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  • 51.
    Foldesi, A
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Trifonova, A
    Kundu, MK
    Chattopadhyaya, J
    The synthesis of deuterionucleosides2000In: NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, Vol. 19, no 10-12, p. 1615-1656Article, book review (Other scientific)
    Abstract [en]

    The synthesis of deuterionucleosides for site-specific incorporation into oligo-DNA or -RNA is herein reviewed for NMR or biological studies. The review covers the following aspects: (i) deuteration of the aglycone; (ii) single-site chemical deuteration o

  • 52.
    Földesi, A
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Kundu, M K
    Dinya, Z
    Chattopadhyaya, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Synthesis of 2'-2H1-Ribonucleosides2004In: Helvetica Chemica Acta, Vol. 87, p. 742-757Article in journal (Refereed)
  • 53.
    Földesi, Andras
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaya, Jyoti
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Studies towards the large scale chemical synthesis of the precursors of ribonucleosides-3',4',5',5''-2H4 and -2',3',4',5',5''-2H5.2003In: Nucleosides Nucleotides Nucleic Acids, ISSN 1525-7770, Vol. 22, no 12, p. 2093-104Article in journal (Other scientific)
  • 54.
    Honcharenko, D.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Varghese, O.P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Plashkevych, O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Barman, J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Synthesis and Structure of Novel Conformationally-constrained 1'2'-Azetidine-Fused Bicyclic Pyrimidine Nucleosides: Their Incorporation into Oligo-DNAs and the Thermal Stability of the Heteroduplexes2006In: Journal of Organic Chemistry, Vol. 71, p. 299-314Article in journal (Refereed)
  • 55.
    Honcharenko, Dmytro
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Barman, Jharna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Varghese, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Comparison of the RNase H Cleavage Kinetics and Blood Serum Stability of the North-Conformationally Constrained and 2‘-Alkoxy Modified Oligonucleotides2007In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 46, no 19, p. 5635-5646Article in journal (Refereed)
    Abstract [en]

    The RNase H cleavage potential of the RNA strand basepaired with the complementary antisense oligonucleotides (AONs) containing NorthEast conformationally constrained 1‘,2‘-methylene-bridged (azetidine-T and oxetane-T) nucleosides, North-constrained 2‘,4‘-ethylene-bridged (aza-ENA-T) nucleoside, and 2‘-alkoxy modified nucleosides (2‘-O-Me-T and 2‘-O-MOE-T modifications) have been evaluated and compared under identical conditions. When compared to the native AON, the aza-ENA-T modified AON/RNA hybrid duplexes showed an increase of melting temperature (ΔTm = 2.5−4 °C per modification), depending on the positions of the modified residues. The azetidine-T modified AONs showed a drop of 4−5.5 °C per modification with respect to the native AON/RNA hybrid, whereas the isosequential oxetane-T modified counterpart, showed a drop of 5−6 °C per modification. The 2‘-O-Me-T and 2‘-O-MOE-T modifications, on the other hand, showed an increased of Tm by 0.5 °C per modification in their AON/RNA hybrids. All of the partially modified AON/RNA hybrid duplexes were found to be good substrates for the RNase H mediated cleavage. The Km and Vmax values obtained from the RNA concentration-dependent kinetics of RNase H promoted cleavage reaction for all AON/RNA duplexes with identical modification site were compared with those of the reference native AON/RNA hybrid duplex. The catalytic activities (Kcat) of RNase H were found to be greater (1.4−2.6-fold) for all modified AON/RNA hybrids compared to those for the native AON/RNA duplex. However, the RNase H binding affinity (1/Km) showed a decrease (1.7−8.3-fold) for all modified AON/RNA hybrids. This resulted in less effective (1.1−3.2-fold) enzyme activity (Kcat/Km) for all modified AON/RNA duplexes with respect to the native counterpart. A stretch of five to seven nucleotides in the RNA strand (from the site of modifications in the complementary modified AON strand) was found to be resistant to RNase H digestion (giving a footprint) in the modified AON/RNA duplex. Thus, (i) the AON modification with azetidine-T created a resistant region of five to six nucleotides, (ii) modification with 2‘-O-Me-T created a resistant stretch of six nucleotides, (iii) modification with aza-ENA-T created a resistant region of five to seven nucleotide residues, whereas (iv) modification with 2‘-O-MOE-T created a resistant stretch of seven nucleotide residues. This shows the variable effect of the microstructure perturbation in the modified AON/RNA heteroduplex depending upon the chemical nature as well as the site of modifications in the AON strand. On the other hand, the enhanced blood serum as well as the 3‘-exonuclease stability (using snake venom phosphodiesterase, SVPDE) showed the effect of the tight conformational constraint in the AON with aza-ENA-T modifications in that the 3‘-exonuclease preferentially hydrolyzed the 3‘-phosphodiester bond one nucleotide away (n + 1) from the modification site (n) compared to all other modified AONs, which were 3‘-exonuclease cleaved at the 3‘-phosphodiester of the modification site (n). The aza-ENA-T modification in the AONs made the 5‘-residual oligonucleotides (including the n + 1 nucleotide) highly resistant in the blood serum (remaining after 48 h) compared to the native AON (fully degraded in 2 h). On the other hand, the 5‘-residual oligonucleotides (including the n nucleotide) in azetidine-T, 2‘-O-Me-T, and 2‘-O-MOE-T modified AONs were more stable compared to that of the native counterpart but more easily degradable than that of aza-ENA-T containing AONs.

