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  • 1.
    Acharya, P
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Plashkevych, O
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Morita, C
    Yamada, S
    Chattopadhyaya, J
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    A repertoire of pyridinium-phenyl-methyl cross-talk through a cascade of intramolecular electrostatic interactions.2003In: J Org Chem, ISSN 0022-3263, Vol. 68, no 4, p. 1529-38Article in journal (Other scientific)
  • 2.
    Chatterjee, S.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Biochemistry and Organic Chemistry.
    Pathmasiri, W.
    Plashkevych, O.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Honcharenko, D.
    Varghese, O.P.
    Maiti, M.
    Chattopadhyaya, J.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    The chemical nature of the 2'-substituent in the pentose-sugar dictates the pseudoaromatic character of the nucleobase (pKa) in DNA/RNA.2006In: Org. Biomol. Chem., Vol. 4, p. 1675-1686Article in journal (Refereed)
    Abstract
  • 3.
    Chatterjee, Subhrangsu
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Pathmasiri, Wimal
    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.
    Honcharenko, D.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Varghese, O.P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Maiti, M
    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.
    The chemical nature of the 2'-substituent in the pentosesugar dictates the pseudoaromatic character of the nucleobase (pKa) in DNA/RNA2006In: Org Biomol Chem, Vol. 4, p. 1675-1686Article in journal (Refereed)
  • 4.
    Chatterjee, Subhrangsu
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Pathmasiri, Wimal
    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.
    Honcharenko, D.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Varghese, O.P.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Maiti, M
    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.
    The chemical nature of the 2'-substituent in the pentosesugar dictates the pseudoaromatic character of the nucleobase (pKa) in DNA/RNA2006In: Org Biomol Chem, Vol. 4, p. 1675-1686Article in journal (Refereed)
  • 5.
    Chatterjee, Subhrangsu
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Pathmasiri, Wimal
    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.
    Honcharenko, Dmytro
    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.
    Maiti, Mohitosh
    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.
    The chemical nature of the 2' substituent in the pentose-sugar dictates the pseudoaromatic character of the nucleobase (pKa) in DNA/RNA2006In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 9, p. 1675-1686Article in journal (Refereed)
    Abstract [en]

    We here show that the pK(a) (error limit: 0.01 to 0.03 pK(a) unit) of a nucleobase in a nucleotide can be modulated by the chemical nature of the 2'-substituent at the sugar moiety. This has been evidenced by the measurement of nucleobase pK(a) in 47 different model nucleoside 3',5'-bis- and 3'-mono-ethylphosphates. The fact that the electronic character of each of the 2'-substituents ( Fig. 1) alters the chemical shift of the H2' sugar proton, and also alters the pKa of the nucleobase in the nucleotides has been evidenced by a correlation plot of pK(a) of N3 of pyrimidine (T/C/U) or pK(a) of N7 of 9-guaninyl with the corresponding delta H2' chemical shifts at the neutral pH, which shows linear correlation with high Pearson's correlation coefficients ( R = 0.85 - 0.97). That this modulation of the pK(a) of the nucleobase by a 2'-substituent is a through-bond as well as through-space effect has been proven by ab initio determined pK(a) estimation. Interestingly, experimental pK(a)s of nucleobases from NMR titration and the calculated pK(a)s (by ab initio calculations utilizing closed shell HF6-31G** basis set) are linearly correlated with R = 0.98. It has also been observed that the difference of ground and protonated/de-protonated HOMO orbital energies (Delta HOMO, a. u.) for the nucleobases (A/ G/ C/ T/ U) are well correlated with their pK(a)s in different 2'-substituted 3', 5'-bis-ethylphosphate analogs suggesting that only the orbital energy of HOMO can be successfully used to predict the modulation of the chemical reactivity of the nucleobase by the 2'-substituent. It has also been demonstrated that pKa values of nucleobases in 3',5'-bis-ethylphosphates ( Table 1) are well correlated with the change in dipole moment for the respective nucleobases after protonation or de-protonation. This work thus unambiguously shows that alteration of the thermodynamic stability (T-m) of the donor - acceptor complexes [ref. 20], as found with various 2'-modified duplexes in the antisense, siRNA or in triplexes by many workers in the field, is a result of alteration of the pseudoaromatic character of the nucleobases engineered by alteration of the chemical nature of the 2'-substitution.    

  • 6. Chatterjee, Subhrangsu
    et al.
    Pathmasiri, Wimal
    Plashkevych, Oleksandr
    Honcharenko, Dmytro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Varghese, Oommen P
    Maiti, Mohitosh
    Chattopadhyaya, Jyoti
    The Chemical Nature of the 2'-Substituent in the Pentose-Sugar Dictates the Pseudoaromatic Character of the Nucleobase (pKa) in DNA/RNA2006In: Organic & Biomolecular Chemistry, ISSN 1477-0520, Vol. 4, p. 1675-1686Article in journal (Refereed)
  • 7.
    Chatterjee, Subhrangsu
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Pathmasiri, Wimal
    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.
    Honcharenko, Dmytro
    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.
    Maiti, Mohitosh
    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.
    The chemical nature of the 2'-substituent in the pentose-sugar dictates the pseudoaromatic character of the nucleobase (pKa) in DNA/RNA2006In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 4, no 9, p. 1675-1686Article in journal (Refereed)
  • 8. Dutta, Suman
    et al.
    Bhaduri, Nipa
    Upadhayaya, Ram Shankar
    Rastogi, Neha
    Chandel, Sunita G.
    Vandavasi, Jaya Kishore
    Plashkevych, Oleksandr
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Kardile, Ramakant A.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    The R-diastereomer of 6 '-O-toluoyl-carba-LNA modification in the core region of siRNA leads to 24-times improved RNA silencing potency against the HIV-1 compared to its S-counterpart2011In: MedChemComm, ISSN 2040-2503, E-ISSN 2040-2511, Vol. 2, no 11, p. 1110-1119Article in journal (Refereed)
    Abstract [en]

