TY - JOUR
T1 - Modification of the aminopyridine unit of 2-deoxyaminopyridinyl-pseudocytidine allowing triplex formation at CG interruptions in homopurine sequences
AU - Wang, Lei
AU - Taniguchi, Yosuke
AU - Okamura, Hidenori
AU - Sasaki, Shigeki
N1 - Funding Information:
Grant-in-Aid for Scientific Research (B) [16H05100 to Y.T., 15H04633 to S.S.]; Japan Society for the Promotion of Science (JSPS) for Challenging Exploratory Research [26670056 to Y.T.]; China Scholarship Council [201506220182 to L.W.]. Funding for open access charge: Grant-in-Aid for Scientific Research (B) [16H05100 to Y.T.]. Conflict of interest statement. None declared.
Publisher Copyright:
© The Author(s) 2018.
PY - 2018/9/28
Y1 - 2018/9/28
N2 - The antigene strategy based on site-specific recognition of duplex DNA by triplex DNA formation has been exploited in a wide range of biological activities. However, specific triplex formation is mostly restricted to homo-purine strands within the target duplex DNA, due to the destabilizing effect of CG and TA inversion sites where there is an absence of natural nucleotides that can recognize the CG and TA base pairs. Hence, the design of artificial nucleosides, which can selectively recognize these inversion sites with high affinity, should be of great significance. Recently, we determined that 2-amino-3-methylpyridinyl pseudo-dC (3MeAP-dC) possessed significant affinity and selectivity toward a CG inversion site and showed effective inhibition of gene expression. We now describe the design and synthesis of new modified aminopyridine derivatives by focusing on small chemical modification of the aminopyridine unit to tune and enhance the selectivity and affinity toward CG inversion sites. Remarkably, we have newly found that 2-amino-4-methoxypyridinyl pseudo-dC (4OMeAP-dC) could selectively recognize the CG base pair in all four adjacent base pairs and form a stable triplex structure against the promoter sequence of the human gene including multiple CG inversion sites.
AB - The antigene strategy based on site-specific recognition of duplex DNA by triplex DNA formation has been exploited in a wide range of biological activities. However, specific triplex formation is mostly restricted to homo-purine strands within the target duplex DNA, due to the destabilizing effect of CG and TA inversion sites where there is an absence of natural nucleotides that can recognize the CG and TA base pairs. Hence, the design of artificial nucleosides, which can selectively recognize these inversion sites with high affinity, should be of great significance. Recently, we determined that 2-amino-3-methylpyridinyl pseudo-dC (3MeAP-dC) possessed significant affinity and selectivity toward a CG inversion site and showed effective inhibition of gene expression. We now describe the design and synthesis of new modified aminopyridine derivatives by focusing on small chemical modification of the aminopyridine unit to tune and enhance the selectivity and affinity toward CG inversion sites. Remarkably, we have newly found that 2-amino-4-methoxypyridinyl pseudo-dC (4OMeAP-dC) could selectively recognize the CG base pair in all four adjacent base pairs and form a stable triplex structure against the promoter sequence of the human gene including multiple CG inversion sites.
UR - http://www.scopus.com/inward/record.url?scp=85054358926&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054358926&partnerID=8YFLogxK
U2 - 10.1093/nar/gky704
DO - 10.1093/nar/gky704
M3 - Article
C2 - 30102410
AN - SCOPUS:85054358926
VL - 46
SP - 8679
EP - 8688
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 17
ER -