Synthesis and biophysical evaluation of minor-groove binding C-terminus modified pyrrole and imidazole triamide analogs of distamycin.
Five polyamide derivatives with rationally modified C-terminus moieties were synthesized and their DNA binding specificity and affinity determined. A convergent approach was employed to synthesize polyamides containing an alkylaminopiperazine (4 and 5), a truncated piperazine (6), or an alkyldiamino-C-terminus moiety (7 and 8) with two specific objectives: to investigate the effects of number of potential cationic centers and steric bulk at the C-terminus. CD studies confirmed that compounds 4, 5, 7, and 8 bind in the minor groove of DNA. The alkylpiperazine containing compounds (4 and 5) showed only moderate binding to DNA with DeltaT(m) values of 2.8 and 8.3 degrees C with their cognate sequence, respectively. The alkyldiamino compounds (7 and 8) were more impressive producing a DeltaT(m) of >17 and >22 degrees C, respectively. Compound 6 (truncated piperazine) did not stabilize its cognate DNA sequence. Footprints were observed for all compounds (except compound 6) with their cognate DNA sequence using DNase I footprinting, with compound 7 producing a footprint of 0.1 microM at the expected 5'-ACGCGT-3' site. SPR analysis of compound 7 binding to 5'-ACGCGT-3', 5'-ACCGGT-3', and 5'-AAATTT-3' produced binding affinities of 2.2x10(6), 3.3x10(5), and 1x10(5)M(-1), respectively, indicating a preference for its cognate sequence of 5'-ACGCGT-3'. These results are in good agreement with the footprinting data. The results indicate that steric crowding at the C-terminus is important with respect to binding. However, the number of cationic centers within the molecule may also play a role. The alkyldiamino-containing compounds (7 and 8) warrant further investigation in the field of polyamide research.
Brown
Toni
T
Division of Natural Sciences and Department of Chemistry, Hope College, Holland, MI 49423, USA.
Taherbhai
Zarmeen
Z
Sexton
Jim
J
Sutterfield
Arden
A
Turlington
Mark
M
Jones
Justin
J
Stallings
Lindsay
L
Stewart
Michelle
M
Buchmueller
Karen
K
Mackay
Hilary
H
O'hare
Caroline
C
Kluza
Jerome
J
Nguyen
Binh
B
Wilson
David
D
Lee
Moses
M
Hartley
John A
JA
D000577:Amides / Q000737:chemistry*; D001483:Base Sequence; D001665:Binding Sites; D001667:Binding, Competitive; D002942:Circular Dichroism / Q000379:methods; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D018983:DNA Footprinting / Q000379:methods; D004214:Distamycins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry*; D008969:Molecular Sequence Data; D015394:Molecular Structure; D009757:Nylons / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry*; D012680:Sensitivity and Specificity; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D020349:Surface Plasmon Resonance / Q000379:methods; D013696:Temperature; D013997:Time Factors
D000577:Amides; D004214:Distamycins; D007093:Imidazoles; D009757:Nylons; D011758:Pyrroles; D004247:DNA