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Chattopadhyaya, J
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Publications (10 of 52) Show all publications
Moriou, C., Da Silva, A. D., Vianelli Prado, M. J., Denhez, C., Plashkevych, O., Chattopadhyaya, J., . . . Clivio, P. (2018). C2 '-F Stereoconfiguration As a Puckering Switch for Base Stacking at the Dinucleotide Level. Journal of Organic Chemistry, 83(4), 2473-2478
Open this publication in new window or tab >>C2 '-F Stereoconfiguration As a Puckering Switch for Base Stacking at the Dinucleotide Level
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2018 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 83, no 4, p. 2473-2478Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
AMER CHEMICAL SOC, 2018
National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-351016 (URN)10.1021/acs.joc.7b03186 (DOI)000427094200085 ()29364674 (PubMedID)
Funder
Swedish Research CouncilEU, European Research CouncilNational Supercomputer Centre (NSC), Sweden
Available from: 2018-05-24 Created: 2018-05-24 Last updated: 2018-05-25Bibliographically approved
Togtema, M., Jackson, R., Grochowski, J., Villa, P. L., Mellerup, M., Chattopadhyaya, J. & Zehbe, I. (2018). Synthetic siRNA targeting human papillomavirus 16 E6: a perspective on in vitro nanotherapeutic approaches. Nanomedicine, 13(4), 455-474
Open this publication in new window or tab >>Synthetic siRNA targeting human papillomavirus 16 E6: a perspective on in vitro nanotherapeutic approaches
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2018 (English)In: Nanomedicine, ISSN 1743-5889, E-ISSN 1748-6963, Vol. 13, no 4, p. 455-474Article in journal, Editorial material (Other academic) Published
Abstract [en]

High-risk human papillomaviruses infect skin and mucosa, causing approximately 5% of cancers worldwide. In the search for targeted nanotherapeutic approaches, siRNAs against the viral E6 transcript have been molecules of interest but have not yet seen successful translation into the clinic. By reviewing the past approximately 15 years of in vitro literature, we identify the need for siRNA validation protocols which concurrently evaluate ranges of key treatment parameters as well as characterize downstream process restoration in a methodical, quantitative manner and demonstrate their implementation using our own data. We also reflect on the future need for more appropriate cell culture models to represent patient lesions as well as the application of personalized approaches to identify optimal treatment strategies.

Keywords
cell culture models, cervical cancer, dicer substrate siRNA, E6 oncogene, human papillomavirus 16, RNA interference, siRNA, siRNA therapy
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
urn:nbn:se:uu:diva-355835 (URN)10.2217/nnm-2017-0242 (DOI)000427394600007 ()29382252 (PubMedID)
Available from: 2018-07-06 Created: 2018-07-06 Last updated: 2018-07-06Bibliographically approved
Plashkevych, O., Li, Q. & Chattopadhyaya, J. (2017). 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?. Molecular Biosystems, 13(5), 921-938
Open this publication in new window or tab >>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?
2017 (English)In: Molecular Biosystems, ISSN 1742-206X, E-ISSN 1742-2051, Vol. 13, no 5, p. 921-938Article in journal (Refereed) Published
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.

National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-323445 (URN)10.1039/c6mb00762g (DOI)000400659600011 ()28352859 (PubMedID)
Funder
Swedish Research Council
Available from: 2017-07-04 Created: 2017-07-04 Last updated: 2018-01-13Bibliographically approved
Moriou, C., Denhez, C., Plashkeyych, O., Coantic-Castex, S., Chattopadhyaya, J., Guillaume, D. & Clivio, P. (2015). A Minute Amount of S-Puckered Sugars Is Sufficient for (6-4) Photoproduct Formation at the Dinucleotide Level. Journal of Organic Chemistry, 80(1), 615-619
Open this publication in new window or tab >>A Minute Amount of S-Puckered Sugars Is Sufficient for (6-4) Photoproduct Formation at the Dinucleotide Level
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2015 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 80, no 1, p. 615-619Article in journal (Refereed) Published
Abstract [en]

