Molecular recognition of DNA by rigid [N]-polynorbornane-derived bifunctional intercalators: synthesis and evaluation of their binding properties.
We have exploited the concept of multivalency in the context of DNA recognition, using novel chemistry to synthesize a new type of bis-intercalator with unusual sequence-selectivity. Bis-intercalation has been observed previously, but design principles for de novo construction of such molecules are not known. Our compounds feature two aromatic moieties projecting from a rigid, polynorbornane-based scaffold. The length and character of the backbone as well as the identity of the intercalators were varied, resulting in mono- or divalent recognition of the double helix with varying affinity. Our lead compound proved to be a moderately sequence-selective bis-intercalator with an unwinding angle of 27 degrees and a binding constant of about 8 microM. 9-aminoacridine rings were preferred over acridine carboxamides or naphthalimides, and a rigid [3]-polynorbornane scaffold was superior to a [5]-polynorbornane. The flexibility of the linker connecting the rings to the scaffold, although less influential, could affect the strength and character of the DNA binding.
Van Vliet
Liisa D
LD
Department of Biochemistry, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, United Kingdom.
Ellis
Tom
T
Foley
Patrick J
PJ
Liu
Ligong
L
Pfeffer
Frederick M
FM
Russell
Richard A
RA
Warrener
Ronald N
RN
Hollfelder
Florian
F
Waring
Michael J
MJ
D000166:Acridines / Q000138:chemical synthesis* / Q000737:chemistry; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry; D000609:Aminoacridines / Q000138:chemical synthesis / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D003851:Deoxyribonucleases / Q000737:chemistry; D003956:Dialysis; D015180:Electrophoresis, Gel, Two-Dimensional; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry; D053644:Naphthalimides / Q000138:chemical synthesis / Q000737:chemistry; D009636:Norbornanes / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D000166:Acridines; D000577:Amides; D000609:Aminoacridines; D007364:Intercalating Agents; D053644:Naphthalimides; D009636:Norbornanes; C520854:dimethyl 6,,16-(2',2''-di-(9'''-acridinylamino)ethyl)-6,16-diaza-21-oxaoctacyclo(9.9.1.1.(3,9)1.(13,19)0.(2,10)0.(4,8)0.(12,20)0.(14,18))tricosane-5,7,15,17-tetraone-1,11-dicarboxylate; D004247:DNA; D003851:Deoxyribonucleases