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Biomedical subjects

Frank Seela

Publications and source records attributed to Frank Seela.

At least 19 recordsLinked to original sources
PubMed2006

2'-Deoxy-5-propynylcytidine: a nucleoside forming two solid-state conformations.

The title compound, 4-amino-1-(2-deoxy-beta-D-erythropentofuranosyl)-5-(prop-1-ynyl)pyrimidin-2(1H)-one, C12H15N3O4, shows two conformations in the crystalline state which differ mainly in the glycosylic bond torsion angle and the sugar pucker. Both molecules exhibit an anti glycosylic bond conformation, with torsion angles chi = -135.0 (2) and -156.4 (2) degrees for molecules 1 and 2, respectively. The sugar moieties show a twisted C2'-endo sugar pucker (S-type), with P = 173.3 and 192.5 degrees for molecules 1 and 2, respectively. The crystal structure is characterized by a three-dimensional network that is stabilized by several intermolecular hydrogen bonds between the two conformers.

Crystallography, X-Ray↗
PubMed2006

pH-Dependent mismatch discrimination of oligonucleotide duplexes containing 2'-deoxytubercidin and 2- or 7-substituted derivatives: protonated base pairs formed between 7-deazapurines and cytosine.

Oligonucleotides incorporating 2'-deoxytubercidin (1a), its 2-amino derivative 2a and related 2-, or 7-substituted analogs (1d, 2b-d, 3 and 4) are synthesized. For this purpose, a series of novel phosphoramidites are prepared and employed in solid-phase synthesis. Hybridization experiments performed with 12mer duplexes indicate that 7-halogenated nucleosides enhance the duplex stability both in antiparallel and parallel DNA, whereas 2-fluorinated 7-deaza-2'-deoxyadenosine residues destabilize the duplex structure. The 7-deazaadenine nucleosides 1a, 1d and their 2-amino derivatives 2a-d form stable base pairs with dT but also with dC and dG. The mispairing with dC is pH-dependent. Ambiguous base pairing is observed at pH 7 or under acid conditions, whereas base discrimination occurs in alkaline medium (pH 8.0). This results from protonated base pairs formed between 1a or 2a and dC under neutral or acid condition, which are destroyed in alkaline medium. It is underlined by the increased basicity of the pyrrolo[2,3-d]pyrimidine nucleosides over that of the parent purine compounds (pK(a) values: 1a = 5.30; 2a = 5.71; dA = 3.50).

Amides↗
PubMed2006

pH-Independent triplex formation: hairpin DNA containing isoguanine or 9-deaza-9-propynylguanine in place of protonated cytosine.

Triplex-forming oligonucleotides (TFOs) containing 2'-deoxyisoguanosine (2), 7-bromo-7-deaza-2'-deoxyisoguanosine (2) as well as the propynylated 9-deazaguanine N7-(2'-deoxyribonucleoside) were prepared. For this the phosphoramidites 9a, b of the nucleoside 1 and, the phosphoramidites 19, 20 of compound 3b were synthesized. They were employed in solid-phase oligonucleotide synthesis to yield the protected 31-mer oligonucleotides. The deblocking of the allyl-protected oligonucleotides containing 1 was carried out by Pd(0)[PPh3]4-PPh3 followed by 25% aq. NH3. Formation of the 31-mer single-stranded intramolecular triplexes was studied by UV-melting curve analysis. In the single-stranded 31-mer oligonucleotides the protonated dC in the dCH(+)-dG-dC base triad was replaced by 2'-deoxyisoguanosine (1), 7-bromo-7-deaza-2'-deoxyisoguanosine (2) and, 9-deaza-9-propynylguanine N7-(2'-deoxyribonucleoside) (3b). The replacement of protonated dC by compounds 1 and 3b resulted in intramolecular triplexes which are formed pH-independently and are stable under neutral conditions. These triplexes contain "purine" nucleosides in the third pyrimidine rich strand of the oligonucleotide hairpin.

Base Sequence↗
PubMed2006

2-Amino-7-chloro-2'-deoxytubercidin.

In 4-chloro-7-(2-deoxy-beta-D-erythro-pentofuranosyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine, C11H14ClN5O3, the conformation of the N-glycosylic bond is between anti and high-anti [chi = -102.5 (6) degrees]. The 2'-deoxyribofuranosyl unit adopts the C3'-endo-C4'-exo (3T4) sugar pucker (N-type) with P = 19.6 degrees and taum = 32.9 degrees [terminology: Saenger (1989). Landolt-Börnstein New Series, Vol. 1, Nucleic Acids, Subvol. a, edited by O. Madelung, pp. 1-21. Berlin: Springer-Verlag]. The orientation of the exocyclic C4'-C5' bond is +ap (trans) with a torsion angle gamma = 171.5 (4) degrees. The compound forms a three-dimensional network that is stabilized by four intermolecular hydrogen bonds (N-H...O and O-H...N) and one intramolecular hydrogen bond (N-H...Cl).

