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Synthesis of carbon-analogues of 2,4-diaminopyrimidine and 2-oxo-4-aminopyrimidine homo-DNA nucleosides


Löpfe, M. Synthesis of carbon-analogues of 2,4-diaminopyrimidine and 2-oxo-4-aminopyrimidine homo-DNA nucleosides. 2009, University of Zurich, Faculty of Science.

Abstract

This doctoral work is divided into two sections: the first part deals with the synthesis
of carbon-analogues of 2,4-diamonpyrimidin homo-DNA nucleosides and 2-oxo-4-
aminopyrimidin homo-DNA nucleosides. In the second part homo-DNA-oligonucleotides
containing carbon-analogues of the 2,4-diaminopyrimidine homo-DNA nucleoside were
investigated.
Starting from known stabilities of exocyclic amino nucleosides (EAN’s) a model
compound was designed to increase the stability of these compounds. By replacing the
exocyclic nitrogen by a carbon the unstable aminohemiacetal was replaced by a stable cyclic
ether. Due to the fact that EAN’s undergo a furanose-pyranose isomerization and the pyranose
is thermodynamically favored species, a pyranoside analogue of DNA, the homo-DNA was
evaluated. In the first part of the thesis a series of homo-DNA-carbon-nucleosides were
prepared from tris-O-acetyl-D-glucal. The key step of the synthesis was the diastereoselective
preparation of the β-C-glycoside, as shown below. The β-C-glycoside was accessible by a
rearrangement from the α-C-glycoside under Lewis acidic conditions.
ii
In the second part of the thesis the carbon-analogue of the 2,4-diaminopyrimidinehomo-
DNA-nucleoside was incorporated by solid phase synthesis in homo-DNAoligonucleotides.
It was shown that an adenine(A)-2,4-diaminopyrimidine(D) exchange near
the 4’ end in the self complementary octamer ddGlc[UX(UA)3] did not result in a enthalpic
destabilization of the Watson-Crick A-U base pairing (ΔH -165 kJ/mol (D); -163 kJ/mol (A)).
The entropic destabilization was explained by the increase of rotational degrees of freedom of
the D-nucleoside compared to the A-nucleoside. An exchange of an A nucleoside in a central
position of a selfcomplementary homo-DNA oligonucleotide with the general formula
ddGlc[(UA)n] resulted in a much stronger influence on the homo-DNA duplex stability
compared to the A-D exchange near the 4’ end: For the 14-mer ddGlc[(UA)3UD(UA)3] an
inter- or intramolecular duplex formation was found dependant on the oligonucleotide
concentration.
An investigation of an A-D exchange on the stability of the reverse Hoogsteen A-A
pairing resulted in no enthalpic destabilization by an A-D exchange: Compared to the octamer
ddGlc[A8] even an enthalpic stabilization was found if two reverse Hoogsteen A-A base
pairings were replaced by two A-D base pairings (ΔH -208 kJ/mol (ddGlc[A8]); ΔH -322
kJ/mol ddGlc[A2DA5]), although the enthalpic stabilization was overcompensated by an
entropic destabilization (ΔS -520 J/(mol*K) (ddGlc[A8]); ΔS -917 J/(mol*K) ddGlc[A2DA5]).
Also in the nonamer ddGlc[UD8], in which all A nucleosides were replaced against D
nucleosides, an interaction was still detectable.
iii
Further investigations were performed with non selfcomplementary oligonucleotides
of the general formula ddGlc[CAUA-X1-GUGA] und ddGlc[UCAC-X2-UAUG].
Comparisons of the Watson-Crick A-U (X1 = A; X2 = U) base pairing with the corresponding
D-U base pairing (X1 = D, X2 = U) were performed. Further studies were performed to study
the influence of a A-D exchange in the following base pairings A-A (X1 = A; X2 = A to X1 =
D; X2 = A); A-C (X1 = A; X2 = C) and A-G (X1 = A; X2 = G). All these investigations
resulted in a enthalpic destabilization and entropic stabilization of the duplex formation.

