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

Journal of Organic Chemistry

Volumn 76, Issue 11, 2011, Pages 4408-4431

  Upadhayaya, Ramshankar ^a   Deshpande, Sachin Gangadhar ^a   Li, Qing ^b   Kardile, Ramakant Asaram ^a   Sayyed, Aftab Yusuf ^a   Kshirsagar, Eknath Kamalakar ^a   Salunke, Rahul Vilas ^a   Dixit, Shailesh Satish ^a   Zhou, Chuanzheng ^b   Földesi, András ^b   Chattopadhyaya, Jyoti ^b  

^a Institute of Molecular Medicine   (India)

^b UPPSALA UNIVERSITY   (Sweden)

Author keywords

[No Author keywords available]

Indexed keywords

ANTISENSE; ANTISENSE OLIGONUCLEOTIDES; BIOCHEMICAL PROPERTIES; BLOOD SERUM; DIASTEREOMERIC; DNAZYME; EXONUCLEASE ACTIVITY; ISOMERIC MIXTURES; LOCKED NUCLEIC ACID; RNA CLEAVAGE; RNASE H; SINGLE SITES; SPECIFIC SITES;

OLIGONUCLEOTIDES; STABILITY;

RNA;

3 (ADENIN 9 YL) 7 HYDROXYL 1 (HYDROXYMETHYL) 5 METHYL 2 OXA BICYCLO[2.2.1]HEPTANE; 3 (N 2 ACETYL O 6 DIPHENYLCARBAMOYLGUANIN 9 YL) 1 BENZYLOXYMETHYL 7 BENZYLOXY 5 METHYL 2 OXA BICYLCO[2.2.1]HEPTANE; 3 (N 2 ACETYL O 6 DIPHENYLCARBAMOYLGUANIN 9 YL) 1 BENZYLOXYMETHYL 7 BENZYLOXY 5 METHYL 2 OXABICYLCO[2.2.1]HEPTANE; 3 (N 2 ACETYLGUANIN 9 YL) 1 (4,4' DIMETHOXYTRITYLOXYMETHYL) 7 HYDROXYL 5 METHYL 2 OXA BICYLCO[2.2.1]HEPTANE; 3 (N 2 ACETYLGUANIN 9 YL) 1 BENZYLOXYMETHYL 7 BENZYLOXY 5 METHYL 2 OXA BICYLCO[2.2.1]HEPTANE; 3 (N 2 ACETYLGUANIN 9 YL) 7 (2 CYANOETHOXYDIISOPROPYLAMINO PHOSPHINOXY) 1 (4,4' DIMETHOXYTRITYLOXYMETHYL) 5 METHYL 2 OXA BICYCLO[2.2.1]HEPTANE; 3 (N 2 ACETYLGUANIN 9 YL) 7 HYDROXYL 1 HYDROXYMETHYL 5 METHYL 2 OXA BICYLCO[2.2.1]HEPTANE; 3 (N 6 BENZOYLADENIN 9 YL) 1 (4,4' DIMETHOXYTRITYLOXY)METHYL 5 METHYL 7 HYDROXYL 2 OXA BICYCLO[2.2.1]HEPTANE; 3 (N 6 BENZOYLADENIN 9 YL) 7 (2 CYANOETHOXY DIISOPROPYLAMINO PHOSPHINOXY) 1 (4,4' DIMETHOXYTRITYLOXY)METHYL 5 METHYL 2 OXA BICYCLO[2.2.1]HEPTANE; 3 (N 6 BENZOYLADENIN 9 YL) 7 BENZYLOXY 1 BENZYLOXYMETHYL 5 METHYL 2 OXA BICYCLO[2.2.1]HEPTANE; 3 (N 6 BENZOYLADENIN 9 YL) 7 HYDROXYL 1 HYDROXYMETHYL 5 METHYL 2 OXA BICYCLO[2.2.1]HEPTANE; 5 METHYLCYTOSINE 1 YL; 7 (N 2 ACETYL O 6 DIPHENYLCARBAMOYLGUANIN 9 YL) 5 BENZYLOXYMETHYL 8 BENZYLOXY 6 OXA BICYCLO[3.2.1]OCTANE; 7 (N 6 BENZOYLADENIN 9 YL) 8 BENZYLOXY 7 BENZYLOXYMETHYL 5 BENZYLOXMETHYL 6 OXA BICYCLO[3.2.1]HEPTANE; 9 (4 C ALLYL 3,5 DI O BENZYL 2 O ACETYL BETA DEXTRO RIBOFURANOSYL) N 2 ACETYL O 6 DIPHENYLCARBAMOYL GUANINE; 9 (4 C ALLYL 3,5 DI O BENZYL 2 O ACETYL BETA DEXTRO RIBOFURANOSYL) N 6 BENZOYLADENINE; 9 (4 C ALLYL 3,5 DI O BENZYL 2 O PHENOXYTHIOCARBONYL BETA DEXTRO RIBOFURANOSYL) N 2 ACETYL O 6 DIPHENYLCARBAMOYLGUANINE; 9 (4 C ALLYL 3,5 DI O BENZYL 2 O PHENOXYTHIOCARBONYL BETA DEXTRO RIBOFURANOSYL) N 6 BENZOYLADENINE; 9 (4 C ALLYL 3,5 DI O BENZYL BETA DEXTRO RIBOFURANOSYL) N 2 ACETYL O 6 DIPHENYLCARBAMOYL GUANINE; 9 ADENINYL; 9 GUANINYL; AMINO ACID DERIVATIVE; ANTISENSE OLIGONUCLEOTIDE; COMPLEMENTARY DNA; DEOXYRIBONUCLEASE; HETERODUPLEX; NUCLEIC ACID BASE; RIBONUCLEASE H; SPLEEN EXONUCLEASE; UNCLASSIFIED DRUG; UNINDEXED DRUG; EXONUCLEASE; LOCKED NUCLEIC ACID; OLIGONUCLEOTIDE; ORGANOPHOSPHORUS COMPOUND; PHOSPHORAMIDOUS ACID; RNA;