  • 56.
    Honcharenko, Dmytro
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Varghese, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Plashkevych, Oleksandr
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Barman, Jharna
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Synthesis and Structure of Novel Conformationally Constrained 1‘,2‘-Azetidine-Fused Bicyclic Pyrimidine Nucleosides: Their Incorporation into Oligo-DNAs and Thermal Stability of the Heteroduplexes2006In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 71, no 1, p. 299-314Article in journal (Refereed)
  • 57. Isaksson, J.
    et al.
    Acharya, S.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Barman, J.
    Cheruku, P.
    Chattopadhyaya, J.
    Single-Stranded Adenine-Rich DNA and RNA Retain Structural Characteristics of Their Respective Double-Stranded Conformations and Show Directional Differences in Stacking Pattern2004In: Biochemistry, Vol. 43, p. 15996-16010Article in journal (Refereed)
  • 58.
    Isaksson, J
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Acharya, S
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Barman, J
    Cheruku, P
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaya, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Single-stranded adenine-rich DNA and RNA retain structural characteristics of their respective double-stranded conformations and show directional differences in stacking pattern.2004In: Biochemistry, ISSN 0006-2960, Vol. 43, no 51, p. 15996-6010Article in journal (Other scientific)
  • 59.
    Isaksson, J
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Chattopadhyaya, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry. Department of Cell and Molecular Biology, Bioorganic Chemistry.
    A uniform mechanism correlating dangling-end stabilization and stacking geometry.2005In: Biochemistry, ISSN 0006-2960, Vol. 44, no 14, p. 5390-401Article in journal (Other scientific)
  • 60.
    Isaksson, J
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Zamaratski, E
    Maltseva, TV
    Agback, P
    Kumar, A
    Chattopadhyaya, J
    The first example of a Hoogsteen basepaired DNA duplex in dynamic equilibrium with a Watson-Crick basepaired duplex - A structural (NMR), kinetic and thermodynamic study2001In: JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS, ISSN 0739-1102, Vol. 18, no 6, p. 783-806Article in journal (Refereed)
    Abstract [en]

    A single-point substitution of the O4' oxygen by a CH2 group at the sugar residue of (A) under bar (6) (i.e. 2'-deoxyaristeromycin moiety) in a self-complementary DNA duplex, 5'd-(C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)C(9)G(10)C(11)G(12))(2)(-3,), has been show

  • 61.
    Isaksson, Johan
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Studies on Nucleic Acids – Structure and Dynamics2005Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis is based on six papers, Papers I-VI, focusing on the interplay between the stabilizing elements of nucleic acids self-assembly; hydrogen bonding, stacking and solvent effects. In Paper I we investigate how the substitution of the O4' for CH2 in the sugar moiety of adenosine (2'-deoxyaristeromycin) at the A6 position of the Dickerson-Drew dodecamer makes the two modified bases exist in a dynamic equilibrium between Hoogsteen and Watson-Crick base pairing in the NMR time scale. Paper II is a structural study of the incorporation of 1-(1',3'-O-anhydro-β-D-psicofuranosyl)thymine in the T7 position of the Dickerson-Drew dodecamer. NMR constrained molecular dynamics and hydration studies show the base-base distortions caused by the introduction of a North-type locked sugar in an otherwise B-type DNA•DNA duplex. Paper III shows that the stacking distortion caused by the 1-(1',3'-O-anhydro-β-D-psicofuranosyl)thymine building block perturbs the charge transfer similar to a DNA mismatch. Paper IV highlights how the sequence context affects the physico-chemical properties, monitored by the pKa of guanine itself as well as how the charge perturbation is experienced by the neighboring bases, in ssDNA and ssRNA. Paper V focuses on the differences between the structural equilibria of single-stranded ssDNA and ssRNA. Directional differences in single-stranded stacking between ssDNA and ssRNA are identified and provide a basis to explain directional differences in pKa modulation and dangling-end stabilization. In Paper VI the thermodynamic gains of dangling ends on DNA and RNA core duplexes are found to correlate with the X-ray geometries of dangling nucleobases relative to the hydrogen bonds of the closing base pairs.