    The modified siRNA with pure [6'(S)-O-(p-toluoyl)-7'(S)-methyl]-carba-LNA [6'(S)-O-toluoyl-jcLNA] at position T(13) displayed an IC(50) of 79.8 nM, which has been found to be nearly 24-times less potent as a HIV-1 RNAi silencing agent against TAR RNA than that of the corresponding pure [6'(R)-O-(ptoluoyl)-7'(S)-methyl]jcLNA [6'(R)-O-(p-toluoyl)-jcLNA] counterpart [IC(50) 3.3 nM]. The later [6'(R)-O-(p-toluoyl)-jcLNAl-modified siRNAs have been found to be nearly 2-fold more efficient as a silencing agent than the corresponding 6'-deoxy-jcLNA modified siRNA [IC(50) 8.1 nM], and also nearly 3-fold more effective as a silencing agent than that of LNA-modified siRNA [IC(50) 11.7 nM], thereby showing that the 6'-carbon center in the jcLNA-modified siRNA in the core region is relatively more exposed to the Ago protein in the RISC with a clear chirality preference for the siRNA cleavage reaction. It is noteworthy that the IC(50) of jcLNA-modified siRNAs are very comparable to that of the native siRNA [1.8 nM]. The jcLNA derivatized siRNAs, however, have a clear advantage of being, in general, considerably more stable in human serum. The main structural difference in duplexes of the antisense strand of the 6'(R or S)-O-(p-toluoyl)-jcLNA modified siRNA and target RNA duplex is found to be the spatial orientation of the 6'(R)-O-toluoyl group, which is exposed towards the edge of the duplex backbone, while the 6'(S) makes the minor groove relatively inaccessible for the Ago protein in the RISC. Clearly, any further C6'-modification in jcLNA-modified siRNAs with any hydrophobic group for tighter binding and cleavage or for cross-linking in the core region should preferably be done in the 6'(R)-stereochemistry.

  • 9.
    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)
  • 10.
    Honcharenko, Dmytro
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Varghese, Oommen P
    Plashkevych, Oleksandr
    Barman, Jharna
    Chattopadhyaya, Jyoti
    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, Vol. 71, p. 299-314Article in journal (Refereed)
  • 11.
    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)
  • 12.
    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.

  • 13.
    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)
  • 14.
    Li, Qing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Plashkevych, Oleksandr
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Upadhayaya, RamShankar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Deshpande, Sachin Gangadhar
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Földesi, Andras
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    The Physicochemical Properties of DNA-RNA Duplexes Containing Pure 7′R-Me- or 7′S-Me-Carba-LNA Derivatives of A, G, 5-MeC or T in the DNA Strand: Diastereomer Specific Comparison of The 3′-Exonuclease Stability and RNase H ElicitationIn: Article in journal (Refereed)
    Abstract [en]

       Recently, the intramolecular 5-exo-5-hexenyl free-radical cyclization gave access to 2′, 4′-locked carba-LNAs with different nucleobase moieties, i.e. 7′S- and 7′R-Me-cLNA-A, -G, -MeC and -T nucleosides (J. Am. Chem. Soc. 2007, 129, 8362-8379; J. Org. Chem. 2011, 76, 4408-4431). In these studies, diastereomeric mixtures of 7′S/R-Me-cLNA-MeC and -T and diastereomerically pure 7′R-Me-cLNA-A and -G have been incorporated into antisense oligonucleotides (AONs) for biological evaluations. These cLNA modified oligos have shown to have comparable RNA affinity and highly improved nuclease and blood serum stabilities relative to that of their LNA modified counterparts. In order to fully understand the spatial effect of diastereomeric orientation of 7′-methyl group in cLNA-A/G/MeC/T on the RNA affinity, nuclease stability and RNase H elicitation efficiency, we have synthesized and preparatively HPLC separated and tested each of the 7′S- (minor) and 7′R- (major) pure diastereomer of 7′S/R-Me-cLNA-A/G/MeC/T nucleosides. Incorporation into oligos of each pure diastereomer of cLNA led to higher RNA affinity (1-4°C/mod).  Tm increase was found to be dependent both on the modification site in the AON as well as whether it is 7′S or 7′R modified cLNA is incorporated. RNA selectivity (DDTm) was found to be in the range of 3.1-6.7°C compared to DDTm of 2.7°C for the native counterpart. The Tm variations modulated by 7′S- and 7′R-Me-cLNAs in the AON have been found to be sequence and position-dependent. Molecular dynamics (MD) simulations of DNA-RNA duplexes with AON2 and AON5, with pure diastereomer incorporated at the 7th position of the AON strand from 3′-end, revealed that both 7′S- and 7′R-Me-cLNA-A modifications have only small local effect on stacking and hydrogen bonding within the duplexes, with Watson-Crick base-pairing remained intact during 98-100% duration of the MD simulations. It has been however found that the Tm of each of the modified heteroduplex is dictated by the individual solvation energy (CPCM) of the 7′S- or 7′R-Me-cLNA diastereomer of A, G, MeC or T nucleobase. This demonstrates that the major factor behind variation in the thermal stabilities of the 7′R- or 7′S-Me-cLNA modified AON-RNA duplexes lies in the intrinsic hydrophobicity, hence its relative solvation energy, inherent in the 7′R- vis-a-vis 7′S-Me-cLNA modified monomer blocks, compared to those of the native and LNA counterparts. We have also found that AONs containing 7′S- and 7′R-Me-cLNA-MeC modifications exhibited unprecedented nuclease stabilities: the most stable AON is the one that contains 7′S-Me-cLNA-MeC, which is ~40 times more stable towards 3′-exonuclease (SVPDE) than 7′S- and 7′R-Me-cLNA-T modified AONs, which was in turn much more stable than 7′S- and 7′R-Me-cLNA-A and G modified counterparts. It is noteworthy that 7′S-methyl group of cLNAs endows the AON strand with more nuclease stability than that of 7′R configured counterpart when compared within the same nucleobase. Thus the carba-LNA modified AONs show nucleobase-dependent activity in the following order: MeC > T > A > G, regardless of 7′S- or 7′R-configurations in the carba-LNA. All of the cLNA and LNA modified AON/RNA hybrids can elicit RNase H activity with similar or even more enhanced rates of digestion by E. coli RNase H1 compared to that of the native AON/RNA. The cleavage rates and patterns of modified AON/RNA hybrids by E. coli RNase H1 are only correlated with the modification site in AON sequence of AON/RNA hybrids, but irrelevant to the structural features of incorporated modifications.

