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Novel Pentofuranose Chemistry to Modulate RNA Function
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Chemical Biology. (Chemical Biology)
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Chemical modifications of oligonucleotides provide an important tool to understand how the natural substrate works as well as how to improve their biochemical and biological properties as potential therapeutics and diagnostics. Our carba-LNA (2',4'-carba-bridged Locked Nucleic Acid) modified oligo-DNA or -RNA have been found to be useful to modulate oligo-RNA and -DNA activity. This thesis is based on four papers: Paper I (J. Org. Chem. 2010, 75, 7112-7128) deals with the synthesis of 2',4'-propylene-bridged (Carba-ENA) thymidine and its analogues. These carba-ENA nucleosides have been subsequently incorporated into 15mer antisense oligodeoxynucleotides (AON), and their affinity toward complementary mRNA and DNA, as well as their nuclease resistance and RNase H recruitment capability have been investigated in comparison with those of the native and ENA counterparts. Paper II (J. Org. Chem. 2012, 77, 6855–6872) illustrates the synthesis of dimethylbicyclo[2.2.1]heptane and a diastereomeric mixture of oxabicyclo[2.2.1]heptanes by the free-radical ring-closure reaction approach. The role of steric factors for different chair- and the boat-like transition states was evaluated involving the 5-exo radical ring closure reaction to a tethered olefin. Paper III (J. Org. Chem. 2012, 77, 9747-9755) shows an unusual strain releasing reaction of 1-mesyloxy-8,7-dimethylbicyclo[2.2.1]heptane by a base-promoted substitution at the chiral C3 followed by spontaneous concerted ring opening involving the most strained C2-C3-C4 bonds (with bond angle 94°) and the C2 bridgehead leading to anti-endo elimination of the C1-mesyloxy group by the conjugate base of adenine or thymine to give two diastereomeric C3'(S) and C3'(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene, and a mechanistic rational has been formulated. Paper IV (J. Org. Chem. 2014, 79, 7266−7276) focuses on the diastereospecific synthesis of E/Z bicyclo[2.2.1]heptane-7- and oxabicyclo[2.2.1]heptane-8-oximes and their corresponding C-nitroso derivatives. The comparative kinetic and thermodynamic studies of the conversions of the C-nitroso side products to the required oximes have been delineated leading to the synthesis of desmethyl sugar derivatives.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. , 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1189
Keyword [en]
pentofuranose chemistry, conformationally locked nucleoside, carbocyclic-LNA, bicyclo[2.2.1]heptane
National Category
Natural Sciences
Identifiers
URN: urn:nbn:se:uu:diva-233898ISBN: 978-91-554-9069-0 (print)OAI: oai:DiVA.org:uu-233898DiVA: diva2:754841
Public defence
2014-11-28, A1:104b, Uppsala university , BMC, Husargatan 3, Uppsala, 14:15 (English)
Opponent
Supervisors
Available from: 2014-11-06 Created: 2014-10-13 Last updated: 2015-02-13Bibliographically approved
List of papers
1. Synthesis of 2',4' -Propylene-Bridged (Carba-ENA) Thymidine and Its Analogues: The Engineering of Electrostatic and Steric Effects at the Bottom of the Minor Groove for Nuclease and Thermodynamic Stabilities and Elicitation of RNase H
Open this publication in new window or tab >>Synthesis of 2',4' -Propylene-Bridged (Carba-ENA) Thymidine and Its Analogues: The Engineering of Electrostatic and Steric Effects at the Bottom of the Minor Groove for Nuclease and Thermodynamic Stabilities and Elicitation of RNase H
Show others...
2010 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 75, no 21, 7112-7128 p.Article in journal (Refereed) Published
Abstract [en]

2',4'-Propylene-bridged thymidine (carba-ENA-T) and five 8'-Me/NH2/OH modified carba-ENA-T analogues have been prepared through intramolecular radical addition to C=N of the tethered oxime-ether. These carba-ENA nucleosides have been subsequently incorporated into 15mer oligodeoxynucleotides (AON), and their affinity toward cDNA and RNA, nuclease resistance, and RNase H recruitment capability have been investigated in comparison with those of the native and ENA counterparts. These carba-ENAs modified AONs are highly RNA-selective since all of them led to slight thermal stabilization effect for the AON: RNA duplex, but quite large destabilization effect for the AON:DNA duplex. It was found that different C8' substituents (at the bottom of the minor groove) on carba-ENA-T only led to rather small variation of thermal stability of the AON:RNA duplexes. We, however, observed that the parent carba-ENA-T modified AONs exhibited higher nucleolytic stability than those of the ENA-T modified counterparts. The nucleolytic stability of carba-ENA-T modified AONs can be further modulated by C8' substituent to variable extents depending on not only the chemical nature but also the stereochemical orientation of the C8' substituents: Thus, (1) 8'S-Me on carba-ENA increases the nucleolytic stability but 8'R-Me leads to a decreased effect; (2) 8'R-OH on carba-ENA had little, if any, effect on nuclease resistance hut 8'S-OH resulted in significantly decreased nucleolytic stability; and (3) 8'-NH2 substituted carba-ENA leads to obvious loss in the nuclease resistance. The RNA strand in all of the carba-ENA derivatives modified AON:RNA hybrid duplexes can be digested by RNase HI with high efficiency, even at twice the rate of those of the native and ENA modified counterpart.

National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-134109 (URN)10.1021/jo101207d (DOI)000283531100009 ()
Available from: 2010-12-03 Created: 2010-11-22 Last updated: 2017-12-12Bibliographically approved
2. 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
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: J. Org. Chem., Vol. 77, 6855-6872 p.Article in journal (Refereed) Published
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-233861 (URN)
Available from: 2014-10-11 Created: 2014-10-11 Last updated: 2014-11-06
3. Unusual strain-releasing nucleophilic rearrangement of a bicyclo[2.2.1]heptane system to a cyclohexenyl derivative
Open this publication in new window or tab >>Unusual strain-releasing nucleophilic rearrangement of a bicyclo[2.2.1]heptane system to a cyclohexenyl derivative
2012 (English)In: Journal of Organic Chemistry, ISSN 0022-3263, E-ISSN 1520-6904, Vol. 77, no 21, 9747-9755 p.Article in journal (Refereed) Published
Abstract [en]

We report an unusual strain-releasing reaction of 1-mesyloxy-8,7- dimethylbicyclo[2.2.1]heptane (3) by a base-promoted substitution at the chiral C3 followed by spontaneous concerted ring opening involving the most strained C2-C3-C4 bonds (with bond angle 94°) and the C2 bridgehead leading to anti-endo elimination of the C1-mesyloxy group by the conjugate base of adenine or thymine to give two diastereomeric C3′(S) and C3′(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene: 3 → T-4a + T-4b and 3 → A-5a + A-5b. These products have been unambiguously characterized by detailed 1D and 2D NMR (J-coupling constants and nOe analysis), mass, and UV spectroscopy. Evidence has been presented suggesting that the origin of these diastereomeric C3′(S) and C3′(R) derivatives of 1-thyminyl and 9-adeninyl cyclohexene from 3 is most probably a rearrangement mechanism of a trigonal bipyramidal intermediate formed in the S N2 displacement-ring-opening reaction.

National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-184927 (URN)10.1021/jo301871d (DOI)000311190200034 ()
Available from: 2012-11-19 Created: 2012-11-15 Last updated: 2017-12-07Bibliographically approved
4. 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
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, 7266-7276 p.Article 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

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