Novel diamino imidazole and pyrrole-containing polyamides: Synthesis and DNA binding studies of mono- and diamino-phenyl-ImPyIm polyamides designed to target 5′-ACGCGT-3

• Published in: Bioorganic & medicinal chemistry Vol. 20; no. 2; pp. 693 - 701
• Main Authors: Satam, Vijay, Babu, Balaji, Chavda, Sameer, Savagian, Mia, Sjoholm, Robert, Tzou, Samuel, Liu, Yang, Kiakos, Konstantinos, Lin, Shicai, David Wilson, W., Hartley, John A., Lee, Moses
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15.01.2012
• Subjects: ACGCGT; Base Sequence; Benzamides - chemical synthesis; Benzamides - chemistry; binding agents; binding capacity; Calorimetry; Cell-cycle box; Circular Dichroism; deoxyribonuclease I; Deoxyribonuclease I - metabolism; Diamino; Dicationic; Distamycins - chemistry; DNA; DNA - chemistry; DNA - metabolism; Gene control; genes; Imidazoles - chemical synthesis; Imidazoles - chemistry; MCB; Mlu1; molecular weight; nucleotide sequences; Nylons - chemical synthesis; Nylons - chemistry; Polyamides; Pyrroles - chemistry; Surface Plasmon Resonance; water solubility; Dicationic; Polyamides; Diamino; ACGCGT; Gene control; Cell-cycle box; MCB; Mlu1
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.12.010

Pyrrole- and imidazole-containing polyamides are widely investigated as DNA sequence selective binding agents that have potential use as gene control agents. The key challenges that must be overcome to realize this goal is the development of polyamides with low molar mass so the molecules can readily diffuse into cells and concentrate in the nucleus. In addition, the molecules must have appreciable water solubility, bind DNA sequence specifically, and with high affinity. It is on this basis that the orthogonally positioned diamino/dicationic polyamide Ph-ImPy*Im 5 was designed to target the sequence 5′-ACGCGT-3′. Py* denotes the pyrrole unit that contains a N-substituted aminopropyl pendant group. The DNA binding properties of diamino polyamide 5 were determined using a number of techniques including CD, ΔTM, DNase I footprinting, SPR and ITC studies. The effects of the second amino moiety in Py* on DNA binding affinity over its monoamino counterpart Ph-ImPyIm 3 were assessed by conducting DNA binding studies of 3 in parallel with 5. The results confirmed the minor groove binding and selectivity of both polyamides for the cognate sequence 5′-ACGCGT-3′. The diamino/dicationic polyamide 5 showed enhanced binding affinity and higher solubility in aqueous media over its monoamino/monocationic counterpart Ph-ImPyIm 3. The binding constant of 5, determined from SPR studies, was found to be 1.5×107M−1, which is ∼3 times higher than that for its monoamino analog 3 (4.8×106M−1). The affinity of 5 is now approaching that of the parent compound f-ImPyIm 1 and its diamino equivalent 4. The advantages of the design of diamino polyamide 5 over 1 and 4 are its sequence specificity and the ease of synthesis compared to the N-terminus pyrrole analog 2.