    List of papers
    1. The First Example of a Hoogsteen Basepaired DNA Duplex in Dynamic Equilibrium with a Watson-Crick Basepaired Duplex –A Structural (NMR), Kinetic and Thermodynamic Study
    Open this publication in new window or tab >>The First Example of a Hoogsteen Basepaired DNA Duplex in Dynamic Equilibrium with a Watson-Crick Basepaired Duplex –A Structural (NMR), Kinetic and Thermodynamic Study
    Show others...
    2001 In: J. Biomol. Struct. Dyn., ISSN 0739-1102, Vol. 18, p. 783-806Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93246 (URN)
    Available from: 2005-06-01 Created: 2005-06-01Bibliographically approved
    2. 3'-endo/4'-exo Locked Thymidine in the Dickerson-Drew Dodecamer Causes Local Base Pairing Distortions – An NMR Structure and Hydration Study
    Open this publication in new window or tab >>3'-endo/4'-exo Locked Thymidine in the Dickerson-Drew Dodecamer Causes Local Base Pairing Distortions – An NMR Structure and Hydration Study
    Show others...
    2005 In: Nucleic Acids ResArticle in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-93247 (URN)
    Available from: 2005-06-01 Created: 2005-06-01 Last updated: 2015-05-19Bibliographically approved
    3. An electrochemical probe of DNA stacking in an antisense oligonucleotide containing a C3'-endo-locked sugar
    Open this publication in new window or tab >>An electrochemical probe of DNA stacking in an antisense oligonucleotide containing a C3'-endo-locked sugar
    Show others...
    2002 In: Angew. Chem. Int. Ed., ISSN 1433-7851, Vol. 41, p. 3402-3405Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93248 (URN)
    Available from: 2005-06-01 Created: 2005-06-01Bibliographically approved
    4. Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
    Open this publication in new window or tab >>Significant pKa Perturbation of Nucleobases Is an Intrinsic Property of the Sequence Context in DNA and RNA
    Show others...
    2004 In: J. Am. Chem. Soc., ISSN 0002-7863, Vol. 126, p. 8674-8681Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93249 (URN)
    Available from: 2005-06-01 Created: 2005-06-01Bibliographically approved
    5. Single-Stranded Adenine-Rich DNA and RNA Retain Structural Characteristics of Their Respective Double-Stranded Conformations and Show Directional Differences in Stacking
    Open this publication in new window or tab >>Single-Stranded Adenine-Rich DNA and RNA Retain Structural Characteristics of Their Respective Double-Stranded Conformations and Show Directional Differences in Stacking
    Show others...
    2004 In: Biochemistry, ISSN 0006-2960, Vol. 43, p. 15996-16010Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93250 (URN)
    Available from: 2005-06-01 Created: 2005-06-01Bibliographically approved
    6. A Uniform Mechanism Correlating Dangling-End Stabilization and Stacking Geometry
    Open this publication in new window or tab >>A Uniform Mechanism Correlating Dangling-End Stabilization and Stacking Geometry
    2005 In: Biochemistry, ISSN 0006-2960, Vol. 44, p. 5390-5401Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-93251 (URN)
    Available from: 2005-06-01 Created: 2005-06-01Bibliographically approved
  • 62.
    Isaksson, Johan
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Acharya, Sandipta
    Barman, Jharna
    Cheruku, Pradeep
    Chattopadhyaya, Jyoti
    Single-Stranded Adenine-Rich DNA and RNA Retain Structural Characteristics of Their Respective Double-Stranded Conformations and Show Directional Differences in Stacking2004In: Biochemistry, ISSN 0006-2960, Vol. 43, p. 15996-16010Article in journal (Refereed)
  • 63.
    Isaksson, Johan
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaya, Jyoti
    A Uniform Mechanism Correlating Dangling-End Stabilization and Stacking Geometry2005In: Biochemistry, ISSN 0006-2960, Vol. 44, p. 5390-5401Article in journal (Refereed)
  • 64.
    Isaksson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Plashkevych, Oleksandr
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Pradeepkumar, P. I.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chatterjee, Subhrangsu
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Barman, J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Pathmasiri, Wimal
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Srivastava, P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Petit, C.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Oxetane locked thymidine in the Dickerson-Drew dodecamer causes local base pairing distortions: an NMR structure and hydration study2005In: Journal of Biomolecular Structure and Dynamics, ISSN 0739-1102, E-ISSN 1538-0254, Vol. 23, no 3, p. 299-330Article in journal (Refereed)
    Abstract [en]

    The introduction of a North-type sugar conformation constrained oxetane T block, 1-(1',3'-O-anhydro-beta-D-psicofuranosyl) thymine, at the T(7) position of the self-complementary Dickerson-Drew dodecamer, d[(5'-C(1)G(2)C(3)G(4)A(5)A(6)T(7)T(8)C(9)G(10)C(11)G(12)-3')](2), considerably perturbs the conformation of the four central base pairs, reducing the stability of the structure. UV spectroscopy and 1D NMR display a drop in melting temperature of approximately 10 degrees C per modification for the T(7) oxetane modified duplex, where the T(7) block has been introduced in both strands, compared to the native Dickerson-Drew dodecamer. The three dimensional structure has been determined by NMR spectroscopy and has subsequently been compared with the results of 2.4 ns MD simulations of the native and the T(7) oxetane modified duplexes. The modified T(7) residue is found to maintain its constrained sugar- and the related glycosyl torsion conformations in the duplex, resulting in staggered and stretched T(7).A(6) and A(6).T(7) non-linear base pairs. The stacking is less perturbed, but there is an increased roll between the two central residues compared to the native counterpart, which is compensated by tilts of the neighboring base steps. The one dimensional melting profile of base protons of the T(7) and T(8) residues reveals that the introduction of the North-type sugar constrained thymine destabilizes the core of the modified duplex, promoting melting to start simultaneously from the center as well as from the ends. Temperature dependent hydration studies by NMR demonstrate that the central T(7).A(6)/A(6).T(7) base pairs of the T(7) oxetane modified Dickerson-Drew dodecamer have at least one order of magnitude higher water exchange rates (correlated to the opening rate of the base pair) than the corresponding base pairs in the native duplex.

