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Winner of the IUPAC Prize
for Young Chemists - 2000

 

Hiroyuki Isobe wins one of the first 4 IUPAC Prize for Young Chemists, for his Ph.D. thesis work entitled "Design and Synthesis of DNA Binding Organofullerene"

Current address (at the time of application)

Department of Chemistry
The University of Tokyo
Hongo 7-3-1, Bunkyo-ku
Tokyo, Japan 113-0033

Tel.: +81-3-5841-4368
Fax: +81-3-3812-8099
E-mail: hisobe@chem.s.u-tokyo.ac.jp

Academic degrees

  • Ph.D., The University of Tokyo, April, 1999, Chemistry
  • M.S., Tokyo Institute of Technology, March, 1996, Chemistry
  • B.A., Tokyo Institute of Technology, March, 1994, Chemistry

Ph.D. Thesis

Title Design and Synthesis of DNA Binding Organofullerene
Adviser Eiichi Nakamura
Thesis Committee Eiichi Nakamura (Professor, The University of Tokyo); Koichi Narasaka (Professor, The University of Tokyo); Kazuo Tachibana (Professor, The University of Tokyo); Yoshio Umezawa (Professor, The University of Tokyo); Kaoru Yamanouchi (Professor, The University of Tokyo).

Essay

My thesis entitled "Design and Synthesis of DNA Binding Organofullerene" describes design and synthesis of functional DNA binding molecules with fullerene scaffold. The binding to and recognition of DNA by synthetic organic compounds is important and challenging subjects, and the present study shed the light on the new synthetic route to DNA binding molecules. Development of symmetry-defined multiple addition reactions to [60]fullerene has led to the rational design of functional DNA binding molecule.

Fullerene was discovered as the third carbon allotrope by a group led by three scientists, Kroto, Curl and Smalley in 1985. After the development of an arc vaporization method for the production of [60] and [70]fullerenes in a large quantity, application of a wide range of reactions revealed its basic chemical reactivities and led to the synthesis of "organo-functionalized" fullerenes (organofullerenes). This work in my thesis started when such studies on the organofunctionalization of fullerene were started by chemists in the world. I started with the fundamental studies on the reactivities of fullerene toward vinylcarbene species and silyl ketene acetals. The work on the thermal and photochemical reactions with fullerene gave an important information of inherent reactivity of fullerenes. With such fundamental method in hand, I started to investigate a new route to the structurally unique organofullerenes.

Controlled multiple addition reactions to spherical fullerene can provide a useful scaffold for construction of structurally unique functional molecules. From synthetic point of view, challenging problems of regio- and stereochemical issue are inherent to the multiple addition reactions to [60]fullerene, which possesses thirty equivalent double bonds on its spherical surface. With the aim of synthesizing DNA binding fullerene, two symmetry-defined multiple functionalizations of [60]fullerene have been developed, and synthesis of structurally unique organofullerenes has been achieved. At the time this work was started, there were no preceding work on the multiple addition reaction to [60]fullerene, and I have decided to develop multiple addition reactions that can be utilized for the rational design of organofullerenes with a wide range of structures.

In my thesis work, by utilizing inherent reactivities of [60]fullerene, a cage compound with fullerene end caps has been synthesized. Four-fold photochemical addition reaction was utilized for the construction of cage compound with fullerene end caps. The new cage compound showed hypochromic effect that is induced by dipolar coupling between fullerene chromophores. This is the first interesting example of physical communication between far-separated fullerenes, which may lead to the development of optical devices based on the fullerenes. The presented route to the cage compounds is also applicable to the other reagents and varieties of the cage compounds may be synthesized.

The tether-directed method in double addition to [60]fullerene, on the other hand, provided a symmetry-defined functionalization route to a series of organofullerenes (two-handed fullerenes) with spatially defined orientation of organic residues. I synthesized various tris-annulating reagents that enabled double-cycloaddition reaction to fullerene, and the thus obtained double functionalized fullerenes led to the basic design of "two-handed fullerenes". In my work, systematic computational studies also led to the development of a "double differential" procedure, which is useful for estimating the directing effects of the tether. The regio- and stereo-controlled formation of C2 chiral derivatives opened a new possibility for the asymmetric synthesis of optically active chiral polyfunctionalized fullerenes.

After development of multiple addition reactions to fullerene, I started investigating the synthesis and binding properties of DNA binding fullerene. Interaction of organofullerenes with DNA continues to attract the interest of chemists since the discovery that a photo-excited water-soluble fullerene oxidatively cuts DNA duplex. In the following years, a number of studies on structural variations of the reagent, the mechanism of the photo cleavage, and the applications to photodynamic therapy have been reported. Further detailed studies on the fullerene-DNA interactions have been required for the development of fullerene-based functional DNA binding molecules.

Tailor-made organofullerene was designed based on the tether-directed double cycloaddition reaction and synthesis of DNA binding molecule with fullerene has been carried out in this study. Two-handed fullerene tetramine as well as the reference fullerenes have been synthesized for the study of DNA binding abilities. Structure/activity relationship of the DNA binding properties of organofullerenes showed that the structural synergy of hydrophobic core and hydrophilic residues plays important roles in binding. The new tight binding fullerene was found to be inert in the photo cleavage, which suggest that the interactions of fullerenes with nucleobases changes the energy transfer path after photo-excitation. Detailed study on the photo-induced damage on the DNA suggested that covalent bond formation may occur with the DNA binding fullerenes. This observation calls recently proposed mechanisms of photo cleavage in question, and further detailed mechanistic study on this subject is awaited.

The DNA-binding fullerene has also been found to induce formation of higher order structure of DNA. Microscopic studies with AFM on the DNA/fullerene complex revealed that tight binding as well as the hydrophobic nature of fullerene led to highly efficient condensation of DNA. This study also showed that the size and morphology of the condensed materials is dependent on the fullerene to DNA ratio. Recent studies on the gene transfer technology suggested that the size and morphology of DNA condensates plays an important role in the gene transfer, which suggest the development of transfection agents based on the DNA binding fullerenes. Extension of the thesis work now led to the development of organofullerene as a new artificial vector for gene transfer. The fullerene-based design does not rely on lipid-mimicry generally used for "lipofection", but on the strong hydrophobicity of the fullerene core that is not "lipo"philic. Success of this new gene transfer vector will lead to the development of future gene transfer reagent that will be metabolized to inorganic soot.

In this thesis was described the development of new synthetic methods for new organofullerenes and the design and synthesis of functional DNA binding fullerenes. Through this study, I, as a young chemist, learned that powerful synthetic methods and thus synthesized new organic architectures are the new source of imagination.


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