Sesquiterpene Furan Compound CJ-01, a Novel Chitin Synthase 2 Inhibitor from Chloranthus japonicus SIEB.

Abstract

Fungal cell walls have essential roles in the life of the fungal cell. They protect mechanically the cell from the environment, prevent osmotic bursting of the cell by the tugor pressure and act as a sieve for large molecules that might harm the cell membrane. 1)Chitin, along with (1,3)-b-D-glucan, represents the main structural components of the fungal cell wall. As a crystalline polymer composed of b-1,4-linked homopolymer of N-acetylglucosamine (GlcNAc), chitin contributes to the rigidity of the cell wall.2) It is synthesized on the cytoplasmic surface of the plasma membrane, extruded perpendicularly to the cell surface as microfibrils and crystallized outside the cell through extensive hydrogen bonding as a-chitin (the polyGlcNAc chains run antiparallel).3) Chitin is synthesized by chitin synthase 1 (ScCHS1p), 2 (ScCHS2p), and 3 (ScCHS3p) in Saccharomyces cerevisiae. 4,5) Among them, chitin synthase 1 is a nonessential repair enzyme, 5) whereas chitin synthase 2 and 3 are essential enzymes in primary septum formation 6) and bud ring formation, 7) respectively. Although the content of chitin in the fungal cell wall varies from species to species, 8) its synthesis constitutes a model for fungal morphogenesis. Thus, specific inhibitors of chitin synthase 2 and 3 might serve as interesting lead compounds for the development of effective antifungal agents.The Chloranthus japonicus (Chloranthaceae) is a perennial herb that grows in the southern part of Korea, Japan, and China. This plant has been long recognized to be useful for boils, dermatopathy, and enteric fever in Korea as a folk remedy.9) Recently, shizukaol B, cycloshizukaol A, and shizukaol F isolated from the roots of Chloranthus japonicus were reported as cell adhesion inhibitors.10) In addition, many plants of the genus Chloranthus have been used in Chinese folk medicine for the treatment of bone fractures.11) A number of sesquiterpenoids 12,13) and sesquiterpenoid oligomers 14,15) have been isolated from the genus Chloranthus, and a quite recent study showed that chlorahololides A and B isolated from Chloranthus holostegius were potent and selective blockers of potassium channel. 16)In the course of search for chitin synthase 2 inhibitors from plant extracts, a novel type of chitin synthase 2 inhibitor was found in the methanol extract of the whole bodies of C. japonicus Sieb. Although the extract of C. japonicus has been long recognized to be useful as a folk remedy in Korea,9) this is the first report that the extract of C. japonicus could be used as antifungal agents by the inhibition of chitin synthase 2. Here, we describe the isolation and structure elucidation of a novel sesquiterpene furan compound CJ-01, and its inhibitory activities against chitin synthase 2 of S. cerevisiae and various human and phytopathogenic fungi. A novel sesquiterpene furan compound CJ-01 was isolated from the methanol extract of the whole plant of Chloranthus japonicus SIEB. by monitoring the inhibitory activity of chitin synthase 2 from Saccharomyces cerevisiae. Based...

Novel antifungal agents, targets or therapeutic strategies for the treatment of invasive fungal diseases: a review of the literature (2005-2009)

“…Recently, the in vitro antifungal activity of the acidic mammalian chitinase against C. albicans and A. fumigatus was demonstrated; efficient hydrolysis of chitin was observed 18 . These results confirmed earlier observations regarding the antifungal in vitro activity against a variety of fungal pathogens of other natural chitin synthase inhibitors such as sesquiterpene furan compound C-J-01 110 , O-methyl pisiferic acid and 8,20-dihydroxy-9(11),13abietadien-12-one and 2'-benzoyloxycinnamaldehyde 47,48 .…”

Aphanomyces euteiches Cell Wall Fractions Containing Novel Glucan-Chitosaccharides Induce Defense Genes and Nuclear Calcium Oscillations in the Plant Host Medicago truncatula

“…Indeed, 1,3,4-linked glucosyl and GlcNAc residues were not detected in Aphanomyces and Phytophthora species, respectively, in a recent, more global cell wall analysis of Oomycetes [19]. The involvement of very minor chitosaccharide components in cell wall function would reconcile the inability to detect chitin in many Oomycetes [7] despite the presence and expression of CHS -like genes [10], [14], [15] and the sensitivity of certain Oomycetes to CHS inhibitors ([49], and A. Bottin, unpublished results). A striking example of a very minor cell wall compound having an essential role in cell wall integrity is the case of Saprolegnia monoica chitin, which represents only 0.7% of the cell wall polysaccharides [12], [16].…”

Three Sesquiterpenoid Dimers from Chloranthus japonicus: Absolute Configuration of Chlorahololide A and Related Compounds

“…The previous phytochemical investigations on this plant have resulted in the isolation of a number of sesquiterpenoid dimers . Some of them were reported to show multibiological activities, such as antifungal, potent and selective tumor growth‐inhibitory, inhibition of cell adhesion molecule expression, and of tyrosinase …”

“…[6][7][8][9] Some of them were reported to show multibiological activities, such as antifungal, potent and selective tumor growth-inhibitory, inhibition of cell adhesion molecule expression, and of tyrosinase. [10][11][12] As part of our ongoing search for new bioactive natural products from the traditional Chinese herbal medicines in the Qinba Mountains, [13][14][15][16][17] a chemical study of the whole plant of C. japonicus was carried out, leading to the discovery of a new sesquiterpenoid dimer, named multistalide C (1), together with two known compounds, shizukaols C and D (2 and 3) (Chart 1). Herein, we describe the isolation, structural identification, including the absolute configuration, and brine shrimp larvae toxicity of the three compounds.…”