  • 65.
    Isaksson, Johan
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Plashkevych, Oleksandr
    Pradeepkumar, Pushpangadan Indira
    Pathmasiri, Wimal
    Petit, Catherine
    Chattopadhyaya, Jyoti
    3'-endo/4'-exo Locked Thymidine in the Dickerson-Drew Dodecamer Causes Local Base Pairing Distortions – An NMR Structure and Hydration Study2005In: Nucleic Acids ResArticle in journal (Refereed)
  • 66.
    Isaksson, Johan
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Zamaratski, Edouard
    Maltseva, Tatiana V.
    Agback, Peter
    Kumar, Anil
    Chattopadhyaya, Jyoti
    The First Example of a Hoogsteen Basepaired DNA Duplex in Dynamic Equilibrium with a Watson-Crick Basepaired Duplex –A Structural (NMR), Kinetic and Thermodynamic Study2001In: J. Biomol. Struct. Dyn., ISSN 0739-1102, Vol. 18, p. 783-806Article in journal (Refereed)
  • 67.
    J, Barman
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    P, Acharya
    J, Isaksson
    S, Acharya
    P, Cheruku
    A, Földesi
    J, Chattopadhyaya
    The Nucleobases in Single-stranded DNA are Better Stacked and Yet Their Pseudoaromatic Characters are More Poorly Cross-modulated Than in the RNA Counterparts Due to Variable Tandem Nearest-neighbour Electrostatic InteractionsIn: J. Am. Chem. Soc.Article in journal (Refereed)
  • 68.
    J., Chattopadhyaya,
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    I, Velikian
    P, Acharya
    A, Trifonova
    A, Földesi
    J, Chattopadhyaya
    The RNA Molecular Wire: The pH-Dependent Change in Electronic Character of Adenine-9-yl is Transmitted to Drive the Sugar-Phosphate Backbone Torsions in Adenosine 3', 5'-bisphosphate2000In: J. Phys. Org. Chem., Vol. 13, p. 300-305Article in journal (Refereed)
  • 69.
    J., Chattopadhyaya,
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    P, Acharya
    B, Nawrot
    M, Sprinzl
    C, Thibaudeau
    J, Chattopadhyaya
    The Strength of the 3'-gauche effect Dictates the Structure of 3'-anthraniloyladenosine and its 5'-phosphate, Two Analogues of the 3'-end of Aminoacyl tRNA1999In: J. Chem. Soc. Perkin 2, p. 1531-1536Article in journal (Refereed)
  • 70. Kundu, M K
    et al.
    Földesi, A
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaya, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Studies on the Stereoselective Synthesis of Deuterated- Ribose Derivatives2003In: Helvetica Chemica Acta, Vol. 86, p. 633-643Article in journal (Refereed)
  • 71.
    Kundu, MK
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Trifonova, A
    Dinya, Z
    Foldesi, A
    Chattopadhyaya, J
    Synthetic studies to improve the deuterium labelling in nucleosides for facilitating structural studies of large RNAs by high-field NMR spectroscopy2001In: NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, ISSN 1525-7770, Vol. 20, no 4-7, p. 1333-1337Article in journal (Refereed)
    Abstract [en]

    Synthetic studies to prepare ribonucleosides deuterated at C2' and the application of the developed procedures for the synthesis of H-2(5)-ribonucleosides from 1,2-O-isopropylidene-3-O-benzyl-ribofuranose-3,4,5,5'-H-2(4) have been reported.

  • 72.
    Lewandowicz, Andrzej
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Rudzinski, Juliusz
    Tronstad, Lisa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Widersten, Mikael
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Ryberg, Per
    Matsson, Olle
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Paneth, Piotr
    Chlorine kinetic isotope effects on the haloalkane dehalogenase reaction2001In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 123, no 19, p. 4550-4555Article in journal (Refereed)
    Abstract [en]

    We have found chlorine kinetic isotope effects on the dehalogenation catalyzed by haloalkane dehalogenase from Xanthobacter autotrophicus GJ10 to be 1.0045 ± 0.0004 for 1,2-dichloroethane and 1.0066 ± 0.0004 for 1-chlorobutane. The latter isotope effect approaches the intrinsic chlorine kinetic isotope effect for the dehalogenation step. The intrinsic isotope effect has been modeled using semiempirical and DFT theory levels using the ONIOM QM/QM scheme. Our results indicate that the dehalogenation step is reversible; the overall irreversibility of the enzyme-catalyzed reaction is brought about by a step following the dehalogenation.

