Supramolecular pairing system, its preparation and use

Details Supramolecular pairing system, its preparation and use Supramolecular pairing system, its preparation and use

2000-08-03

2004-02-10

Wilson, James O. (Department: 1623)

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

Organic compounds

Four or more ring nitrogens in the bicyclo ring system

C544S264000, C536S023100, C536S027100, C536S027110

Reexamination Certificate

active

06689884

ABSTRACT:

The present invention relates to a compound of the formula I
its preparation and use in pairing and/or test systems.
Pairing systems are supramolecular systems of non-covalent interaction, which are distinguished by selectivity, stability and reversibility, and their properties are preferably influenced thermodynamically, i.e. by temperature, pH and concentration. DNA and RNA play a fundamental role here as carriers of the genetic traits. Such pairing systems can be used, for example, as a result of their selective properties but also as “molecular adhesive” for the bringing together of different metal clusters to give cluster associations having potentially novel properties [R. L. Letsinger, et al., Nature, 1996, 382, 607-9; P. G. Schultz et al., Nature, 1996, 382, 609-11).
Strong and thermodynamically controllable pairing systems therefore play a more and more important role for use in the field of nanotechnology, for the preparation of novel materials, diagnostics, therapeutics and microelectronic, photonic and optoelectronic components and for the controlled bringing together of molecular species to give supramolecular units, such as, for example, the (combinatorial) synthesis of protein assemblies [see, for example, A. Lombardi, J. W. Bryson, W. F. DeGrado, Biomoleküls (Pept. Sci.) 1997, 40, 495-504].
For the preparation of pairing systems of this type, DNA and RNA units, however, have the following disadvantages:
a) The forces which hold together the two strands, especially hydrogen bridges and stacking effects, are naturally very low. Such duplices therefore have a low stability. This can be easily determined by recording of a so-called transition curve and determination of the transition point. Consequently, for the preparation of pairing systems relatively long individual strands are necessary, which has the result that the portion of the pairing system on the supramolecular unit predominates, i.e. the “nucleotide load” is high.
b) Owing to the formation of Hoogsteen pairings, which are possible alternatively to Watson-Crick pairings, the selectivity decreases. Parallel duplices or irreversible pairing processes are thus often combined.
c) Owing to the high flexibility of the sugar phosphate backbone, helical conformations are formed, as a result of which the spatial arrangement in supramolecular units can be less readily controlled.
d) The chemical instability of the phosphodiester bond in the backbone permits only a slight variance in physical conditions, such as pH or temperature, for the use of the supramolecular units.
e) The nuclease sensitivity of the products leads to a rapid enzymatic degradation, which can only be avoided with difficulty, and thus to the destruction of the supramolecular unit.
f) Possible interference with the genetic material of biological systems is not to be excluded if the supramolecular units are used in a biological system, i.e. an orthogonality of the pairing process is absent.
g) The preparation of relatively large amounts of oligonucleotides is difficult on account of the low loading ability of the solid phase customarily used, for example in comparison with peptide synthesis.
h) The preparation of the unnatural L enantiomeric form is made difficult by the poor accessibility of the appropriately configured sugar units.
Thus use of DNA or RNA units, for example, in complementarily bonded two- and three-dimensional supramolecular structures (see, for example, WO96/13522) in a physiological medium can only be realized with difficulty, especially in view of item e), f) and g).
