Angelica acutiloba (Japanese name: Toki), and Ligusticum porteri (Hispanic name: Oshá). Phthalides are also constituents of several genera of fungi, such as Penicillium, Alternaria and Pestalotiopsis, and some liverworts.Different chromatographic, spectrometric, and two-dimensional nuclear magnetic resonance (NMR) techniques have been used for the isolation and structural characterization of phthalides in extracts, and for assessing the quality of plant material containing this type of compound. Isotopic labeling has established the biosynthesis of phthalides via linkage of acetate units forming polyketide intermediates.Chemical transformations of monomeric phthalides have included oxidation, reduction, addition, elimination, and cycloaddition reactions, and treatments with Lewis acids of (Z)-ligustilide have afforded linear dimers. Some intramolecular condensations and differentiated cyclizations of the dimeric phthalides have been carried out, providing evidences for the particular chemical reactivity of these compounds.Several structural modifications of phthalides have been carried out subjecting them to microbial transformations by different species of bacteria, fungi and algae, and these included resolutions of racemic mixtures and oxidations, among others.The [π4s + π2s] and [π2s + π2s] cycloadditions of (Z)-ligustilide for the synthesis of dimeric phthalides have been reported, and different approaches involving cyclizations, Alder-Rickert reactions, Sharpless asymmetric hydroxylations, or Grignard additions have been used for the synthesis of monomeric phthalides. The use of phthalides as building blocks for divergent oriented synthesis has been proven.Many of the naturally occurring phthalides display different biological activities including antibacterial, antifungal, insecticidal, cytotoxic, and anti-inflammatory effects, among many others, with a considerable recent research on the topic. In the case of compounds isolated from the Apiaceae, the bioactivities correlate with the traditional medicinal uses of the natural sources. Some monomeric phthalides have shown their ability to attenuate certain neurological diseases, including stroke, Alzheimer's and Parkinson's diseases.The present contribution covers the distribution of phthalides in nature and the findings in the structural diversity, chemical reactivity, biotransformations, syntheses, and bioactivity of natural and semisynthetic phthalides.

Anti-inflammatory effect of natural and semi-synthetic phthalides.

This study evaluated the potential anti-inflammatory effects of natural phthalides, isolated from Ligusticum porteri, and of semi-synthetic phthalides. Anti-inflammatory activity was investigated in two mouse models; one with ear edema, induced with 12-O-tetradecanoylphorbol-13-acetate, and the other with paw edema, induced with carrageenan. The effect on the RAW 264.7 stimulated with lipopolysaccharide cells was evaluated and after application of 12-O-tetradecanoylphorbol-13-acetate, the activity of myeloperoxidase was assessed to serve as an index of leukocytes infiltration together with the histological evaluations. We also assessed the inhibition of cyclooxygenases 1 and 2 in vitro. Our results demonstrated that administration of semi-synthetic phthalides significantly inhibited the ear edema induced by 12-O-tetradecanoylphorbol-13-acetate, and reduced the paw edema caused by carrageenan. The anti-inflammatory activity of phthalides could, in part, be explained by the reduction in myeloperoxidase activity and the infiltration of leukocytes. The semi-synthetic phthalides also inhibited the production of oxide nitric in RAW cells.

pH- and thermosensitive polyaniline colloidal particles prepared by enzymatic polymerization.

Polyaniline colloids were prepared by enzymatic polymerization using chitosan and poly(N-isopropylacrylamide) as steric stabilizers. The resulting nanoparticles undergo flocculation by changing the pH or temperature of the aqueous dispersions. The environmentally responsive behavior of these colloids contrasts with that of polyaniline colloids synthesized using poly(vinyl alcohol) as the steric stabilizer. The colloid size was a function of the steric stabilizers and ranged from approximately 50 nm for polyaniline particles prepared in the presence of chitosan and partially hydrolyzed poly(vinyl alcohol) up to 350 nm for the particles synthesized using poly(N-isopropylacrylamide). UV-visible and Fourier transform infrared spectroscopic studies indicate that polyaniline colloids are spectroscopically similar to those obtained by traditional dispersion polymerization of aniline by chemical oxidation. These polyaniline colloids have potential applications in thermochromic windows and smart fluids.