The di-2'-alpha-fluoro analogue of thymidylyl(3',5')thymidine, synthesized to probe the effect of a minimum amount of S conformer on the photoreactivity of dinucleotides, is endowed with only 3% and 8% of S sugar conformation at its 5'- and 3'-end, respectively. This analogue gives rise to the (6-4) photoproduct as efficiently as the dithymine dinucleotide (74% and 66% at the 5'- and 3'-end, respectively) under 254 nm. Our results suggest that the 5'-N, 3'-S conformer gives rise to the (6-4) photoproduct.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-244488 (URN)10.1021/jo502230n (DOI)000347506400062 ()
Available from: 2015-02-24 Created: 2015-02-17 Last updated: 2017-12-04Bibliographically approved
Karimiahmadabadi, M., Erfan, S., Földesi, A. & Chattopadhyaya, J. (2014). Distal Two-Bond versus Three-Bond Electronegative Oxo-Substituent Effect Controls the Kinetics and Thermodynamics of the Conversion of a C-Nitroso Function to the Corresponding Oxime in the Conformationally Locked Pentofuranose (Bicyclo[2.2.1]heptane) System. Journal of Organic Chemistry, 79(16), 7266-7276
Open this publication in new window or tab >>Distal Two-Bond versus Three-Bond Electronegative Oxo-Substituent Effect Controls the Kinetics and Thermodynamics of the Conversion of a C-Nitroso Function to the Corresponding Oxime in the Conformationally Locked Pentofuranose (Bicyclo[2.2.1]heptane) System
2014 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 79, no 16, p. 7266-7276Article in journal (Refereed) Published
Abstract [en]

We report the high-yielding and scalable diastereospecific synthesis of isomeric bicyclo [2.2.1]heptane-7- and -8-oximes and their corresponding C-nitroso derivatives, which are the key intermediates for the synthesis of carbanucleosides. Neither the (C7-R)-nitroso- nor (C8-S)-nitrosobicycloheptane system requires any external base in DMSO-d(6) to afford the corresponding oxime, and no reverse isomerization from the oxime to the C-nitroso compound was observed. The conversion of the (C8-S)-nitroso compound to the E/Z-oximes was similar to 8 times faster (at 40 degrees C) than that of the (C7-R)-nitroso derivative. The mechanism involves first-order reaction kinetics for the conversion of either the (C7-R)- or (C8-S)-nitroso derivative to the corresponding E/Z-oximes. The lower rate of conversion of the (C7-R)-nitroso compound to the corresponding crimes compared with that of the (C8-S)-nitroso derivative is attributed to the fact that the acidic H8 ionizing center is two bonds away from the OPMB group on C1 in the latter whereas H7 is three bonds away from the C1 OMe group in the former, making the effect of the electron-withdrawing group on C1 stronger in the latter.

National Category
Organic Chemistry
Identifiers
urn:nbn:se:uu:diva-231998 (URN)10.1021/jo500266k (DOI)000340517600002 ()
Available from: 2014-09-15 Created: 2014-09-12 Last updated: 2017-12-05Bibliographically approved
Upadhayaya, R. S., Dixit, S. S., Földesi, A. & Chattopadhyaya, J. (2013). New antiprotozoal agents: Their synthesis and biological evaluations. Bioorganic & Medicinal Chemistry Letters, 23(9), 2750-2758
Open this publication in new window or tab >>New antiprotozoal agents: Their synthesis and biological evaluations
2013 (English)In: Bioorganic & Medicinal Chemistry Letters, ISSN 0960-894X, E-ISSN 1090-2120, Vol. 23, no 9, p. 2750-2758Article in journal (Refereed) Published
Abstract [en]

Here we report identification of new lead compounds based on quinoline and indenoquinolines with variable side chains as antiprotozoal agents. Quinolines 32, 36 and 37 (Table 1) and indenoquinoline derivatives 14 and 23 (Table 2) inhibit the in vitro growth of the Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma brucei rhodesiense subspecies and Leishmania infantum with IC50 = 0.25 mu M. These five compounds have superior activity to that of the front-line drugs such as benznidazole, nifurtimox and comparable to amphotericin B. Thus these compounds constitute new 'leads' for further structure-activity studies as potential active antiprotozoal agents. 

