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¡Professor@Toshio TANAKA

Synthesis of hybrid molecules with antifungal activities and the analysis of their modes of actions

Each bio-molecule has individual function or activity depending on its own molecular structure. It seems possible to create a biologically active molecule by chemical conjugation of two different molecules so that the hybrid molecule generates a novel unique activity that has never been observed with its constituents. Hybrid molecules are being synthesized by using nucleotides such as AMP and lipid in order to find out unique activities against fungal and malignant tumor cell growth.


Generation of reactive oxygen species (ROS) in cells of S. cerevisiae
untreted cells farnesol-treated cells
unstained stained for ROS
production
unstained stained for ROS
production

A potent antifungal or anti-cancer activity can be generated by means of simple addition of lipophilic chain to some of nucleotides or the relating molecules. Nucleotides can also exhibit unique activities of regulating cell differentiation and cell morphogenesis depending on appropriate structural modifications. Farnesol (FOH) is a typical isoprenoid that can cause apoptosis in a number of malignant tumor cells. Recent study revealed an antifungal effect of FOH depending on its promotive effect on ROS production selectively against cells of some yeast strains. ROS is inevitably produced in cells of any organisms whenever they grow under aerobic condition whereas it could be an effective weapon to attack infectious microorganisms and tumor cells as in the case with our immune system.
@ FOH and other isoprenoids are attractive sources of biologically active hybrid molecules. The chemical conjugation of FOH and pyridine gave a hybrid molecule, 1-farnesylpyridinium (FPy), in which the apoptosis-inducing activity against human leukemic HL-60 cells could be extremely elevated together with generation of actin deploymerizing activity. FPy-induced apoptosis is quite unique since it can selectively and beautifully cause fragmentation of nucleus which contains a mutated gene. Our studies are under progress for the syntheses of another hybrid molecules using various naturally occurring compounds and lipid molecules including isoprenoids. We generally use cells of some yeast strains such as S. cerevisiae and S. pombe as a model of mammalian cells.

Generation of reactive oxygen species (ROS)
in cells of human leukemic HL-60 cells
untreated cells FPy-treated cells
unstained nuclear-stained
cells
unstained nuclear-stained
cells

¡Associate Professor@Ken-ichi FUJITA

Screening, isolation and action mode of bioactive substances inducing morphological changes in the hyphae of filamentous fungi
Certain kinds of filamentous fungi often show dimorphic forms of cells, yeast- or hyphae-like those, under various growth conditions. For example, when Candida albicans grows as hyphal forms, it expresses pathogenic characteristcs against human. Among natural resources including isolates of Streptomyces spp., we are screening the bioactive substances, which affect morphogenesis of such filamentous fungi thereby regulating the pathogenesis caused by the fungi including Aspergillus fumigatus and C. albicans. The ideal targets of these substances on the fungi are thought to be biosynthetic pathways and maintenance systems of fungal cell wall, and/or those of cytoskeletons, which holds cell shape themselves. Especially, there is no the structure "cell wall" in human. The substances affecting the structures and functions unique for pathogenic fungi expectedly should be applied for the chemotherapies of deep seated mycoses, which are caused by AIDS, long-term dosage of immunosuppressive drugs after organ transplantation. Moreover we are analyzing in details the mechanism that the substances screened induce morphological changes in the hyphae of the fungi and that of the morphogenesis in filamentous fungi.




Structure-Activity relationships of an antifungal antibiotic, UK-2A
UK-2A, which has been isolated in our lab from Streptomyces sp., shows an antifungal activity specifically against fungi. UK-2A binds complex III of electron transport chain in eukaryotes thereby blocking electron transport. Antimycin As, which also act on the complex III, are not applied for practical use, because these show toxicity for animals and plants. We are investigating contribution of dilacton ring, which is believed only to give hydrophobicity to the molecule, to the expression of antifungal activity of the drug. For this purpose, we are synthesizing new derivatives of UK-2A and then studying the biological activities of those against fungi and animal cell lines including human. Now we could make the derivatives possess additional biological activity besides the inhibitory one against oxygen respiration.
TANAKA & FUJITA

Basic and Applied Studies on a Viscous Substance, Polyglutamic Acid
We found a bacterium that produces a tremendous amount of gamma-polyglutamic acid (PGA). As far back as ancient time, PGA was already found as a main component of the stickiness from Natto (Japanese traditional fermented food). It is a natural compound with no harm to human beings or animals. One of the most important characteristics is its bio-degradable property. On the other hand, the warter-absorbing ability of PGA can be remarkably enhanced by gamma-irradiation. Recently, PGA, as a new material with various functions, has been catching people's eyes. It may also shed light on the solution to environmental and energy problems. Concretely, now we are studying how to apply gamma-irradiated PGA for water purification and desert greening. Meanwhile, we are also trying to explicate the molecular structure of gamma-radiated PGA by physical, chemical and biological means.



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