Crystallography, X-Ray↗
PubMed2006

7-Deaza-2,8-diazaadenosine.

In the title compound [systematic name: 4-amino-7-(beta-D-ribofuranosyl)-7H-pyrazolo[3,4-d][1,2,3]triazine], C(9)H(12)N(6)O(4), the torsion angle of the N-glycosylic bond is high anti [chi = -83.2 (3) degrees ]. The ribofuranose moiety adopts the C2'-endo-C1'-exo ((2)T(1)) sugar conformation (S-type sugar pucker), with P = 152.4 degrees and tau(m) = 35.0 degrees . The conformation at the C4'-C5' bond is +sc (gauche,gauche), with the torsion angle gamma = 52.0 (3) degrees . The compound forms a three-dimensional network that is stabilized by several hydrogen bonds (N-H...O, O-H...N and O-H...O).

Adenosine↗
PubMed2006

Association temperature governs structure and apparent thermodynamics of DNA-gold nanoparticles.

Apparent thermodynamics of association of DNA-modified gold nanoparticles has been characterized by UV spectroscopy and dynamic light scattering (DLS). Extinction coefficients of unlabelled and DNA-labelled gold nanoparticles have been determined to permit quantitative analysis of the absorption measurements. In contrast to previous studies the associating gold nanoparticles were furnished with complementary oligonucleotide DNA single strands. This resulted in direct complex formation between the nanoparticles on mixing without the requirement of a DNA linker sequence for initiation of cluster formation. Melting curves of the nanoparticle assemblies formed at different temperatures were subjected to two-state analysis. A comparison of the apparent thermodynamic parameters obtained for the dissociation of these aggregates suggests that both thermodynamically and structurally different nanoparticle clusters are obtained depending on the temperature at which assembly proceeds. The van't Hoff enthalpies permit an estimate of the DNA duplexes: gold nanoparticle ratio involved in network formation.

DNA, Single-Stranded↗
PubMed2006

2'-Deoxy-7-propynyl-7-deazaadenosine: a DNA duplex-stabilizing nucleoside.

In the title compound, 2'-deoxy-7-propynyl-7-deazaadenosine, C14H16N4O3, the torsion angle of the N-glycosylic bond is anti [chi = -130.7 (2) degrees ]. The sugar pucker of the 2'-deoxyribofuranosyl moiety is C2'-endo-C3'-exo, 2T3 (S-type), with P = 185.9 (2) degrees and tau(m) = 39.1 (1) degrees , and the orientation of the exocyclic C4'-C5' bond is -ap (trans). The 7-substituted propynyl group is nearly coplanar with the heterocyclic base moiety. Molecules of the nucleoside form a layered network in which the heterocyclic bases are stacked head-to-tail with a closest distance of 3.197 (1) A. The crystal structure of the nucleoside is stabilized by three intermolecular hydrogen bonds of types N-H... O, O-H... N and O-H... O.

Crystallography, X-Ray↗
PubMed2006

Binding of actinomycin C1 (D) and actinomin to base-modified oligonucleotide duplexes with parallel chain orientation.

The binding of actinomycin D (C1, 1) and its analog actinomin (2) was studied on base-modified oligonucleotide duplexes with parallel chain orientation (ps) and with anti-parallel chains (aps) for comparison. Actinomycin D binds not only to aps duplexes containing guanine-cytosine base pairs but also to those incorporating modified bases such as 7-deazaguanine or its 6-deoxo derivative. For this, novel phosphoramidites were prepared. The new building block of 7-deaza-2'-deoxyguanosine is significantly more stable than the one currently used and allows normal oxidation conditions during solid-phase oligonucleotide synthesis. Actinomycin binds weakly to ps duplexes containing guanine-isocytosine base pairs but not to ps-DNA incorporating pairs of isoguanine-cytosine residues. On the contrary, the actinomycin D analog actinomin, which contains positively charged side chains instead of the chiral peptide rings, is strongly bound to both ps- and aps-DNA. Guanines, isoguanine, as well as other 7-deaza derivatives are accepted as nucleobases. Apparently, the pentapeptide lacton rings of actinomycin do not fit nicely into the groove of ps-DNA thereby reducing the binding strength of the antibiotic while the groove size of ps-DNA does not affect actinomin binding notably.

