473290-47-0Relevant academic research and scientific papers
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 H
Li, Qing,Yuan, Fengfeng,Zhou, Chuanzheng,Plashkevych, Oleksandr,Chattopadhyaya, Jyoti
experimental part, p. 6122 - 6140 (2010/11/18)
Figure presented. 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 Tm 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 Tm 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.
Conformationally constrained analogues of diacylglycerol (DAG). Part 19: Asymmetric syntheses of (3R)- and (3S)-3-hydroxy-4,4-disubstituted heptono-1,4-lactones as protein kinase C (PK-C) ligands with increased hydrophilicity
Nacro, Kassoum,Lee, Jeewoo,Barchi Jr., Joseph J,Lewin, Nancy E,Blumberg, Peter M,Marquez, Victor E
, p. 5335 - 5345 (2007/10/03)
The stereospecific introduction of (R)- and (S)-OH groups at position C-3 of two diacylglycerol γ-lactones (DAG-lactones) previously identified as strong protein kinase C (PK-C) ligands is presented. The compounds were designed to investigate whether the extra OH group in a specific orientation could establish an additional hydrogen bond with the C1 domain of PK-C, thus providing a DAG analogue with reduced lipophilicity. The OH groups were introduced following two different diastereoselective multistep syntheses starting from diacetone-D-glucose. The PK-C binding affinities for the new compounds were weaker in comparison to those of the parent compounds, suggesting that the extra OH does not engage efficiently in hydrogen bonding at the receptor.