An alternative to DNA and RNA units is the so-called pyranosyl-RNA (p-RNA). pRNA is an oligonucleotide which contains ribopyranose as a sugar unit instead of ribofuranose and therefore exclusively forms Watson-Crick-paired, antiparallel, reversibly “melting”, quasi-linear and stable duplices. In addition, there are also homochiral p-RNA strands with an opposite sense of chirality, which likewise pair controllably and are not strictly helical in the duplex formed. This valuable specificity for the synthesis of supramolecular units is connected with the relatively low flexibility of the ribopyranose phosphate backbone and with the strong inclination of the base plane to the strand axis and the tendency resulting from this for intercatenary base stacking in the resulting duplex and can finally be attributed to the participation of a 2′,4′-cis-disubstituted ribopyranose ring in the synthesis of the backbone. p-RNA thus solves some of the described disadvantages of DNA and RNA, but not the disadvantages according to items d), e), g) and h).
A further alternative is the linkage of the monomer units by means of amide bonds, i.e. the synthesis of an oligomeric peptide, so-called peptide nucleic acids (PNAs).
Owing to their open-chain structure, PNAs have a high flexibility and are thus not suitable for the controlled synthesis of supramolecular systems in view of their conformational preorganization.
It is therefore the object of the present invention to make available compounds which do not have the disadvantages described above.
One subject of the present invention is therefore compounds of the formula I
in which R
1
is equal to NR
3
R
4
, OR
3
or SR
3
where R
3
and R
4
independently of one another, identically or differently, are H or C
n
H
2n+1
, n being an integer from 1-12, preferably 1-8, in particular 1-4; preferably R
1
is equal to NR
3
R
4
or OR
3
, in particular NR
3
R
4
, especially NH
2
;
R
2
is equal to C
m
H
2m
—C(X)—Y where X is equal to ═O, ═S or ═N—H, wherein Y is OR
3
, NR
3
R
4
or SR
3
, or R
2
is equal to C
m
H
2m
—CH
2
—X or C
m
H
2m
—CH(X)—Y, wherein X is equal to NR
3
R
4
, OR
3
, or SR
3
; or R
2
is equal to C
m
H
2m
—Z—Y′ where Z is equal to a S(═O)
2
or P(═O)(O
−
), wherein Y′ is equal to H, C
n
H
2n+1
, OR
3
, NR
3
R
4
or SR
3
, and wherein m is an integer from 1-4;
A, B and D independently of one another, identically or differently, are CR
5
R
6
, O, NR
7
or S where R
5
, R
6
, R
7
independently of one another are H or C
n
H
2n+1
, where n has the abovementioned meaning; and
C is equal to CR
8
or N, where R
8
independently thereof denotes the meaning of R
5
, but where A—B, B—C or C—D are not two identical heteroatoms; and
the term nucleobase within the meaning of the present invention denotes thymine, uracil, adenine, cytosine, guanine, isocytosine, isoguanine, xanthine or hypoxanthine, preferably thymine, uracil, adenine, cytosine or guanine.
In particular, compounds are preferred in which R
1
is equal to NH
2
and R
2
is equal to CH
2
—COOH, especially a [2-amino-4-(carboxymethyl)cyclohexyl]nucleobase, such as 1-[2-amino-4-(carboxymethyl)cyclohexyl]thymine, 1-[2-amino-4-(carboxymethyl)cyclohexyl]uracil, 1-[2-amino-4-(carboxymethyl)cyclohexyl]-cytosine, 9-[2-amino-4-(carboxymethyl)cyclohexyl]adenine or 9-[2-amino-4-(carboxymethyl)cyclohexyl]guanine.
It is furthermore advantageous if the compound according to the invention is enantiomerically pure.
For the synthesis, it is further advantageous if R
1
is also provided with protective groups, such as, for example, in the case of R
1
is equal to NH
2
with tert-butoxycarbonyl groups (BOC) or 9-fluorenylmethoxycarbonyl groups (FMOC) or in the case of R
1
equal to OH, with ether or acetal protective groups. Protective groups are in general understood as meaning radicals which protect reactive groups of compounds from undesired reactions and are easily removable. Groups of this type are, for example, benzyloxymethyl (BOM), BOC, FMOC, ether or acetal protective groups.
In addition, Y can also be reacted with activating reagents to give reactive intermediates, e.g. mixed anhydrides.
Preferably, the compounds according to the invention are cyclohexane derivatives which, in the 1′-position, carry a nucleobase and in the 2′-position a nucleophile, such as, for example, a nitrogen atom which can be reacted with the reactive g

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