  • 73.
    Lundquist, Anna
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Engvall, Caroline
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Boija, Elisabet
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Kurtovic, Sanela
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Chattopadhyaya, Jyoti
    Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Lagerquist Hägglund, Christine
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Lundahl, Per
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Chemistry, Department of Biochemistry.
    Interactions of drugs and an oligonucleotide with charged membranes analyzed by immobilized liposome chromatography2006In: Biomedical Chromatography, Vol. 20, p. 83-87Article in journal (Refereed)
    Abstract [en]

    We studied the effect of charged lipids or detergent on the retention of drugs and an oligonucleotide by immobilized liposome chromatography to characterize solute-membrane interactions. This is a novel approach in analysis of oligonucleotide-liposome interactions. The charged lipids (phosphatidylserine or distearoyltrimethylammoniumpropane) or detergent (sodium dodecylsulfate) interacted electrostatically in a concentration-dependent matter with the solutes. The oligonucleotide ions presumably bound to the liposomes by multipoint interactions, which was saturable. Sodium dodecylsulfate seemed to affect the drug-membrane interactions more strongly than phosphatidylserine did, probably due to different positioning in the bilayer.

  • 74.
    Luzhkov, Victor
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Österberg, Fredrik
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
    Acharya, Parag
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaha, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Åqvist, Johan
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Computational and NMR study of quaternary ammonium ion conformations in solution2002In: Physical Chemistry Chemical Physics, Vol. 4, no 19, p. 4640-4647Article in journal (Refereed)
  • 75.
    MacMillar, Susanna
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Isotopes as Mechanism Spies: Nucleophilic Bimolecular Substitution and Monoamine Oxidase B Catalysed Amine Oxidation Probed with Heavy Atom Kinetic Isotope Effects2006Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis concerns the study of reaction mechanisms by means of kinetic isotope effects (KIEs). Studies of the nucleophilic bimolecular substitution (SN2) reaction had the dual purpose of improving our fundamental understanding of molecular reactivity and assessing the ability of kinetic isotope effects to serve as mechanistic tools. The transition state of the SN2 reaction between a cyanide ion and ethyl chloride in tetrahydrofuran was found to be reactant like and only slightly tighter than has been found previously for the same reaction in dimethyl sulphoxide. One conclusion was that the transition-state structure in this reaction was predicted fairly well by the theoretical calculations, even without solvent modelling. The SN2 reactions between cyanide ions and para-substituted benzyl chlorides were found to have reactant-like transition states, of which the Cα-Cl bond was most influenced by the para-substitution. Theoretical calculations indicated that the chlorine KIEs could be used as probes of the substituent effect on the Cα-Cl bond if bond fission was not too advanced in the transition state. Furthermore, the nucleophile carbon 11C/14C KIEs were determined for the reactions between cyanide ions and various ethyl substrates in dimethyl sulphoxide.

    Precision conductometry was employed to estimate the aggregation status of tetrabutylammonium cyanide in tetrahydrofuran and in dimethyl sulphoxide, which is of interest as tetrabutylammonium cyanide is frequently used as the nucleophilic reagent in mechanistic investigations and synthetic reactions. The tendency for ion-pair formation was found to be very slight, significant, and very strong in dimethyl sulphoxide, water, and tetrahydrofuran, respectively.

    The nitrogen kinetic isotope effect on monoamine oxidase B catalysed deamination of benzylamine was determined in an attempt to obtain conclusive evidence regarding the mechanism of the oxidation. Monoamine oxidase is an important drug target in connection with the treatment of, for example, depression and Parkinson’s disease, and knowledge on how the enzyme effects catalysis would facilitate the design of highly selective and efficient inhibitors.

    List of papers
    1. The Effect of Solvent on the Structure of the Transition State for the SN2 Reaction between Cyanide Ion and Ethyl Chloride in DMSO and THF Probed with Six Different Kinetic Isotope Effects
    Open this publication in new window or tab >>The Effect of Solvent on the Structure of the Transition State for the SN2 Reaction between Cyanide Ion and Ethyl Chloride in DMSO and THF Probed with Six Different Kinetic Isotope Effects
    Show others...
    2006 In: Journal of Organic Chemistry, ISSN 0022-3263, Vol. 71, no 13, p. 4742-4747Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-95360 (URN)
    Available from: 2007-01-05 Created: 2007-01-05Bibliographically approved
    2. A New Insight into Using Chlorine Leaving Group and Nucleophile Carbon Kinetic Isotope Effects To Determine Substituent Effects on the Structure of SN2 Transition States
    Open this publication in new window or tab >>A New Insight into Using Chlorine Leaving Group and Nucleophile Carbon Kinetic Isotope Effects To Determine Substituent Effects on the Structure of SN2 Transition States
    Show others...
    2007 (English)In: Journal of Physical Chemistry A, ISSN 1089-5639, E-ISSN 1520-5215, Vol. 111, no 33, p. 8110-8120Article in journal (Refereed) Published
    Abstract [en]