Keywords
Antiprotozoal agents, Trypanosoma, Leishmania, Parasite inhibitors, Conformationally constrained quinoline
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-200043 (URN)10.1016/j.bmcl.2013.02.054 (DOI)000317333900054 ()
Available from: 2013-05-23 Created: 2013-05-20 Last updated: 2017-12-06Bibliographically approved
Martinez-Montero, S., Fernandez, S., Sanghvi, Y. S., Chattopadhyaya, J., Ganesan, M., Ramesh, N. G., . . . Ferrero, M. (2012). Design and Divergent Synthesis of Aza Nucleosides from a Chiral Imino Sugar. Journal of Organic Chemistry, 77(10), 4671-4678
Open this publication in new window or tab >>Design and Divergent Synthesis of Aza Nucleosides from a Chiral Imino Sugar
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2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 10, p. 4671-4678Article in journal (Refereed) Published
Abstract [en]

Several novel nucleoside analogues as potential inhibitors of glycosidases and purine nucleoside phosphorylase (PNP) have been synthesized via selective coupling of an appropriate nucleobase at different positions of an orthogonally protected imino sugar as a common precursor. This synthetic strategy offers a straightforward protocol for the assembly of imino sugar containing nucleosides, establishing a new repertoire of molecules as potential therapeutics.

National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-175612 (URN)10.1021/jo3004452 (DOI)000304129400017 ()
Available from: 2012-06-12 Created: 2012-06-11 Last updated: 2017-12-07Bibliographically approved
Zhou, C. & Chattopadhyaya, J. (2012). Intramolecular Free-Radical Cyclization Reactions on Pentose Sugars for the Synthesis of Carba-LNA and Carba-ENA and the Application of Their Modified Oligonucleotides as Potential RNA Targeted Therapeutics. Chemical Reviews, 112(7), 3808-3832
Open this publication in new window or tab >>Intramolecular Free-Radical Cyclization Reactions on Pentose Sugars for the Synthesis of Carba-LNA and Carba-ENA and the Application of Their Modified Oligonucleotides as Potential RNA Targeted Therapeutics
2012 (English)In: Chemical Reviews, ISSN 0009-2665, E-ISSN 1520-6890, Vol. 112, no 7, p. 3808-3832Article, review/survey (Refereed) Published
National Category
Chemical Sciences
Identifiers
urn:nbn:se:uu:diva-182336 (URN)10.1021/cr100306q (DOI)000306298800005 ()
Available from: 2012-10-09 Created: 2012-10-09 Last updated: 2017-12-07Bibliographically approved
Dixit, S. S., Upadhayaya, R. S. & Chattopadhyaya, J. (2012). New parasite inhibitors encompassing novel conformationally-locked 5 '-acyl sulfamoyl adenosines. Organic and biomolecular chemistry, 10(30), 6121-6129
Open this publication in new window or tab >>New parasite inhibitors encompassing novel conformationally-locked 5 '-acyl sulfamoyl adenosines
2012 (English)In: Organic and biomolecular chemistry, ISSN 1477-0520, E-ISSN 1477-0539, Vol. 10, no 30, p. 6121-6129Article in journal (Refereed) Published
Abstract [en]