  • 15.
    Li, Qing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Yuan, Fengfeng
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Zhou, Chuanzheng
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Plashkevych, Oleksandr
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Free-Radical Ring Closure to Conformationally Locked alpha-L-Carba-LNAs and Synthesis of Their Oligos: Nuclease Stability, Target RNA Specificity, and Elicitation of RNase H2010In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 18, p. 6122-6140Article in journal (Refereed)
    Abstract [en]

    A new class of conformationally constrained nucleosides, alpha-L-ribo-carbocyclic LNA thymidine (alpha-L-carba-LNA-T, LNA is an abbreviation of locked nucleic acid) analogues and a novel "double-locked" alpha-L-ribo-configured tetracyche thymidine (6,7'-methylene-bridged-alpha-L-carba-LNA-T) in which both the sugar puckering and glyeosidic torsion are simultaneously constrained, have been synthesized through a key step involving 5-exo free-radical intramolecular cyclization. These alpha-L-carba-LNA analogues have been subsequently transformed to corresponding phosphoramidites and incorporated into isosequential antisense oligonucleotides (AONs), which have then been examined for the thermal denaturation of their duplexes, nuclease stability, and RNase H recruitment capabilities. Introduction of a single 6',7'-substituted alpha-L-carba-LNA-T modification in the AON strand of AON/RNA heteroduplex led to T-m reduction by 2-3 degrees C as compared to the native heteroduplex, whereas the parent 2'-oxa-alpha-L-LNA-T modification at the identical position in the AON strand has been found to lead to an increase in the T-m by 3-5 degrees C. This suggests that the 6' and 7' substitutions lead to much reduced thermal stability for the modified heteroduplex, especially the hydrophobic 7'-methyl on alpha-L-carba-LNA, which is located in the major groove of the duplex. All of the AONs incorporating 6',7'-substituted alpha-L-earba-LNA-T have, however, showed considerably improved nuclease stability toward 3'-exonuclease (SVPDE) and in human blood serum compared to the 2'-oxa-alpha-L-LNA-T incorporated AONs. The hybrid duplexes that are formed by 6',7'-substituted alpha-L-carba-LNA-T-modified AONs with complementary RNA have been found to recruit RNase H with higher efficiency than those of the beta-D-LNA-T or beta-D-carba-LNA-T-modified counterparts. These greatly improved nuclease resistances and efficient RNasc H recruitment capabilities elevate the alpha-L-carba-LNA-modified nucleotides into a new class of locked nucleic acids for potential RNA targeting therapeutics.

  • 16.
    Li, Qing
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Yuan, Fengfeng
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Zhou, Chuanzheng
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Plashkevych, Oleksandr
    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 Cell and Molecular Biology, Bioorganic Chemistry.
    Free-Radical Ring Closure to Conformationally Locked α-l-Carba-LNAs and Synthesis of Their Oligos:: Nuclease Stability, Target RNA Specificity, and Elicitation of RNase H2010In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 18, p. 6122-6140Article in journal (Refereed)
    Abstract [en]

    A new class of conformationally constrained nucleosides, α-L-ribo-carbocyclic LNA thymidine (α-L-carba-LNA-T, LNA is an abbreviation of locked nucleic acid) analogues and a novel "double-locked" α-L-ribo-configured tetracyclic thymidine (6,7'-methylene-bridged-α-L-carba-LNA-T) in which both the sugar puckering and glycosidic torsion are simultaneously constrained, have been synthesized through a key step involving 5-exo free-radical intramolecular cyclization. These α-L-carba-LNA analogues have been subsequently transformed to corresponding phosphoramidites and incorporated into isosequential antisense oligonucleotides (AONs), which have then been examined for the thermal denaturation of their duplexes, nuclease stability, and RNase H recruitment capabilities. Introduction of a single 6',7'-substituted α-L-carba-LNA-T modification in the AON strand of AON/RNA heteroduplex led to T(m) reduction by 2-3 °C as compared to the native heteroduplex, whereas the parent 2'-oxa-α-L-LNA-T modification at the identical position in the AON strand has been found to lead to an increase in the T(m) by 3-5 °C. This suggests that the 6' and 7' substitutions lead to much reduced thermal stability for the modified heteroduplex, especially the hydrophobic 7'-methyl on α-L-carba-LNA, which is located in the major groove of the duplex. All of the AONs incorporating 6',7'-substituted α-L-carba-LNA-T have, however, showed considerably improved nuclease stability toward 3'-exonuclease (SVPDE) and in human blood serum compared to the 2'-oxa-α-L-LNA-T incorporated AONs. The hybrid duplexes that are formed by 6',7'-substituted α-L-carba-LNA-T-modified AONs with complementary RNA have been found to recruit RNase H with higher efficiency than those of the β-D-LNA-T or β-D-carba-LNA-T-modified counterparts. These greatly improved nuclease resistances and efficient RNase H recruitment capabilities elevate the α-L-carba-LNA-modified nucleotides into a new class of locked nucleic acids for potential RNA targeting therapeutics.