    Chlorine leaving group k(35)/k(37), nucleophile carbon k(11)/k(14), and secondary alpha-deuterium [(k(H)/k(D))(alpha)] kinetic isotope effects (KIEs) have been measured for the S(N)2 reactions between para-substituted benzyl chlorides and tetrabutylammonium cyanide in tetrahydrofuran at 20 degrees C to determine whether these isotope effects can be used to determine the substituent effect on the structure of the transition state. The secondary alpha-deuterium KIEs indicate that the transition states for these reactions are unsymmetric. The theoretical calculations at the B3LYP/aug-cc-pVDZ level of theory support this conclusion; i.e., they suggest that the transition states for these reactions are unsymmetric with a long NC-C-alpha and reasonably short C-alpha-Cl bonds. The chlorine isotope effects suggest that these KIEs can be used to determine the substituent effects on transition state structure with the KIE decreasing when a more electron-withdrawing para-substituent is present. This conclusion is supported by theoretical calculations. The nucleophile carbon k(11)/k(14) KIEs for these reactions, however, do not change significantly with substituent and, therefore, do not appear to be useful for determining how the NC-C-alpha transition-state bond changes with substituent. The theoretical calculations indicate that the NC-C-alpha bond also shortens as a more electron-withdrawing substituent is placed on the benzene ring of the substrate but that the changes in the NC-C-alpha transition-state bond with substituent are very small and may not be measurable. The results also show that using leaving group and nucleophile carbon KIEs to determine the substituent effect on transition-state structure is more complicated than previously thought. The implication of using both chlorine leaving group and nucleophile carbon KIEs to determine the substituent effect on transition-state structure is discussed.

    National Category
    Chemical Sciences
    Identifiers
    urn:nbn:se:uu:diva-95361 (URN)10.1021/jp0729765 (DOI)000248758800010 ()
    Available from: 2007-01-05 Created: 2007-01-05 Last updated: 2017-12-14Bibliographically approved
    3. The Nucleophile Carbon 11C/14C Kinetic Isotope Effect for the Reactions between Cyanide Ions and Ethyl Substrates in DMSO
    Open this publication in new window or tab >>The Nucleophile Carbon 11C/14C Kinetic Isotope Effect for the Reactions between Cyanide Ions and Ethyl Substrates in DMSO
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-95362 (URN)
    Available from: 2007-01-05 Created: 2007-01-05 Last updated: 2010-01-13Bibliographically approved
    4. Solvent Effects on Ion Pairing of Tetrabutylammonium Cyanide. A Conductometric Study
    Open this publication in new window or tab >>Solvent Effects on Ion Pairing of Tetrabutylammonium Cyanide. A Conductometric Study
    Show others...
    Article in journal (Refereed) Submitted
    Identifiers
    urn:nbn:se:uu:diva-95363 (URN)
    Available from: 2007-01-05 Created: 2007-01-05Bibliographically approved
    5. Nitrogen Kinetic Isotope Effects as Probes of the Mechanism of Monoamine Oxidase B
    Open this publication in new window or tab >>Nitrogen Kinetic Isotope Effects as Probes of the Mechanism of Monoamine Oxidase B
    Manuscript (Other academic)
    Identifiers
    urn:nbn:se:uu:diva-95364 (URN)
    Available from: 2007-01-05 Created: 2007-01-05 Last updated: 2010-01-13Bibliographically approved
  • 76.
    MacMillar, Susanna
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Edmondson, Dale E.
    Matsson, Olle
    Nitrogen Kinetic Isotope Effects as Probes of the Mechanism of Monoamine Oxidase BManuscript (Other academic)
  • 77.
    MacMillar, Susanna
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Fang, Yao-ren
    Westaway, Kenneth C.
    Matsson, Olle
    Beronius, Per
    Solvent Effects on Ion Pairing of Tetrabutylammonium Cyanide. A Conductometric StudyArticle in journal (Refereed)
  • 78.
    MacMillar, Susanna
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Matsson, Olle
    The Nucleophile Carbon 11C/14C Kinetic Isotope Effect for the Reactions between Cyanide Ions and Ethyl Substrates in DMSOManuscript (Other academic)
  • 79.
    Maltseva, T
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Foldesi, A
    Chattopadhyaya, J
    The identification of the A-type RNA helices in a 55mer RNA by selective incorporation of deuterium-labelled nucleotide residues (Uppsala NMR-window concept)2000In: JOURNAL OF BIOCHEMICAL AND BIOPHYSICAL METHODS, ISSN 0165-022X, Vol. 42, no 3, p. 153-178Article in journal (Refereed)
    Abstract [en]

    The 55-nt long RNA, modelling a three-way junction, with non-uniformly incorporated deuterated nucleotides has been synthesised in a pure form. The NMR-window part in this partially deuterated 55mer RNA consists of natural non-enriched nucleotide blocks a

  • 80.
    Maltseva, T
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Usova, E
    Eriksson, A
    Milecki, J
    Foldesi, A
    Chattopadhayaya, J
    An NMR conformational study of the complexes of C-13/H-2 double-labelled 2 '-deoxynucleosides and deoxycytidine kinase (dCK)2000In: JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 2, ISSN 1470-1820, no 11, p. 2199-2207Article in journal (Refereed)
    Abstract [en]

    The structures of the bound C-13/H-2 double-labelled [(2' R/S,5' R/S)-H-2(2)-1',2',3',4',5'-C-13(5)]-2'-deoxyadenosine (dAdo) and the corresponding 2'-deoxycytidine (dCyd) moieties in the complexes with human recombinant deoxycytidine kinase (dCK) have be

  • 81.
    Maltseva, T
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Usova, E
    Eriksson, S
    Milecki, J
    Foldesi, A
    Chattopadhayaya, J
    The NMR conformation study of the complexes of deoxycytidine kinase (dCK) and 2 '-deoxycytidine/2 '-deoxyadenosine2001In: NUCLEOSIDES NUCLEOTIDES & NUCLEIC ACIDS, ISSN 1525-7770, Vol. 20, no 4-7, p. 1225-1228Article in journal (Refereed)
    Abstract [en]

