Maria Letizia Ciavatta

Production and fungitoxic activity of Sch 642305, a secondary metabolite of Penicillium canescens

Production of fungitoxic extrolites was evaluated in culture filtrates of several isolates belonging to Penicillium canescens and P. janczewskii that showed some extent of inhibitory activity against the plant pathogenic fungus Rhizoctonia solani. In addition to griseofulvin and dechlorogriseofulvin that are already known in these species, curvulinic acid, previously unreported in Penicillium, was produced by all isolates assayed. Another extrolite recently characterized from a P. verrucosum strain by the name of Sch 642305 was detected in 5 isolates of P. canescens only. The purified compound completely inhibited mycelial growth of isolates of Rhizoctonia solani and other plant pathogenic fungi in␣vitro. The role of this extrolite as a possible biochemical determinant of antagonism toward plant pathogenic fungi, and implications concerning chemotaxonomy are discussed.

Terretonins E and F, inhibitors of the mitochondrial respiratory chain from the marine-derived fungus Aspergillus insuetus (#).

Two new meroterpenoids, terretonins E and F (1, 2), together with three known compounds, aurantiamine (3), linoleic acid, and uridine, were isolated as fermentation products of the marine-derived fungus Aspergillus insuetus, which was associated with the sponge Petrosia ficiformis. Structures of all isolates were elucidated employing spectroscopic methods, mainly by two-dimensional NMR techniques. Compounds 1-3 showed activity as inhibitors of the mammalian mitochondrial respiratory chain.

In vitro pharmacological and toxicological effects of norterpene peroxides isolated from the Red Sea sponge Diacarnus erythraeanus on normal and cancer cells.

Eight cyclic peroxide norterpenoids, compounds 1-8, have been isolated and characterized from the Red Sea sponge Diacarnus erythraeanus, including two new norsesterterpene derivatives (3, 4). Among these metabolites, (-)-muqubilin A (5) (nine cell lines analyzed) and the new compounds 3 and 4 (seven cell lines analyzed) displayed mean IC₅₀ growth inhibitory concentrations in vitro of <10 μM, while the remaining compounds (1, 6-8) were inactive in these cancer cell lines. Compound 5 displayed no selectivity between normal and cancer cells in terms of in vitro growth inhibition. Quantitative video microscopy analysis carried out on (-)-muqubilin A-treated cells validated the data obtained by means of the MTT colorimetric assay, while flow cytometry analysis revealed ROS production but no induction of apoptosis in cancer cells.

Occurence and Bioactivities of Funicone-Related Compounds

Studies on production of secondary metabolites by fungi have received a substantial boost lately, particularly with reference to applications of their biological properties in human medicine. Funicones represent a series of related compounds for which there is accumulating evidence supporting their possible use as pharmaceuticals. This paper provides a review on the current status of knowledge on these fungal extrolites, with special reference to aspects concerning their molecular structures and biological activities.

3-O-methylfunicone, a secondary metabolite produced by Penicillium pinophilum, induces growth arrest and apoptosis in HeLa cells.

Abstract.  3‐O‐Methylfunicone (OMF) is a secondary metabolite produced by the soil fungus Penicillium pinophilum which has cytostatic properties. The aim of this study was to investigate the mechanisms by which such properties are exerted, with special reference to any anti‐proliferative and apoptotic potential, on HeLa cells. OMF treatment caused about 44% inhibition of cell growth after 24 h, and modifications in the tubulin fibre organization. In addition, a significant increase in p21 mRNA expression and a decrease in cyclin D1 and Cdk4 mRNA expression resulted at the same time. Apoptosis induction was demonstrated by the annexin V assay, cytofluorimetric analysis of the DNA content of the sub‐G1 fraction and DNA laddering. Taken together, our data showed that the compound inhibits proliferation of HeLa cells by several mechanisms, such as disruption of tubulin fibres, cell cycle arrest and apoptosis induction. The capacity of the compound to affect the cell cycle and to modulate apoptosis is indicative of a potential for the development of a new agent for cancer chemotherapy.

3‐O‐methylfunicone produced by penicillium pinophilum affects cell motility of breast cancer cells, downregulating αvβ5 integrin and inhibiting metalloproteinase‐9 secretion

Recent evidence assigns integrins and metalloproteinases (MMPs) an important role in regulating tumor cell progression. Here, we demonstrate that 3‐O‐methylfunicone (OMF), a secondary metabolite produced by Penicillium pinophilum, affects cell proliferation and motility of breast cancer MCF‐7 cells, downregulating αvβ5 integrin, and inhibiting MMP‐9 secretion. This effect was absent when the non‐tumoral MCF‐10 cell line was used. Inhibition of cell motility was also associated to modifications in cell shape and in the distribution of tubulin fibers of OMF‐treated MCF‐7 cells. In addition, a possible effect on survivin and hTERT was also investigated. We found that OMF strongly inhibits survivin and hTERT gene expression. The results of this study indicate that OMF‐induced inhibition of cell motility may be mediated through the modulation of αvβ5 integrin and MMP‐9 secretion. In addition, the inhibition of typical markers of tumor progression such as hTERT and survivin in MCF‐7 and their inactivity towards MCF10 provide strong evidence for a potential use of OMF in anticancer therapy.

3-O-methylfunicone, from Penicillium pinophilum, is a selective inhibitor of breast cancer stem cells

Objectives:  Cancer stem cells make up a subpopulation of cells within tumours that drive tumour initiation, growth and recurrence. They are resistant to many current types of cancer treatment, causing failure of such therapeutic approaches, including chemotherapy and radiotherapy. In the study described here, anti‐proliferative effects of 3‐O‐methylfunicone (OMF), a metabolite from Penicillium pinophilum, were investigated on human breast cancer MCF‐7 cells and cancer stem cells selected as mammospheres derived from MCF‐7s.

Tritoniopsins A–D, Cladiellane-Based Diterpenes from the South China Sea Nudibranch Tritoniopsis elegans and Its Prey Cladiella krempfi

Four diterpenes, tritoniopsins A-D (1-4), have been isolated from the South China Sea nudibranch Tritoniopsis elegans and its prey, the soft coral Cladiella krempfi. They display an unprecedented pyran ring in the cladiellane framework, thus representing a novel cladiellane-based diterpene family. Their structures have been mainly characterized by NMR and mass spectrometric techniques, whereas the relative configuration of compound 1 was secured by X-ray analysis. Antiproliferative assays on tumor and nontumor cell lines have been carried out for the main metabolite, tritoniopsin B (2).

Structure and synthesis of a unique isonitrile lipid isolated from the marine mollusk Actinocyclus papillatus.

The first chemical study of an Actinocyclidae nudibranch, Actinocyclus papillatus, resulted in the isolation of (-)-actisonitrile (1), a lipid based on a 1,3-propanediol ether skeleton. The structure was established by spectroscopic methods, whereas the absolute configuration of the chiral center was determined by comparing the optical properties of natural actisonitrile with those of (+)- and (-)-synthetic enantiomers, opportunely prepared. Both (-)- and (+)-actisonitrile were tested in preliminary in vitro cytotoxicity bioassays on tumor and nontumor mammalian cells.

New Caulerpenyne-derived Metabolites of an Elysia Sacoglossan from the South Indian Coast

Chemical analysis of the secondary metabolite pattern of the sacoglossan mollusc Elysia cf. expansa, collected along South Indian coasts, showed the presence of the typical Caulerpa-derived sesquiterpene caulerpenyne (1) and two new minor co- occurring metabolites, the compounds dihydrocaulerpenyne (4) and expansinol (5). The chemical characterization of these molecules, structurally related to 1, is reported.