Fullerene derivatives

Details Fullerene derivatives Fullerene derivatives

2000-11-17

2004-07-20

Riley, Jezia (Department: 1637)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S186000, C560S101000, C562S441000, C562S442000, C562S488000

Reexamination Certificate

active

06765098

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a fullerene derivative which has DNA compacting activity and is useful as a DNA compaction reagent, among other uses, and is applicable, for example, in the pharmaceutical industry.
BACKGROUND ART
DNA compaction in a protein-DNA complex such as the arrangement of DNAs on a chromosome is a very important subject of biochemical research. Compaction by organic micromolecules and inorganic ions is also an important subject of research relevant to transfection [e.g. Yoshikawa, Y. et al., FEBS Letters, 1996, vol. 396, 71-76; Behr, J-P, Acc. Chem. Res., 1993, vol. 26, 274-278; etc.].
The present invention has for its object to provide a novel means for DNA compaction.
DISCLOSURE OF INVENTION
Thus far has been provided a technology for use-tailored modification of fullerene, and a variety of fullerene derivatives have been synthesized [e.g. Friedman, S. H. et al. J. Am. Chem. Soc., 1993, vol. 115, 6506-6509; Yamago, S. et al., J. Am. Chem. Soc., 1994, vol. 116, 1123; Taki, M. et al., J. Am. Chem. Soc., 1997, vol. 119, 926; An, Y. Z. et al., Tetrahedron, 1996, vol. 52, 5179-5189; Nakamura, E. et al., Bull. Chem. Soc. Jpn., 1996, vol. 69, 2143-2151; Yamago, S. et al., Chemistry Letters, 1996, 395-396; Murata, Y. et al., The 2nd International Forum on Chemistry of Functional Organic Chemicals (IFOC-2), 1997, P-31, Tokyo, Japan, etc.].
The inventors of the present invention discovered that, among such fullerene derivatives, fullerene derivatives having 1 to 4, nitrogen-containing hydrophilic side chain(s), inclusive of salts thereof, are amphiphilic and have exceptionally high DNA-compacting activity and have accordingly developed the present invention.
1. Structure of the Fullerene Derivative of the Invention
The fullerene derivative of the present invention is a “fullerene derivative having 1 to 4, nitrogen-containing hydrophilic side chain(s)”. This fullerene derivative includes not only novel compounds but also known compounds.
The DNA-compacting activity of the fullerene derivative of the present invention is the result of an interplay of the size and hydrophobicity of fullerene and the affinity of the nitrogen-containing hydrophilic side chain(s) of the derivative for the phosphate group. It is supposed that the interaction between fullerene and the hydrophobic moieties of a DNA (e.g. major grooves of the DNA) and the interaction between the nitrogen-containing hydrophilic side chain(s) and the phosphate group of the DNA causes the DNA unimolecule to be bent and folded, and that the hydrophobic moieties of a large number of such folded DNA unimolecules coalesce to cause said compaction.
Therefore, the molecular design of a fullerene derivative may be made liberally by one skilled in the art with the above mechanism taken into consideration. The DNA-compacting activity of the fullerene derivative synthesized accordingly can be evaluated by electrophoresis of a mixed solution of the fullerene derivative and a DNA (e.g. plasmid DNA) and measuring the amount of DNA. Moreover, since this compacting activity of the fullerene derivative is closely associated with the high binding affinity of the derivative for DNA, a screening can be made by an ethidium bromide displacement assay using calf thymus DNA.
While the fullerene derivative may be used in the form of a salt, the salt is preferably a conventionally nontoxic salt, particularly a pharmaceutically acceptable salt. More particularly, the salt includes inorganic acid salts (e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.), organic carboxylic acid or sulfonic acid salts (e.g. formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.), and salts with basic or acidic amino acids (e.g. arginine, aspartic acid, glutamic acid, etc.).