Abstract

This doctoral work is divided into two sections: the first part deals with the synthesis
of carbon-analogues of 2,4-diamonpyrimidin homo-DNA nucleosides and 2-oxo-4-
aminopyrimidin homo-DNA nucleosides. In the second part homo-DNA-oligonucleotides
containing carbon-analogues of the 2,4-diaminopyrimidine homo-DNA nucleoside were
investigated.
Starting from known stabilities of exocyclic amino nucleosides (EAN’s) a model
compound was designed to increase the stability of these compounds. By replacing the
exocyclic nitrogen by a carbon the unstable aminohemiacetal was replaced by a stable cyclic
ether. Due to the fact that EAN’s undergo a furanose-pyranose isomerization and the pyranose
is thermodynamically favored species, a pyranoside analogue of DNA, the homo-DNA was
evaluated. In the first part of the thesis a series of homo-DNA-carbon-nucleosides were
prepared from tris-O-acetyl-D-glucal. The key step of the synthesis was the diastereoselective
preparation of the β-C-glycoside, as shown below. The β-C-glycoside was accessible by a
rearrangement from the α-C-glycoside under Lewis acidic conditions.
ii
In the second part of the thesis the carbon-analogue of the 2,4-diaminopyrimidinehomo-
DNA-nucleoside was incorporated by solid phase synthesis in homo-DNAoligonucleotides.
It was shown that an adenine(A)-2,4-diaminopyrimidine(D) exchange near
the 4’ end in the self complementary octamer ddGlc[UX(UA)3] did not result in a enthalpic
destabilization of the Watson-Crick A-U base pairing (ΔH -165 kJ/mol (D); -163 kJ/mol (A)).
The entropic destabilization was explained by the increase of rotational degrees of freedom of
the D-nucleoside compared to the A-nucleoside. An exchange of an A nucleoside in a central
position of a selfcomplementary homo-DNA oligonucleotide with the general formula
ddGlc[(UA)n] resulted in a much stronger influence on the homo-DNA duplex stability
compared to the A-D exchange near the 4’ end: For the 14-mer ddGlc[(UA)3UD(UA)3] an
inter- or intramolecular duplex formation was found dependant on the oligonucleotide
concentration.
An investigation of an A-D exchange on the stability of the reverse Hoogsteen A-A
pairing resulted in no enthalpic destabilization by an A-D exchange: Compared to the octamer
ddGlc[A8] even an enthalpic stabilization was found if two reverse Hoogsteen A-A base
pairings were replaced by two A-D base pairings (ΔH -208 kJ/mol (ddGlc[A8]); ΔH -322
kJ/mol ddGlc[A2DA5]), although the enthalpic stabilization was overcompensated by an
entropic destabilization (ΔS -520 J/(mol*K) (ddGlc[A8]); ΔS -917 J/(mol*K) ddGlc[A2DA5]).
Also in the nonamer ddGlc[UD8], in which all A nucleosides were replaced against D
nucleosides, an interaction was still detectable.
iii
Further investigations were performed with non selfcomplementary oligonucleotides
of the general formula ddGlc[CAUA-X1-GUGA] und ddGlc[UCAC-X2-UAUG].
Comparisons of the Watson-Crick A-U (X1 = A; X2 = U) base pairing with the corresponding
D-U base pairing (X1 = D, X2 = U) were performed. Further studies were performed to study
the influence of a A-D exchange in the following base pairings A-A (X1 = A; X2 = A to X1 =
D; X2 = A); A-C (X1 = A; X2 = C) and A-G (X1 = A; X2 = G). All these investigations
resulted in a enthalpic destabilization and entropic stabilization of the duplex formation.

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Additional indexing

Item Type:Dissertation
Referees:Siegel J S, Baici A
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:German
Date:2009
Deposited On:14 Jan 2010 08:51
Last Modified:05 Apr 2016 13:42
Number of Pages:211
Related URLs:http://opac.nebis.ch/F/?local_base=NEBIS&con_lng=GER&func=find-b&find_code=SYS&request=005872106

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