  • 17.
    Moriou, Céline
    et al.
    CNRS, Inst Chim Subst Nat, Gif Sur Yvette, France.
    Da Silva, Adilson D.
    Univ Fed Juiz de Fora, Dept Quim, ICE, BR-Juiz De Fora, MG, Brazil.
    Vianelli Prado, Marcos Joel
    Univ Fed Juiz de Fora, Dept Quim, ICE, BR-Juiz De Fora, MG, Brazil.
    Denhez, Clément
    Univ Reims, Inst Chim Mol Reims, CNRS, UMR 7312,UFR Pharm, 51 Rue Cognacq Jay, Reims, France; Univ Reims, Multiscale Mol Modelling Platform, UFR Sci Exactes & Nat, Reims, France.
    Plashkevych, Oleksandr
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Molecular Biology.
    Guillaume, Dominique
    Univ Reims, Inst Chim Mol Reims, CNRS, UMR 7312,UFR Pharm, 51 Rue Cognacq Jay, Reims, France.
    Clivio, Pascale
    Univ Reims, Inst Chim Mol Reims, CNRS, UMR 7312, UFR Pharm, 51 Rue Cognacq Jay, Reims, France.
    C2 '-F Stereoconfiguration As a Puckering Switch for Base Stacking at the Dinucleotide Level2018In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 83, no 4, p. 2473-2478Article in journal (Refereed)
    Abstract [en]

    Fluorine configuration at C2′ of the bis(2′-fluorothymidine) dinucleotide is demonstrated to drive intramolecular base stacking. 2′-β F-Configuration drastically reduces stacking compared to the 2′-α series. Hence, base stacking emerges as being tunable by the C2′-F stereoconfiguration through dramatic puckering variations scrutinized by NMR and natural bond orbital analysis. Accordingly, 2′-β F-isomer photoreactivity is significantly reduced compared to that of the 2′-α F-isomer.

  • 18.
    Plashkevych, O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Physics, Department of Physics.
    Agren, H
    Karlsson, L
    Pettersson, LGM
    Calculations of valence electron binding energies using Kohn-Sham theory and transition potentials2000In: JOURNAL OF ELECTRON SPECTROSCOPY AND RELATED PHENOMENA, ISSN 0368-2048, Vol. 106, no 1, p. 51-63Article in journal (Refereed)
    Abstract [en]

    Motivated by the success in computing X-ray photoelectron binding energies and chemical shifts in the core region we apply the Kohn-Sham density functional and transition potential methodology to calculations of binding energies in the valence electron re

  • 19.
    Plashkevych, O
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Chattopadhyaya, J
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Conformational analysis of antisense 2'-oxetane modified DNA/RNA duplexes as substrates for RNase H2002Report (Other academic)
  • 20.
    Plashkevych, Oleksandr
    et al.
    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.
    Honcharenko, Dmytro
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Pathmasiri, Wimal
    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.
    Chemical and Structural Implications of 1‘,2‘- versus 2‘,4‘- Conformational Constraints in the Sugar Moiety of Modified Thymine Nucleosides2007In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 72, no 13, p. 4716-4726Article in journal (Refereed)
    Abstract [en]

    In order to understand how the chemical nature of the conformational constraint of the sugar moiety in ON/RNA(DNA) dictates the duplex structure and reactivity, we have determined molecular structures and dynamics of the conformationally constrained 1‘,2‘-azetidine- and 1‘,2‘-oxetane-fused thymidines, as well as their 2‘,4‘-fused thymine (T) counterparts such as LNA-T, 2‘-amino LNA-T, ENA-T, and aza-ENA-T by NMR, ab initio (HF/6-31G** and B3LYP/6-31++G**), and molecular dynamics simulations (2 ns in the explicit aqueous medium). It has been found that, depending upon whether the modification leads to a bicyclic 1‘,2‘-fused or a tricyclic 2‘,4‘-fused system, they fall into two distinct categories characterized by their respective internal dynamics of the glycosidic and the backbone torsions as well as by characteristic North-East type sugar conformation (P = 37° ± 27°, φm = 25° ± 18°) of the 1‘,2‘-fused systems, and (ii) pure North type (P = 19° ± 8°, φm = 48° ± 4°) for the 2‘,4‘-fused nucleosides. Each group has different conformational hyperspace accessible, despite the overall similarity of the North-type conformational constraints imposed by the 1‘,2‘- or 2‘,4‘-linked modification. The comparison of pKas of the 1-thyminyl aglycon as well as that of endocyclic sugar-nitrogen obtained by theoretical and experimental measurements showed that the nature of the sugar conformational constraints steer the physicochemical property (pKa) of the constituent 1-thyminyl moiety, which in turn can play a part in tuning the strength of hydrogen bonding in the basepairing.