ARTICLE; BLOOD SAMPLING; CATALYSIS; CYCLIZATION; DEGRADATION; DIASTEREOISOMER; ENZYME ACTIVITY; ENZYME STABILITY; ESCHERICHIA COLI; HETERONUCLEAR MULTIPLE BOND CORRELATION; HUMAN; ISOMER; NUCLEOTIDE METABOLISM; PROTEIN ANALYSIS; PROTEIN MODIFICATION; PROTEIN STABILITY; PROTEIN SYNTHESIS; PROTEIN TARGETING; RNA ANALYSIS; RNA CLEAVAGE; THERMODYNAMICS; BLOOD; CHEMICAL STRUCTURE; CHEMISTRY; CONFORMATION; DNA DENATURATION; ENZYME SPECIFICITY; ENZYMOLOGY; GENETICS; METABOLISM; NUCLEIC ACID HYBRIDIZATION; NUCLEOTIDE SEQUENCE; TRANSITION TEMPERATURE;

BASE SEQUENCE; CYCLIZATION; ENZYME STABILITY; ESCHERICHIA COLI; EXONUCLEASES; HUMANS; MODELS, MOLECULAR; MOLECULAR CONFORMATION; NUCLEIC ACID DENATURATION; NUCLEIC ACID HYBRIDIZATION; OLIGONUCLEOTIDES; OLIGONUCLEOTIDES, ANTISENSE; ORGANOPHOSPHORUS COMPOUNDS; RIBONUCLEASE H; RNA; SUBSTRATE SPECIFICITY; THERMODYNAMICS; TRANSITION TEMPERATURE;

EID: 79957831766     PISSN: 00223263     EISSN: 15206904     Source Type: Journal    
DOI: 10.1021/jo200073q     Document Type: Article

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61. 50 = 1.13 nM) with 3-4-fold higher stability in human blood serum. Apart from these studies, Punit et al. have studied the potential of carba-LNA (cLNA) versus LNA and methylene-cLNA in cell culture (brain endothelial cells using electroporation) and animal experiments (subchronic dosing schedule in mice). Punit J. Am. Chem. Soc. 2010, 132, 14942-14950 These experiments revealed that carba-LNA were slightly less potent compared to LNA and methylene-cLNA AONs. This particular set of experiments differs in their delivery techniques as the electroporation method has been used to assist the delivery of AONs, while the earlier studies have used lipid-based transfacting agents; therefore, the transfection efficiency of carba-LNA modified AONs should be studied in light of the electroporation technique. It is also clear that it is not always straightforward to understand why particularly modified AONs are more effective than others, especially with such a wide variety of targets and experimental conditions. A number of factors can complicate an oligonucleotides ability to reach its target RNA and inhibit gene expression. Simple explanations might include poor transfection or release from endosomes after cell entry and cellular uptake.