Binding Sites↗
PubMed2006

N8-(2'-O-methylribofuranosyl)-8-aza-7-deazaadenine monohydrate.

In the title compound, 4-amino-2-(2-O-methyl-beta-D-ribofuranosyl)-2H-pyrazolo[3,4-d]pyrimidine monohydrate, C11H15N5O4.H2O, the conformation of the N-glycosylic bond is syn [chi = 20.1 (2) degrees ]. The ribofuranose moiety shows a C3'-endo (3T2) sugar puckering (N-type sugar), and the conformation at the exocyclic C4'-C5' bond is -ap (trans). The nucleobases are stacked head-to-head. The three-dimensional packing of the crystal structure is stabilized by hydrogen bonds between the 2'-O-methylribonucleosides and the solvent molecules.

Adenine↗
PubMed2006

7-Functionalized 7-deazapurine ribonucleosides related to 2-aminoadenosine, guanosine, and xanthosine: glycosylation of pyrrolo[2,3-d]pyrimidines with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose.

[reaction: see text] The Silyl-Hilbert-Johnson reaction as well as the nucleobase-anion glycosylation of a series of 7-deazapurines has been investigated, and the 7-functionalized 7-deazapurine ribonucleosides were prepared. Glycosylation of the 7-halogenated 6-chloro-2-pivaloylamino-7-deazapurines 9b-d with 1-O-acetyl-2,3,5-tri-O-benzoyl-D-ribofuranose (5) gave the beta-D-nucleosides 11b-d (73-75% yield), which were transformed to a number of novel 7-halogenated 7-deazapurine ribonucleosides (2b-d, 3b-d, and 4b-d) related to guanosine, 2-aminoadenosine, and xanthosine. 7-Alkynyl derivatives (2e-i, 3e-h, or 4g) have been prepared from the corresponding 7-iodonucleosides 2d, 3d, or 4d employing the palladium-catalyzed Sonogashira cross-coupling reaction. The 7-halogenated 2-amino-7-deazapurine ribonucleosides with a reactive 6-chloro substituent (18b-d) were synthesized in an alternative way using nucleobase-anion glycosylation performed on the 7-halogenated 2-amino-6-chloro-7-deazapurines 13b-d with 5-O-[(1,1-dimethylethyl)dimethylsilyl]-2,3-O-(1-methylethylidene)-alpha-D-ribofuranosyl chloride (17). Compounds 18b-d have been converted to the nucleosides 19b-d carrying reactive substituents in the pyrimidine moiety. Conformational analysis of selected nucleosides on the basis of proton coupling constants and using the program PSEUROT showed that these ribonucleosides exist in a preferred S conformation in solution.

Adenosine↗
PubMed2006

DNA containing side chains with terminal triple bonds: Base-pair stability and functionalization of alkynylated pyrimidines and 7-deazapurines.

The synthesis of a series of oligonucleotides containing 5-substituted pyrimidines as well as 7-substituted 7-deazapurines bearing diyne groups with terminal triple bonds is reported. The modified nucleosides were prepared from the corresponding iodo nucleosides and diynes by the Sonogashira cross-coupling reaction. They were converted into phosphoramidites and employed in solid-phase synthesis of oligonucleotides. The effect of the diyne modifications on the duplex stability was investigated. The modified nucleosides were used for further functionalization using the protocol of Huisgen-Sharpless [2+3] cycloaddition ('click chemistry').

Base Pairing↗
PubMed2006

Progress in 7-deazapurine - pyrrolo[2,3-d]pyrimidine - ribonucleoside synthesis.

This review reports on the synthesis of 7-deazapurine ribonucleosides, including C-nucleosides, 2'-C-methyl derivatives and L-enantiomers. It covers the various aspects of convergent nucleoside synthesis such as the Schiff base procedure, the fusion reaction, the metal salt procedures, the Silyl-Hilbert-Johnson reaction, and the nucleobase anion glycosylation. The review discusses the scope and limitations of glycosylation reactions performed on 7-deazapurines. Peracylated ribose derivatives were now employed in the glycosylation, which overcome difficulties reported earlier.

Purines↗
PubMed2005

Stabilization of tandem dG-dA base pairs in DNA-hairpins: replacement of the canonical bases by 7-deaza-7-propynylpurines.