  • 21.
    Plashkevych, Oleksandr
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology.
    Molecular Structure of the Core-Modified siRNA Duplexes Containing Diastereomeric Pair of [C6′(R)-OH]- versus [C6′(S)-OH]-carba-LNAs Suggests a Model for RNAi Action2011In: Nucleosides, Nucleotides & Nucleic Acids, ISSN 1525-7770, E-ISSN 1532-2335, Vol. 30, no 11, p. 815-825Article in journal (Refereed)
    Abstract [en]

    Molecular structures of native and a pair of modified small interfering RNA-RNA duplexes containing carbocyclic [6'-(R)-OH/7'-(S)-methyl]- and [6'-(S)-OH/7'-(S)-methyl]-carba-LNA-thymine nucleotides, which are two diastereomeric analogs of the native T nucleotide, incorporated at position 13 in the antisense (AS) strand of siRNA, have been simulated using molecular mechanics/dynamics techniques. The main aim of the project has been to find a plausible structural explanation of why modification of siRNA at T(13) position by the [6'(R)-O-(p-Toluoyl)-7' (S)-methyl]-carba-LNA-Thymine [IC(50) of 3.32 +/- 0.17 nM] is ca 24 times more active as an RNA silencing agent against the target HIV-1 TAR RNA than the [6' (S)-O-(p-Toluoyl)-7' (S)-methyl]-counterpart [IC(50) of 79.8 +/- 17 nM] [1]. The simulations reveal that introduction of both C6' (R)-OH and C6' (S)-OH stereoisomers does not lead even to local perturbation of the siRNA-RNA duplex structures compared to the native, and the only significant difference between 6' (S)- and 6' (R)-diastereomers found is the exposure of the 6'-OH group of the 6' (R)-diastereoisomer toward the edge of the duplex while the 6'-hydroxyl group of the 6' (S)-diastereoisomer is somewhat buried in the minor groove of the duplex. This rules out a hypothesis about any possible local distortion by the nature of chemical modification of the siRNA-target the RNA duplex, which might have influenced the formation of the effective RNA silencing complex (RISC) and puts some weight on the hypothesis about the 6'-hydroxy group being directly involved with most probably Ago protein, since it is known from exhaustive X-ray studies [2, 3] that the core residues are indeed involved with hydrogen bonding with the internucleotidyl phosphates.

  • 22.
    Plashkevych, Oleksandr
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Li, Qing
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    How RNase HI (Escherichia coli) promoted site-selective hydrolysis works on RNA in duplex with carba-LNA and LNA substituted antisense strands in an antisense strategy context?2017In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 13, no 5, p. 921-938Article in journal (Refereed)
    Abstract [en]

    A detailed kinetic study of 36 single modified AON-RNA heteroduplexes shows that substitution of a single native nucleotide in the antisense strand (AON) by locked nucleic acid (LNA) or by diastereomerically pure carba-LNA results in site-dependent modulation of RNase H promoted cleavage of complementary mRNA strands by 2 to 5 fold at 5'-GpN-3' cleavage sites, giving up to 70% of the RNA cleavage products. The experiments have been performed using RNase HI of Escherichia coli. The 2nd best cleavage site, being the 5'-ApN-3' sites, cleaves up to 23%, depending upon the substitution site in 36 isosequential complementary AONs. A comparison of the modified AON promoted RNA cleavage rates with that of the native AON shows that sequence-specificity is considerably enhanced as a result of modification. Clearly, relatively weaker 5'-purine (Pu)-pyrimidine (Py)-3' stacking in the complementary RNA strand is preferred (giving similar to 90% of total cleavage products), which plays an important role in RNase H promoted RNA cleavage. A plausible mechanism of RNase H mediated cleavage of the RNA has been proposed to be two-fold, dictated by the balancing effect of the aromatic character of the purine aglycone: first, the locally formed 9-guanylate ion (pK(a) 9.3, similar to 18-20% N1 ionized at pH 8) alters the adjoining sugar-phosphate backbone around the scissile phosphate, transforming its sugar N/S conformational equilibrium, to preferential S-type, causing preferential cleavage at 5'-GpN-3' sites around the center of 20 mer complementary mRNA. Second, the weaker nearest-neighbor strength of 50-Pu-p-Py-30 stacking promotes preferential 5'-GpN-3' and 5'-ApN-3' cleavage, providing similar to 90% of the total products, compared to similar to 50% in that of the native one, because of the cLNA/ LNA substituent effect on the neighboring 50-Pu-p-Py-30 sites, providing both local steric flexibility and additional hydration. This facilitates both the water and water/Mg-2+ ion availability at the cleavage site causing sequence-specific hydrolysis of the phosphodiester bond of scissile phosphate. The enhancement of the total rate of cleavage of the complementary mRNA strand by up to 25%, presented in this work, provides opportunities to engineer a single modification site in appropriately substituted AONs to design an effective antisense strategy based on the nucleolytic stability of the AON strand versus RNase H capability to cleave the complementary RNA strand.

  • 23.
    Pradeepkumar, Pushpangadan I
    et al.
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Cheruku, Pradeep
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Plashkevych, Oleksandr
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Acharya, Parag
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Gohil, Suresh
    Chattopadhyaya, Jyoti
    Uppsala University, Teknisk-naturvetenskapliga vetenskapsområdet, Faculty of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Synthesis, physicochemical and biochemical studies of 1',2'-oxetane constrained adenosine and guanosine modified oligonucleotides, and their comparison with those of the corresponding cytidine and thymidine analogues.2004In: J Am Chem Soc, ISSN 0002-7863, Vol. 126, no 37, p. 11484-99Article in journal (Other scientific)
  • 24.
    Pradeepkumar, Pushpangadan Indira
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Bioorganic Chemistry.
    Cheruku, Pradeep
    Plashkevych, Oleksandr
    Acharya, Parag
    Gohil, Suresh
    Chattopadhyaya, Jyoti
    Synthesis, physicochemical and biochemical studies of 1',2'-oxetane constrained adenosine and guanosine modified oligonucleotides, and their comparison with those of the corresponding cytidine and thymidine analogsIn: Journal of American Chemical SocietyArticle in journal (Refereed)
  • 25.
    Srivastava, Puneet
    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.
    Pathmasiri, Wimal
    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.
    Wenska, Małgorzata
    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.
    Five- and Six-Membered Conformationally Locked 2‘,4‘-Carbocyclic ribo-Thymidines: Synthesis, Structure, and Biochemical Studies2007In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 129, no 26, p. 8362-8379Article in journal (Refereed)
    Abstract [en]

