DNA triple helix formation will be examined in a systematic manner for by exploiting various base analogues in order to study a series of base triplet recognition motifs. For example, we will examine eight different recognition motifs for the targeting of homopurine sequences. These eight motifs include two motifs each of (i) the antiparallel-stranded purine- purine-pyrimidine motif (e.g., see graphic below), (ii) the antiparallel- stranded pyrimidine-purine-pyrimidine motif, (iii) the antiparallel- stranded mixed base motif, and (iv) the parallel-stranded pyrimidine- purine-pyrimidine motif. Various nucleoside analogues will be prepared as needed in order to characterize and study each type of recognition motif. The targeting of pyrimidine-purine base pairs using both antiparallel- stranded and parallel-stranded base triplets will also be undertaken. The purine-pyrimidine-purine triplet motif GTA will be further developed by examining various N2-aminopurine analogues, as well as those containing appended functionality, for their ability to enhance hydrogen bonding/base stacking interactions. Xanthosine (Xn) will be studied for its ability to form the related purine-pyrimidine-purine triplet XnCG. Other pyrimidines or smaller surrogate heterocycles will be functionalized to provide hydrogen bonding characteristics and then examined for their ability to mediate triplex formation. The systematic nature of this study, as well as the advantages of using specifically designed base analogues, should provide important insights into the formation and stability of a variety of triple helix complexes, and provide a route to the generalized targeting of double-stranded sequences of DNA.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
3R01GM053201-04S1
Application #
6132875
Study Section
Bio-Organic and Natural Products Chemistry Study Section (BNP)
Project Start
1995-07-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
2000-06-30
Support Year
4
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Boston College
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045896339
City
Chestnut Hill
State
MA
Country
United States
Zip Code
02467
Stewart, Kristen M; McLaughlin, Larry W (2004) Four-arm oligonucleotide Ni(II)-cyclam-centered complexes as precursors for the generation of supramolecular periodic assemblies. J Am Chem Soc 126:2050-7
Chen, Dongli; Meena, Meena; Sharma, Sunil K et al. (2004) Formation and stability of a Janus-Wedge type of DNA triplex. J Am Chem Soc 126:70-1
Sharma, Sunil K; McLaughlin, Larry W (2004) Triplex mediated delivery of a platinum complex to a specific DNA target site. J Inorg Biochem 98:1570-7
Sharma, Sunil K; McLaughlin, Larry W (2002) Cross-linking of a DNA conjugate tethering a cis-bifunctional platinated complex to a target DNA duplex. J Am Chem Soc 124:9658-9
Gianolio, D A; Segismundo, J M; McLaughlin, L W (2000) Tethered naphthalene diimide-based intercalators for DNA triplex stabilization. Nucleic Acids Res 28:2128-34
Chen, D L; McLaughlin, L W (2000) Use of pK(a) differences to enhance the formation of base triplets involving C-G and G-C base pairs. J Org Chem 65:7468-74
Gianolio, D A; McLaughlin, L W (1999) Synthesis and triplex forming properties of pyrimidine derivative containing extended functionality. Nucleosides Nucleotides 18:1751-69
Wiederholt, K; McLaughlin, L W (1999) A 2,2""-bipyridine ligand for incorporation into oligodeoxynucleotides: synthesis, stability and fluorescence properties of ruthenium-DNA complexes. Nucleic Acids Res 27:2487-93
St Clair, A; Xiang, G; McLaughlin, L W (1998) Synthesis and triplex forming properties of an acyclic N7-glycosylated guanine nucleoside. Nucleosides Nucleotides 17:925-37
Xiang, G; Bogacki, R; McLaughlin, L W (1996) Use of a pyrimidine nucleoside that functions as a bidentate hydrogen bond donor for the recognition of isolated or contiguous G-C base pairs by oligonucleotide-directed triplex formation. Nucleic Acids Res 24:1963-70