    The structures of the bound C-13/H-2 double-labelled 2'(R/S), 5'(R/S)-H-2(2)-1',2',3',4',5'- C-13(5)-2'-deoxyadenosine and the corresponding 2'-deoxycytidine moieties in the complexes with human deoxycytidine kinase (dCK) have been characterized for the f

  • 82.
    Maltseva, TV
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Foldesi, A
    Ossipov, D
    Chattopadhyaya, J
    Comparative C-13 and H-2 relaxation study of microsecond dynamics of the AT tract of selectively C-13/H-2 double-labelled DNA duplexes2000In: MAGNETIC RESONANCE IN CHEMISTRY, ISSN 0749-1581, Vol. 38, no 6, p. 403-414Article in journal (Refereed)
    Abstract [en]

    The microsecond dynamics of the sugar moiety of A and T residues in DNA duplexes, d(5')((1)C(2)G(3)A(4)T(5)T(6)A(7)A(8)T(9)C(10)G)(2)(3') (1b) and d(5')((1)C(2)C(3)A(4)T(5)T(6)A(7)A(8)T(9)G(10)G)(2)(3') (2b), containing C-13/H-2 double-labelled 2'(R/S),5'

  • 83.
    Milecki, J
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Foldesi, A
    Fischer, A
    Adamiak, RW
    Chattopadhyaya, J
    Synthesis of multiply labelled ribonucleosides for sequence-specific labelling of oligo-RNA2001In: JOURNAL OF LABELLED COMPOUNDS & RADIOPHARMACEUTICALS, ISSN 0362-4803, Vol. 44, no 11, p. 763-783Article in journal (Refereed)
    Abstract [en]

    The synthesis of ribonucleotide blocks multiply labelled with H-2, C-13 and N-15 for solid support synthesis of sequence specifically labelled RNA is described. Labels were introduced in the ribose ring ( C-13), C5 position of pyrimidine nucleobases (H-2)

  • 84.
    Nillroth, Ulrika
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Vrang, Lotta
    Ahlsén, Göran
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    Besidsky, Y
    Chattopadhyaya, J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Ugi, I
    Danielson, U. Helena
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry.
    The use of 5'-phosphate derivatives of nucleoside analogs as inhibitors of HIV-1 replication1995In: Antiviral Chemistry & Chemotherapy, ISSN 0956-3202, E-ISSN 2040-2066, Vol. 6, no 1, p. 50-64Article in journal (Refereed)
  • 85. Opalinska, J B
    et al.
    Kalota, A
    Gifford, Lida K
    Lu, Ponzy
    Jen, Kuang-Yu
    Pradeepkumar, P I
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Barman, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Kim, T K
    Swider, C R
    Chattopadhyaya, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Gewirtz, A M
    Oxetane modified, conformationally constrained, antisense oligodeoxyribonucleotides function efficiently as gene silencing molecules.2004In: Nucleic Acids Res, ISSN 1362-4962, Vol. 32, no 19, p. 5791-9Article in journal (Other scientific)
  • 86. Opalinska, Joana B.
    et al.
    Kalota, Anna
    Rodriquez, Lesbeth
    Henningson, Carl
    Gifford, Lida. K.
    Lu, Ponzy
    Jen, Kuang-Yu
    Pradeepkumar, Pushpangadan Indira
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Barman, Jharna
    Kim, Tae K.
    Rationally targeted, conformationally-constrained, oxetane modified oligonucleotides are highly efficient gene silencing moleculesIn: Proceedings of National Academy of Sciences, USAArticle in journal (Refereed)
  • 87. Opalinska, Joanna B.
    et al.
    Kalota, Anna
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Damha, Masad
    Gewirtz, Alan M.
    Nucleic acid therapeutics for hematologic malignancies--theoretical considerations2006In: OLIGONUCLEOTIDE THERAPEUTICS / [ed] Tuschl T; Rossi J, 2006, Vol. 1082, p. 124-136Conference paper (Refereed)
    Abstract [en]

    Our work is motivated by the belief that RNA targeted gene silencing agents can be developed into effective drugs for treating hematologic malignancies. In many experimental systems, antisense nucleic acids of various composition, including antisense oligodeoxynucleotides (AS ODNs) and short interfering RNA (siRNA), have been shown to perturb gene expression in a sequence specific manner. Nevertheless, our clinical experience, and those of others, have led us to conclude that the antisense nucleic acids (ASNAs) we, and others, employ need to be optimized with regard to intracellular delivery, targeting, chemical composition, and efficiency of mRNA destruction. We have hypothesized that addressing these critical issues will lead to the development of practical and effective nucleic acid drugs. An overview of our recent work which seeks to addresses these core issues is contained within this review.