    Two unusual reactions involving the 5-hexenyl or the 6-heptenyl radical cyclization of a distant double bond at C4' and the radical center at C2' of the ribofuranose ring of thymidine have been used as key steps to synthesize North-type conformationally constrained cis-fused bicyclic five-membered and six-membered carbocyclic analogues of LNA (carbocyclic-LNA-T) and ENA (carbocyclic-ENA-T) in high yields. Their structures have been confirmed unambiguously by long range iH-13C NMR correlation (HMBC), TOCSY, COSY, and NOE experiments. The carbocyclic-LNA-T and carbocyclic-ENA-T were subsequently incorporated into the antisense oligonucleotides (AONs) to show that they enhance the Tm of the modified AON/RNA heteroduplexes by 3.5-5 °C and 1.5 °C/modification for carbocyclic-LNA-T and carbocyclic-ENA-T, respectively. Whereas the relative RNase H cleavage rates with carbocyclic-LNA-T, carbocyclic-ENA-T, aza-ENA-T, and LNA-T modified AON/RNA duplexes were found to be very similar to that of the native counterpart, irrespective of the type and the site modification in the AON strand, a single incorporation of carbocyclic-LNA and carbocyclic-ENA into AONs leads to very much more enhanced nuclease stability in the blood serum (stable >48 h) as compared to that of the native (fully degraded <3 h) and the LNA-modified AONs (fully degraded <9 h) and aza-ENA (≈85% stable in 48 h). Clearly, remarkably enhanced lifetimes of these carbocyclic-modified AONs in the blood serum may produce the highly desired pharmacokinetic properties because of their unique stability and consequently a net reduction of the required dosage. This unique quality as well as their efficient use as the AON in the RNase H-promoted cleavage of the target RNA makes our carbocyclic-LNA and carbocyclic-ENA modifications excellent candidates as potential antisense therapeutic agents.

  • 26. Upadhayaya, Ram Shankar
    et al.
    Shinde, Popat D.
    Sayyed, Aftab Y.
    Kadam, Sandip A.
    Bawane, Amit N.
    Poddar, Avijit
    Plashkevych, Oleksandr
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Földesi, Andras
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Chattopadhyaya, Jyoti
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
    Synthesis and structure of azole-fused indeno[2,1-c]quinolines and their anti-mycobacterial properties2010In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 8, no 24, p. 5661-5673Article in journal (Refereed)
    Abstract [en]

    Prompted by our discovery of a new class of conformationally-locked indeno[2,1-c]quinolines as anti-mycobacterials, compounds 2a and 3a (Fig. 1; MIC < 0.39 mu g mL(-1) and 0.78 mu g mL(-1), respectively)(14) with a freely rotating C2-imidazolo substituent, we herein describe the synthesis of pentacyclic azole-fused quinoline derivatives 4 and 5, in which we have restricted the rotation of the C2-imidazolo moiety by fusing it to the adjacent quinoline-nitrogen to give a five-membered fused azole heterocycle. The idea of locking the flexibility of the system by conformational constraint was simply to reduce its entropy, thereby reducing the overall free-energy of its binding to the target receptor. Out of 22 different azole-fused indeno[2,1-c] quinoline derivatives, seven structurally distinct compounds, 9, 15, 17, 25, 27, 28 and 29, have shown 79-99% growth inhibition of Mycobacterium tuberculosis H37Rv at a fixed dose of 6.25 mu g mL(-1). The efficacies of these compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of single dose on day one. Of these, two compounds, 9 and 28, inhibited growth of M. tuberculosis very effectively at MIC < 0.39 mu g mL(-1) (0.89 mu M and 1 mu M, respectively). These active compounds 9, 15, 17, 25, 27, 28 and 29 were screened for their cytotoxic effect on mammalian cells (human monocytic cell line U937), which showed that the human cell survival is almost unperturbed (100% survival), except for compound 25, hence these new compounds with new scaffolds have been identified as potent anti-mycobacterials, virtually with no toxicity. Thus these "hit" molecules constitute our important "leads" for further optimization by structure-activity relationship against TB.

  • 27.
    Varghese, Oommen P.
    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.
    Pathmasiri, Wimal
    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.
    Honcharenko, Dmytro
    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.
    Conformationally constrained 2'-N,4'-C-ethylene-bridged thymidine (aza-ENA-T): synthesis, structure, physical, and biochemical studies of aza-ENA-T-modified oligonucleotides2006In: J. Am. Chem. Soc., Vol. 128, no 47, p. 15173-15187Article in journal (Refereed)
  • 28.
    Varghese, Oommen P.
    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.
    Pathmasiri, Wimal
    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.
    Honcharenko, Dmytro
    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.
    Conformationally Constrained 2'-N,4'-C-Ethylene-Bridged Thymidine (Aza-ENA-T): Synthesis, Structure, Physical, and Biochemical Studies of Aza-ENA-T-Modified Oligonucleotides2006In: Journal of the American Chemical Society, ISSN 0002-7863, E-ISSN 1520-5126, Vol. 128, no 47, p. 15173-15187Article in journal (Refereed)
    Abstract [en]