The fullerene derivative may occur as various isomers owing to the presence of asymmetric carbon and molecular asymmetry and any and all of them are subsumed under the concept of fullerene derivative according to the present invention.
The “fullerene” of the fullerene derivative of the present invention is not restricted to [60]fullerene but includes higher-order fullerenes (e.g. [70]fullerene etc.).
The preferred “nitrogen-containing hydrophilic side chain” includes “a hydrocarbon group which has 1 or 2 straight-chain or branched-chain substituent group(s) each comprising 1 to 10 nitrogen atom(s) and 2 to 30 carbon atoms, and is configured to be bonded to 1 or 2 of the 2 to 8 sp
3
carbon atoms present on the fullerene core”. The more preferred is “a hydrocarbon group which has 1 or 2 straight-chain or branched-chain substituent group(s) each comprising 2 to 8 nitrogen atoms and 2 to 20 carbon atoms, and is configured to be bonded to two of the 2 to 8 sp
3
carbon atoms present on the fullerene core”.
The amino group in said “nitrogen-containing hydrophilic side chain” may be primary, secondary or tertiary and may form a nitrogen-containing heterocyclic group [such as 3 to 8 (preferably 5 or 6)-membered unsaturated hetero-monocyclic groups containing 1 to 4 nitrogen atom(s) (e.g. pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl, tetrazolyl, etc.); and unsaturated fused heterocyclic groups containing 1 to 4 nitrogen atom(s) (e.g. indolyl, isoindolyl, indolidinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, acridinyl, etc.)]. Furthermore, it may optionally be substituted by lower alkyl or the like.
The “nitrogen-containing hydrophilic side chain” mentioned above may have other hetero atoms, such as oxygen, sulfur, etc., as its constituent atoms and/or substituents.
Furthermore, when two or more “nitrogen-containing side chains” are present, there may be a cross-linking alkylene moiety bridging such nitrogen-containing hydrophilic side chains.
The “hydrocarbon group” of the “nitrogen-containing hydrophilic side chain” includes straight-chain, branched-chain, or cyclic hydrocarbon groups, whether saturated or unsaturated, and is preferably a hydrocarbon group of 1 to 20 carbon atom(s) (more preferably of 1 to 15 carbon atom(s)).
The specific structure of said “nitrogen-containing hydrophilic side chain” includes but is not limited to the following (the fullerene core is also shown).
In the above formulas, Rs may be the same or different and each represents a straight-chain or branched-chain acyl group comprising 1 to 10 nitrogen atom(s) and 2 to 30 carbon atoms [more preferably [N-(N,N-di(lower)alkylamino)(lower)alkyl-N-(lower)alkyl]amino(lower)alkanoyl groups, [N-(N-(lower)alkylamino)(lower)alkyl-N-(lower)alkyl]amino(lower)alkanoyl groups, [N-pyrrolyl(lower)alkyl-N-(lower)alkyl]amino(lower)alkanoyl groups, [N-(N,N-di(lower)alkylamino)(higher)alkyl-N-(lower)alkyl]amino(lower)alkanoyl groups, [N-(N-(lower)alkylamino)(lower)alkyl-N-(lower)alkyl]amino(higher)alkanoyl groups, [N-pyrrolyl(higher)alkyl-N-(lower)alkyl]amino(higher)alkanoyl groups; groups of the formula:
(wherein R
1
, R
2
, R
3
, R
4
and R
5
may each be the same or different over its occurrences and represents hydrogen or a lower alkyl group; A represents an alkylene group; Y represents CH or N, and n represents an integer of 1 to 4)]; straight-chain or branched-chain C
2-30
alkyl groups comprising 1 to 10 nitrogen atom(s) and 2 to 30 carbon atoms [more preferably [N-(N,N-di(lower)alkylamino)(lower)alkyl-N-(lower)alkyl]amino(lower)alkyl groups, [N-(N-(lower)alkylamino)(lower)alkyl-N-(lower)alkyl]amino(lower)alkyl groups, [N-pyrrolyl(lower)alkyl-N-(lower)alkyl]amino(lower)alkyl groups, [N-(N,N-di(lower)alkylamino)(higher)alkyl-N-(lower)alkyl]amino(lower)alkyl groups, [N-(N-(lower)alkylamino)(lower)alkyl-N-(lower)alkyl]amino(higher)alkyl groups, [N-pyrrolyl(higher)alkyl-N-(lower)alkyl]amino(higher)alkyl groups; or groups of the formula:
(wherein R
1
, R
2
, R

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