Chemistry of phosphodiesters, DNA and models. 3. Microgonotropens and their interactions with DNA. 1. Synthesis of the tripyrrole peptides dien-microgonotropen-a, -b, and -c and characterization of their interactions with dsDNA Academic Article uri icon


  • Exploration of the novel idea to employ a pyrrole nitrogen of a tripyrrole peptide minor groove binding agent to carry catalytic entities to the phosphates and major groove of DNA has been initiated with the synthesis of dien- microgonotropen-a, -b, and -c (5a, 5b, and 5c). Replacing the carboxyl terminal amidine and amino terminal formyl functionalities of distamycin (Dm) by CH2N(CH3)2 and acetyl substituents, respectively, provides 2, which has greater stability in water than does Dm. The synthetic design allows the N-methyl substituent on the central pyrrole of 2 to be replaced by connectors terminating in a dien ligand [−(CH2)3N{(CH2)3N(CH3)2}2 (5a), −−(CH2)4N{(CH2)3N− (CH2)2}2 (5b), −(CH2)5N{(CH2)3N(CH3)2}2 (5c)]. The binding of 2 is about 20-fold weaker than the binding of 5a, 5b, and 5c to calf thymus DNA, poly(dA-dT), and poly(dI-dC) due to the contribution of the polyamine substituents of the latter. The specificity and affinity of binding of 5a, 5b, and 5c to the 5′-[32P] 167-bp EcoRI/RsaI restriction fragment of pBR322 was determined by DNase I footprint analysis. Specific inhibition of cleavage was observed at each of the four potential A+T-rich binding sites after preincubation with 5a, 5b, and 5c at concentrations as high as 50 μM. At 250 μM, binding at short heteropolymeric A+T secondary sites distal to the cluster of A+T-rich primary binding sites was observed. At such higher concentrations of 5a, 5b, and 5c, increased rates of enzymatic cleavage at specific sequences were observed. DNase I footprinting analysis of the 3′-labeled fragment provided complementary results. Electrophoretic migration of HaeIII restriction digest fragments of φX-174-RF DNA after preincubation with 5a, 5b, and 5c was used to assess induction of gross conformational changes in DNA molecules. As the concentration of the agents increases, the effect of the agents in changing the conformation of larger DNA fragments decreases in the order 5c > 5b ⟫ ≫ Dm > Hoechst 33258. The electrophoretic mobilities of smaller DNA fragments are unaltered in the presence of the various agents. The dien-microgonotropens are much more effective in inducing changes than the sum of the Dm and bis[3-(dimethylamino)propyl]methylamine parts. This is due to the unique relationship between the minor groove binding portion of the dien-microgonotropens and the accompanying electrostatic complexing of the covalently attached dien moiety to the phosphodiester backbone of DNA. © 1993, American Chemical Society. All rights reserved.

published proceedings

  • Journal of the American Chemical Society

altmetric score

  • 6

author list (cited authors)

  • He, G. X., Browne, K. A., Groppe, J. C., Blasko, A., Mei, H. Y., & Bruice, T. C

citation count

  • 43

complete list of authors

  • He, Gong Xin||Browne, Kenneth A||Groppe, Jay C||Blasko, Andrei||Mei, Houng Yau||Bruice, Thomas C

publication date

  • August 1993