    The 2'-deoxy-2'-N,4'-C-ethylene-bridged thymidine (aza-ENA-T) has been synthesized using a key cyclization step involving 2'-ara-trifluoromethylsufonyl-4'-cyanomethylene 11 to give a pair of 3',5'-bis-OBn- protected diastereomerically pure aza-ENA-Ts (12a and 12b) with the fused piperidino skeleton in the chair conformation, whereas the pentofuranosyl moiety is locked in the North-type conformation (7 < P < 27 degrees, 44 degrees < phi(m) < 52 degrees). The origin of the chirality of two diastereomerically pure aza-ENA-Ts was found to be due to the endocyclic chiral 2'-nitrogen, which has axial N-H in 12b and equatorial N-H in 12a. The latter is thermodynamically preferred, while the former is kinetically preferred with E-a 25.4 kcal mol(-1), which is thus far the highest observed inversion barrier at pyramidal N-H in the bicyclic amines. The 5'-O-DMTr-aza-ENA-T-3'-phosphoramidite was employed for solid-phase synthesis to give four different singly modified 15-mer antisense oligonucleotides (AONs). Their AON/RNA duplexes showed a T m increase of 2.5-4 degrees C per modification, depending upon the modification site in the AON. The relative rates of the RNase H1 cleavage of the aza-ENA-T-modified AON/RNA heteroduplexes were very comparable to that of the native counterpart, but the RNA cleavage sites of the modified AON/RNA were found to be very different. The aza-ENA-T modifications also made the AONs very resistant to 3' degradation (stable over 48 h) in the blood serum compared to the unmodified AON (fully degraded in 4 h). Thus, the aza-ENA-T modification in the AON fulfilled three important antisense criteria, compared to the native: (i) improved RNA target affinity, (ii) comparable RNase H cleavage rate, and (iii) higher blood serum stability.

  • 29.
    Zhou, Chuanzheng
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Liu, Yi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Andaloussi, Mounir
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Badgujar, Naresh
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Plashkevych, Oleksandr
    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 Cell and Molecular Biology, Bioorganic Chemistry.
    Fine Tuning of Electrostatics Around the Internucleotidic Phosphate through Incorporations of Functionalized 2', 4'-Carbocyclic-LNAs and –ENAs Lead to Significant Modulation of Antisense Properties2009In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 74, no 1, p. 118-134Article in journal (Refereed)
    Abstract [en]

    In the antisense (AS) and RNA interference (RNAi) technologies, the native single-stranded 2'-deoxyoligonucleotides (for AS) or double-stranded RNA (for RNAi) are chemically modified to bind to the target RNA in order to give improved downregulation of gene expression   through inhibition of RNA translation. It is shown here how the fine adjustment of the electrostatic interaction by alteration of the substituents as well as their stereochemical environment around the intemucleotidic phosphodiester moiety near the edge of the minor grove of the antisense oligonucleotides (AON)-RNA heteroduplex can lead to the modulation of the antisense properties. This was demonstrated through the synthesis of various modified carbocyclic-locked nucleic acids (LNAs) and -ethylene-bridged nucleic acids (ENAs) with hydroxyl and/or methyl substituents attached at the carbocyclic pan and their   integration into AONs by solid-phase DNA synthesis. The target affinity toward the complementary RNA and DNA, nuclease resistance, and RNase H elicitation by these modified AONs showed that both the nature of the modification (-OH versus -CH3) and their respective stereochemical orientations vis-a-vis vicinal phosphate play a very important role in modulating the AON properties. Whereas the affinity to the target RNA and the enzymatic stability of AONs were not favored by the hydrophobic and sterically bulky modifications in the center of the minor groove, their positioning at the edge of the minor groove near the phosphate linkage resulted in significantly improved nuclease resisitance without of target affinity. On the other hand, hydrophilic modification, such as a hydroxyl group, close to the phosphate linkage made the internucleotidic phosphodiester especially nucleolytically unstable, and hence was not recommended. The substitutions on the carbocyclic moiety of the carba-LNA and -ENA did not affect significantly the choice of the cleavage sites of RNase H mediated RNA cleavage in the AON/RNA hybrid duplex, but the cleavage rate depended on the modification site in the AON sequence. If the original preferred cleavage site by RNase H was included in the 4-5nt stretch from the 3'-end of the modification site in the AON, decreassed cleavage rate was observed. Upon screening of 52 modified AONs, containing 13 differently modified derivatives at C6' and C7' (or CS') of the carba-LNAs and -ENAs, two excellent modifications in the carba-LNA series were identified, which synergistically gave outstanding antisense properties such as the target RNA affinity, nuclease resistance, and RNase H activity and were deemed to be ideal candidates as potential antisense or siRNA therapeutic agents.

  • 30.
    Zhou, Chuanzheng
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Plashkevych, Oleksandr
    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 Cell and Molecular Biology, Bioorganic Chemistry.
    Double Sugar and Phosphate Backbone-constrained Nucleotides: Synthesis, Structure, Stability and Their Incorporation into Oligodeoxynucleotides2009In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 74, no 9, p. 3248-3265Article in journal (Refereed)
    Abstract [en]

