| 1. |
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| 2. |
- Földesi, Andras, et al.
(författare)
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Studies towards the large scale chemical synthesis of the precursors of ribonucleosides-3',4',5',5''-2H4 and -2',3',4',5',5''-2H5.
- 2003
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Ingår i: Nucleosides Nucleotides Nucleic Acids. - 1525-7770. ; 22:12, s. 2093-104
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Karimi, Mansoureh, et al.
(författare)
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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
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 77:16, s. 6855-6872
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 4. |
- Karimiahmadabadi, Mansoureh, et al.
(författare)
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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
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 79:16, s. 7266-7276
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 5. |
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| 6. |
- Karimiahmadabadi, Mansoureh, et al.
(författare)
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Unusual strain-releasing nucleophilic rearrangement of a bicyclo[2.2.1]heptane system to a cyclohexenyl derivative
- 2012
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 77:21, s. 9747-9755
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 7. |
- Li, Qing, 1981-, et al.
(författare)
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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 Elicitation
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 8. |
- Semenyuk, Andrey, et al.
(författare)
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Cartridge-based high-throughput purification of oligonucleotides for reliable oligonucleotide arrays
- 2006
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Ingår i: Analytical Biochemistry. - : Elsevier BV. - 0003-2697 .- 1096-0309. ; 356:1, s. 132-141
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Tidskriftsartikel (refereegranskat)abstract
- A novel, cartridge-based procedure for the efficient and irreversible detritylation of oligonucleotides is reported. This method, combined with a process for the elimination of depurinated fragments produces, in a highly parallel fashion, oligonucleotides with better purity than those traditionally obtained using reversed-phase high-performance liquid chromotography purification. Our combined detritylation and purification methodology compares favorably with commercial cartridge-based purification systems. The benefits of working with pure oligonucleotides, with regard to higher signal and better signal linearity, are shown in array-based hybridization experiments.
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| 9. |
- Semenyuk, Andrey, et al.
(författare)
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Synthesis of RNA Using 2'-O-DTM Protection
- 2006
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Ingår i: Journal of the American Chemical Society. - : American Chemical Society (ACS). - 0002-7863 .- 1520-5126. ; 128:38, s. 12356-12357
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Tidskriftsartikel (refereegranskat)abstract
- tert-Butyldithiomethyl (DTM), a novel hydroxyl protecting group, cleavable under reductive conditions, was developed and applied for the protection of 2′-OH during solid-phase RNA synthesis. This function is compatible with all standard protecting groups used in oligonucleotide synthesis, and allows for fast and high-yield synthesis of RNA. Oligonucleotides containing the 2′-O-DTM groups can be easily deprotected under the mildest possible aqueous and homogeneous conditions. The preserved 5′-O-DMTr function can be used for high-throughput cartridge RNA purification.
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| 10. |
- Upadhayaya, RamShankar, et al.
(författare)
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Carba-LNA-5MeC/A/G/T Modified Oligos Show Nucleobase-Specific Modulation of 3′-Exonuclease Activity, Thermodynamic Stability, RNA Selectivity, and RNase H Elicitation : Synthesis and Biochemistry
- 2011
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 76:11, s. 4408-4431
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Tidskriftsartikel (refereegranskat)abstract
- Using the intramolecular 5-exo-5-hexenyl radical as a key cyclization step, we previously reported an unambiguous synthesis of carba-LNA thymine (cLNA-T), which we subsequently incorporated in antisense oligonudeotides (AON) and investigated their biochemical properties [J. Am. Chem. Soc. 2007, 129 (26), 8362-8379]. These cLNA-T incorporated oligos showed specific RNA affinity of +3.5-5 degrees C/modification for AON:RNA heteroduplexes, which is comparable to what is found for those of LNAs (Locked Nucleic Acids). These modified oligos however showed significantly enhanced nuclease stability (ca. 100 times more) in the blood serum compared to those of the LNA modified counterparts without compromising any RNase H recruitment capability. We herein report the synthesis of 5-methylcytosine-1-yl (C-Me), 9-adeninyl (A), and 9-guaninyl (G) derivatives of cLNA and their oligonucleotides and report their biochemical properties as potential RNA-directed inhibitors. In a series of isosequential carba-LNA modified AONs, we herein show that all the cLNA modified AONs are found to be RNA-selective, but the magnitude of RNA-selectivity of 7'-R-Me-cLNA-G (cLNA-G) (Delta T-m = 2.9 degrees C/modification) and intractable isomeric mixtures of 7'-(S/R)-Me-cLNA-T (cLNA-T, Delta T-m = 2.2 degrees C/modification) was found to be better than diastereomeric mixtures of 7'-(S/R)-Me-cLNA-C-Me with trace of cENA-C-Me (cLNA-C-Me, Delta T-m = 1.8 degrees C/modification) and 7'-R-Me-cLNA-A (cLNA-A, Delta T-m = 0.9 degrees C/modification). cLNA-C-Me modified AONs however exhibited the best nuclease stability, which is 4-, 7-, and 20-fold better, respectively, than cLNA-T, cLNA-A, and cLNA-G modified counterparts, which in turn was more than 100 times stable than that of the native. When the modification sites are appropriately chosen in the AONs, the cLNA-A, -G, and -C-Me modified sites in the AON:RNA hybrids can be easily recognized by RNase H, and the RNA strand of the hybrid is degraded in a specific manner, which is important for the design of oligos for therapeutic purposes. The cLNA-C-Me modified AON/RNA, however, has been found to be degraded 4 times faster than cLNA-A and G modified counterparts. By appropriately choosing the carba-LNA modification sites in AON strands, the digestion of AON:RNA can be either totally repressed or be limited to cleavage at specific sites or at a single site only (similar to that of catalytic RNAzyme or DNAzyme). Considering all physico- and biochemical aspects of cLNA modified oligos, the work suggests that the cLNA modified antisense oligos have the potential of being a promising therapeutic candidate due to their (i) higher nucleobase-specific RNA affinity and RNA selectivity, (ii) greatly improved nuclease stability, and (iii) efficient RNase H recruitment capability, which can induce target RNA cleavage in a very specific manner at multiple or at a single site, in a designed manner.
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