  • 88.
    Ossipov, D
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Pradeepkumar, PI
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Holmer, M
    Chattopadhyaya, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Synthesis of [Ru(phen)(2)dppz](2+)-tethered oligo-DNA and studies on the metallointercalation mode into the DNA duplex2001In: JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, ISSN 0002-7863, Vol. 123, no 15, p. 3551-3562Article in journal (Refereed)
    Abstract [en]

    To explore the binding properties of [Ru(phen)(2)dppz](2+) complex (phen = l,10-phenanthroline, dppz = dipyrido[3,2-a:2',3'-c]phenazine) in a sequence-specific manner in DNA duplex. it was tethered through the dppz ligand to a central position as well as

  • 89.
    Ossipov, D
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Zamaratski, E
    Chattopadhyaya, J
    Dipyrido[3,2-a : 2 ',3 '-c]phenazine-tethered oligo-DNA: Synthesis and thermal stability of their DNA center dot DNA and DNA center dot RNA duplexes and DNA center dot DNA center dot DNA triplexes1999In: HELVETICA CHIMICA ACTA, ISSN 0018-019X, Vol. 82, no 12, p. 2186-2200Article in journal (Refereed)
    Abstract [en]

    Dipyrido[3,2-a :2',3'-c]phenazine (dppz) derivatives were conjugated to 9-mer and 18-mer DNA (ODN) at a site without nucleobase, either at the 5'- or 3'-end or at a internucleotide position, via linkers of 7, 12, or 18 atoms lengths. These dppz-linked ODN

  • 90.
    Ossipov, Dimitri
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Aspects of Antisense and Antigene Chemistry of Oligonucleotides Tethered to Intercalators2002Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Synthetic and physicochemical studies on appropriately functionalized ODN-conjugates have been performed to evaluate their abilities to act as antisense agents against RNA or as intramolecular DNA cross-linking agents. Intercalating aromatic systems [phenazine (Pnz), dipyridophenazine (DPPZ)] and metallointercalators such as Ru2+(phen)2(DPPZ) and Ru2+(tpy)(DPPZ)L [where L = chemically or photochemically labile ligand, phen = phenanthroline, tpy = terpyridine], which are covalently tethered to the oligo-deoxynucleotides (ODNs), have been chosen for this purpose. The ODN-conjugates were typically prepared by automated solid phase synthesis using phosphoramidite building blocks, or on solid supports, both functionalized with the chromophore groups. The photosensitive metal complex, Ru2+(tpy)(DPPZ)(CH3CN), has been incorporated by post-synthetic coupling to the amino-linker modified ODNs via an amide bond. The intercalating ability of the tethered chromophores gave enhanced stability of the duplexes and triplexes formed with ODN-conjugates and their complementary targets: DNA, RNA, or double-stranded DNA. The conjugation of DPPZ chromophore to ODN (at 3', 5' or at the middle) led us to incorporate Ru2+(phen)2(DPPZ) through the DPPZ ligand, for the first time. The corresponding (Ru2+-ODN)•DNA duplexes showed dramatic stabilization (ΔTm = 19.4 – 22.0ºC). The CD and DNase I footprinting experiments suggest that the stabilization is owing to metallointercalation by threading of the Ru2+(phen)2 moiety through the ODN•DNA duplex core, thus "stapling" the two helical strands from the minor to major groove. On the other hand, Ru2+(tpy)(DPPZ)(CH3CN)-ODN conjugates represent a new class of oligonucleotides containing the photoactivatible Ru2+ complexes, which can successfully crosslink to the complementary strand. The mechanism of cross-linking upon photoirradiation of [Ru2+(tpy)(DPPZ)(CH3CN)-ODN]•DNA involves in situ conversion to the reactive [Ru2+(tpy)(DPPZ)(H2O)-ODN]•DNA which are subsequently cross-linked through the G residue of the complementary DNA strand. All starting materials and products have been purified by HPLC and/or by PAGE and subsequently characterized by MALDI-TOF as well as ESI mass spectroscopy. Terminal conjugation of the planar Pnz and DPPZ groups through the flexible linkers were also shown to improve thermal stability of the ODN•RNA hybrid duplexes without alteration of the initial AB-type global helical structure as revealed from CD experiments. As a result, RNase H mediated cleavage of the RNA strand in the intercalator-tethered ODN•RNA duplexes was more efficient compared to the natural counterpart. The RNase H cleavage pattern was also found to be dependent on the chemical nature of the chromophore. It appeared that introduction of a tether at the 3'-end of the ODN can be most easily tolerated by the enzyme regardless of the nature of the appending chromophore. The tethered DPPZ group has also been shown to chelate Cu2+ and Fe3+, like phenanthroline group, followed by the formation of redox-active metal complex which cleaves the complementary DNA strand in a sequence-specific manner. This shows that the choice of appropriate ligand is useful to (i) attain improved intercalation giving Tm enhancement, and (ii) sequence-specifically inactivate target RNA or DNA molecules using multiple modes of chemistry (RNase H mediated cleavage, free-radical, oxidative pathways or photocross-linkage).

    List of papers
    1. Synthesis of 1'-Phenazine-Tethered Psicofuranosyl Oligonucleotides: The Thermal Stability and Fluorescence Properties of Their Duplexes and Triplexes
    Open this publication in new window or tab >>Synthesis of 1'-Phenazine-Tethered Psicofuranosyl Oligonucleotides: The Thermal Stability and Fluorescence Properties of Their Duplexes and Triplexes