    Two diastereomerically pure carba-LNA dioxaphosphorinane nucleotides [(S-p)- or (R-p)-D-2-CNA], simultaneously conformationally locked at the sugar and the phosphate backbone, have been designed and synthesized. Structural studies by NMR as well as by ab initio   calculations showed that in (S-p)- and (R-p)-D-2-CNA the Mowing occur: (i) the sugar is locked in extreme North-type conformation with P = 11 degrees and Phi(m) (ii) the six-membered 1,3,2-dioxaphosphorinane ring adopts a half-chair conformation; (iii) the fixed phosphate backbone delta, epsilon, and zeta torsions were found to be delta [gauch(+)],   epsilon (cis), zeta[anticlinal(+)] for (S-p)-D-2-CNA, and delta [gaitche(+)], epsilon(cis), zeta[anticlittal(-)] for (R-p)-D-2-CNA. It   has been found that F- ion can catalyze the isomerization of pure (S-p)-D-2-CNA or (R-p)-D-2-CNA to give an equilibrium mixture (K =   1.94). It turned out that at equilibrium concentration the (S-p)-D-2-CNA isomer is preferred over the (R-p)-D-2-CNA isomer by 0.39 kcal/mol. The chemical reactivity of the six-membered   dioxaphosphorinane ring in D-2-CNA was found to be dependent on the   internucleotidic phosphate stereochemistry. Thus, both (Sp)- and  (Rp)-D2-CNA dimers (17a and 17b) were very labile toward nucleophile attack in concentrated aqueous ammonia [t(1/2) = 12 and 6 min, respectively] to give carba-LNA-6',5'-phosphodiester (21) approximate   to 70-90%, carba-LNA-3',5'-phosphodiester (22) approximate to 10%, and   carba-LNA-6',3'-phosphodiester (23) < 10%. In contrasts the (S-p)-D-2-CNA was about 2 times more stable than (Rp)-D2-CNA under hydrazine hydrate/pyficfine/AcOH (pH = 5.6) [t(1/2) = 178 and 99 h, respectively], which was exploited in the deprotection of pure (S-p)-D-2-CNA incorporated antisense oligodeoxynucleotides (AON). Thus, after removal of the solid supports from the (S-p)-D-2-CNA-modified AON by BDU/MeCN, they were treated with hydrazine hydrate in pyridine/AcOH to give pure AONs in 35-40% yield, which was unequivocally   characterized by MALDI-TOF to show that they have an intact six-membered dioxaphosphorinane ring. The effect of pure (S-p)-D-2-CNA   niodification in the AONs was estimated by complexing to the complementary RNA and DNA strands by the thermal denaturation studies. This showed that this cyclic phosphotriester modification destabilizes   the AON/DNA and AON/RNA duplex by about -6 to -9 degrees C/modification. Treatment of (Sp)-D-2-CNA-modified AON with concentrated aqueous ammonia gave cwba-LNA-6',5'-phosphodiester modified AON (similar to 80%) plus a small amount of carba-LNA-3',5'-Phosphodiester-modified AON (similar to 20%). It is noteworthy that Carba-LNA-3',5'-phosphodiester modification stabilized  the AON/RNA duplex by +4 degrees C/modificafion (J. Org. Chem. 2009, 74, 118), whereas carba-LNA-6', 5'-phosphodiester modification   destabilizes both AON/RNA and AON/DNA significantly (by -10 to -19 degrees C/modification), which, as shown in our comparative CD studies, that the cyclic phosphotriester modified AONs as well as carba-LNA-6'.5'-phosphodiester modified AONs are much more weakly   stacked than carba-LNA-3',5'-phosphodiester-modified AONs.

  • 31.
    Zhou, Chuanzheng
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Plashkevych, Oleksandr
    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 Cell and Molecular Biology, Bioorganic Chemistry.
    Unusual Radical 6-endo Cyclization to the Carbocyclic-ENA and Elucidation of its Solution Conformation by 600 MHz NMR and ab initio Calculations2008In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 6, no 24, p. 4627-4633Article in journal (Refereed)
    Abstract [en]

    In our previous paper (J. Am. Chem. Soc., 2007, 129, 8362), we reported the synthesis of 7'-Me-Carba-LNA and 8'-Me-Carba-ENA thymidine through 5-hexenyl or 6-heptenyl radical cyclization. Both 5-hexenyl and 6-heptenyl radical cyclized exclusively in the exo form, giving   unwanted exocyclic C7'-methyl group. In the present study, we showed that the regioselectivity of the 5-hexenyl radical cyclization could be favorably tuned by introduction of a hydroxyl group beta to the olefinic double bond, yielding about 9% of the 6-endo cyclization product. Possible pathways to give 6-endo cyclization product 9 compared to the intermediates responsible to give the 5-exo cyclization product 5 has been discussed. Based on this unique 6-endo cyclization strategy, a carbocyclic ENA modified thymidine (carba-ENA) has been successfully synthesized, which also enabled us to perform its full solution conformation analysis by using NMR (H-1 at 600 MHz) observables for the first time

  • 32.
    Zhou, Chuanzheng
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Plashkevych, Oleksandr
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Liu, Yi
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Bioorganic Chemistry.
    Badgujar, Naresh
    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 Cell and Molecular Biology, Bioorganic Chemistry.
    Synthesis and Structure of New Methylene-bridged hexopyranosyl nucleoside (BHNA)2009In: Heterocycles, ISSN 0385-5414, E-ISSN 1881-0942, Vol. 78, no 7, p. 1715-1728Article in journal (Refereed)
    Abstract [en]

    A new member of hexopyranosyl nucleoside family, methylene-bridged   hexopyranosyl nucleoside (BHNA), has been synthesized through   generation of carbon radical at C6' in [6'S-Me, 7'S-Me]-carba-LNA T  nucleoside, followed by rearrangement to C4' radical which was quenched   by hydrogen atom to give BHNA. The stereoelectronic requirement for   this unusual radical rearrangement has been elucidated by chemical   model building and ab intio calculations to show that the coplanarity of the single electron occupied p-orbital at C6' with sigma*(O4'-C4')   plays an important role for the rearrangement reaction to take place.   The solution structure of BHNA has also been studied using NMR as well   as by ab initio calculations. The new six-membered pyranosyl ring in  BHNA, unlike other known hexopyranosyl nucleosides, adopts a twist   conformation, with base moiety occupying the axial position while  3'-hydroxymethyl and 4'-hydroxyl occupying the equatorial position.

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