We describe the design, synthesis and biological evaluation of conformationally-locked 5'-acyl sulfamoyl adenosine derivatives as new parasitic inhibitors against Trypanosoma and Leishmania. The conformationally-locked (3'-endo, North-type) nucleosides have been synthesized by covalently attaching a 4'-CH2-O-2' bridge (Fig. 2) across C2'-C4' of adenosine in order to reduce the conformational flexibility of the pentose ring. This is designed to decrease the entropic penalty for complex formation with the target protein, which may improve free-energy of stabilization of the complex leading to improved potency. Conformationally-locked 5'-acyl sulfamoyl adenosine derivatives (16-22) were tested against parasitic protozoans for the first time in this work, and showed potent inhibition of Trypanosoma cruzi, Trypanosoma brucei, Trypanosoma rhodesiense and Leishmania infantum with IC50 = 0.25-0.51 mu M. In particular, the potent 5'-pentanyl acyl sulfamoyl adenosine derivative 17 (IC50 = 0.25 mu M) against intracellular L. infantum amastigotes and Trypanosoma subspecies is interesting in view of its almost insignificant cytotoxicity in murine macrophage host cells (CC50 >4 mu M) and in diploid human fibroblasts MRC-5 cell lines (CC50 4 mu M). This work also suggests that variable alkyl chain length of the acyl group on the acylsulfamoyl side chain at 5' can modulate the toxicity of 5'-O-sulfamoylnucleoside analogues. This conformationally-locked sulfamoyl adenosine scaffold presents some interesting possibilities for further drug design and lead optimization.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-179236 (URN)10.1039/c2ob25879j (DOI)000306276800062 ()
Available from: 2012-12-13 Created: 2012-08-10 Last updated: 2017-12-07Bibliographically approved
Karimi, M., Erfan, S., Földesi, A. & Chattopadhyaya, J. (2012). Steric Effects in the Tuning of the Diastereoselectivity of the Intramolecular Free-Radical Cyclization to an Olefin As Exemplified through the Synthesis of a Carba-Pentofuranose Scaffold. Journal of Organic Chemistry, 77(16), 6855-6872
Open this publication in new window or tab >>Steric Effects in the Tuning of the Diastereoselectivity of the Intramolecular Free-Radical Cyclization to an Olefin As Exemplified through the Synthesis of a Carba-Pentofuranose Scaffold
2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 16, p. 6855-6872Article in journal (Refereed) Published
Abstract [en]

Two free-radical cyclization reactions with the radical at the chiral C4 of the pentose sugar and the intramolecularly C1-tethered olefin (on radical precursors 8 and 17) gave a new diastereospecific C4-C8 bond in dimethylbicyclo[2.2.1]heptane 9, whereas the new C4-C7 bond in 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b gave trans and cis diastereomers, in which the chirality of the C4 center is fully retained as that of the starting material. It has been shown how the chemical nature of the fused carba-pentofuranose scaffolds, dimethylbicyclo[2.2.1]heptane 9 vis-a-vis 7-methyl-2-oxabicyclo[2.2.1]heptanes 18a/18b (C7-Me in the former versus 2-O- in the latter), dictates the stereochemical outcome both at the Grignard reaction step as well as in the free-radical ring-closure reaction. The formation of pure 1,8-trans-bicyclo[2.2.1]heptane 9 from 8 suggests that the boat-like transition state is favored due to the absence of steric clash of the bulky 1(S)-O-p-methoxybenzyl (PMB) and 7(R)-Me substituents (both in the alpha-face) with that of the 8(R)-CH2 center dot radical in the beta-face. The conversion of 17 -> 18a-7(S) and 18b-7(R) in 6:4 ratio shows that the participation of both the chair- and the boat-like transition states is likely.

Keywords
THERMODYNAMIC STABILITIES; CARBOCYCLIC NUCLEOSIDE; MODIFIED OLIGOS; RNASE-H; LNA; OLIGONUCLEOTIDES; ELICITATION; SELECTIVITY; MODULATION; ADENOSINE
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-183898 (URN)10.1021/jo300936g (DOI)000307526700015 ()
Available from: 2012-11-07 Created: 2012-11-05 Last updated: 2017-12-07Bibliographically approved
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