Parallel synthesis of H-pin polyamides by alkene metathesis on solid phase.
A small library of H-pin polyamides with variable aliphatic bridge lengths (CH(2))(n)(), where n = 4-8, connecting a central Py/Py pair was prepared via parallel synthesis with Ru-catalyzed alkene metathesis on solid phase as a complexity-generating cross-linking reaction. DNA binding affinities and sequence specificities were analyzed for each member of the library to determine the optimum linker length. An H-pin polyamide with a six-methylene bridge was found to have the highest affinity to its match site with high selectivity over a 1-bp mismatch site. The relationship between the number of methylenes in the linker (CH(2))(n)() and affinity is n = 6 > 4 > 7 > 5 > 8. These results indicate that 6 followed by 4 methylene-bridged polyamides represent the optimum spacer length for the H-pin motif in the DNA minor groove. Importantly, the H-pin is competitive with hairpin polyamides with respect to affinity and specificity. The metathesis-based convergent synthetic route to H-pin polyamides expands the scope of readily available DNA recognition motifs for small molecule-based gene regulation studies.
Olenyuk
Bogdan
B
Division of Chemistry and Chemical Engineering, The Beckman Institute, California Institute of Technology, Pasadena, California 91125, USA.
Jitianu
Cristian
C
Dervan
Peter B
PB
D000475:Alkenes / Q000737:chemistry*; D001483:Base Sequence; D004247:DNA / Q000737:chemistry* / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry; D007700:Kinetics; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009757:Nylons / Q000138:chemical synthesis* / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000737:chemistry; D013379:Substrate Specificity
D000475:Alkenes; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D004247:DNA; C096654:N-methylpyrrole; C018100:1-methylimidazole