The stabilizing effect of 7-propynylated 7-deazapurine nucleosides on DNA-hairpins and DNA-duplexes containing d(GA) mismatches was investigated. The corresponding oligonucleotides were synthesized using solid-phase synthesis. For this purpose, the phosphoramidite of 7-deaza-7-propynyl-2'-deoxyadenosine (3c) was prepared. The incorporation of 3c instead of dA into the tandem d(GA) base pair of a DNA-hairpin alters the secondary structure, but has a positive effect on the duplex stability. A complete replacement of the canonical nucleosides of the tandem d(GA) base pair by 3c and 7-deaza-7-propynyl-2'-deoxyguanosine results in a significant base pair stabilization.

Base Pairing↗
PubMed2005

8-Aza-7-deaza-2'-deoxy-2-(methylsulfanyl)adenosine.

In the title compound, 4-amino-1-(2-deoxy-beta-D-erythro-pentofuranosyl)-6-methylsulfanyl-1H-pyrazolo[3,4-d]pyrimidine, C11H16N5O3S, the conformation of the glycosidic bond is between anti and high anti. The 2'-deoxyribofuranosyl moiety adopts the C3'-exo-C4'-endo conformation (3T4, S-type sugar pucker), and the conformation at the exocyclic C-C bond is +sc (+gauche). The exocyclic 6-amine group and the 2-methylsulfanyl group lie on different sides of the heterocyclic ring system. The molecules form a three-dimensional hydrogen-bonded network that is stabilized by O-H...N, N-H...O and C-H...O hydrogen bonds.

Adenosine↗
PubMed2005

Base-pairing, tautomerism, and mismatch discrimination of 7-halogenated 7-deaza-2'-deoxyisoguanosine: oligonucleotide duplexes with parallel and antiparallel chain orientation.

Oligonucleotides containing 2'-deoxyisoguanosine (1, iG(d)), 7-deaza-2'-deoxyisoguanosine (2, c(7)iG(d)), and its 7-halogenated derivatives 3 and 4 were synthesized on solid phase using the phosphoramidite building blocks 5-7. The hybridization properties of oligonucleotides were studied on duplexes with parallel and antiparallel chain orientation. It was found that the 7-halogenated nucleoside analogues 3 and 4 enhance the duplex stability significantly in both parallel (ps) and antiparallel (aps) DNA. Moreover, the halogenated nucleosides shift the tautomeric keto-enol equilibrium strongly toward the keto form, with K(TAUT) [keto]/[enol] approximately 10(4) coming close to that of 2'-deoxyguanosine (10(4)-10(5)), while the nonhalogenated 7-deaza-2'-deoxyisoguanosine 2 shows a K(TAUT) of around 2000 and the enol concentration of 1 is 10% in aqueous solution. Consequently, nucleosides 3 and 4 show a much better mismatch discrimination against dT than compound 1 or 2 in antiparallel as well as in parallel DNA. 3 and 4 are expected to increase the selectivity of base incorporation opposite to isoC(d) in the form of triphosphates or in the polymerase-catalyzed reaction in comparison to 1 or 2.

Base Pair Mismatch↗
PubMed2005

2'-Deoxy-5-fluorotubercidin.

In the title compound, 4-amino-7-(2-deoxy-beta-D-erythro-pentofuranosyl)-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine, C11H13FN4O3, the conformation of the glycosyl bond lies between anti and high anti [chi = -101.1 (3) degrees ]. The furanose moiety adopts the S-type sugar pucker (2T3), with P = 164.7 (3) degrees and tau = 40.1 (2) degrees . The extended structure is a three-dimensional hydrogen-bond network involving a C-H...F, two N-H...O and two O-H...O hydrogen bonds.

Crystallography, X-Ray↗
PubMed2005

1,N6-Etheno-7-deaza-2,8-diazaadenosine: syntheses, properties and conversion to 7-deaza-2,8-diazaadenosine.

1,N6-Etheno-7-deaza-2,8-diazaadenosine (4) was synthesized from 8-aza-7-deazaadenosine (6) in 64% overall yield. The starting material 6 was obtained by the direct glycosylation of 8-aza-7-deazaadenine (7) with 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-d-ribofuranose (8) (NO2 CH3, BF3 x Et2O; 77% yield). Compound 4 was transformed into 7-deaza-2,8-diazaadenosine (5). The fluorescence of compound 4 shows an emission maximum at 531 nm (phosphate buffer; pH 7.0), which is bathochromically shifted compared to 1,N(6)-etheno-2-azaadenosine (3a) (495 nm). A conformational analysis was performed in the solid state and in solution.

Adenosine↗