Design, synthesis and evaluation of 4,7-diamino-1,10-phenanthroline G-quadruplex ligands

TY - JOUR

T1 - Design, synthesis and evaluation of 4,7-diamino-1,10-phenanthroline G-quadruplex ligands

AU - Nielsen, Mads Corvinius

AU - Borch, Jonas

AU - Ulven, Trond

PY - 2009/12/15

Y1 - 2009/12/15

N2 - A series of 4,7-diamino-1,10-phenanthroline derivatives carrying positively charged side chains has been synthesized, and their G-quadruplex interaction evaluated by circular dichroism (CD) and surface plasmon resonance (SPR). In absence of side chains, 4,7-diamino-1,10-phenanthroline exhibits a weak but significant G-quadruplex stabilizing effect, compared to no stabilization by 1,10-phenanthroline. We hypothesize that this effect is due to increased basicity of the phenanthroline nitrogens and protonation or ion chelation to form a central positive charge which stack on the G-tetrad above the central ionic column. Introduction of positively charged side chains results in compounds with appreciable G-quadruplex stabilizing properties and high aqueous solubility, with the longer side chains giving more potent compounds. Ligands carrying guanidine side chains in general show higher quadruplex stabilizing activity and distinctly slower kinetic properties than their amino and dimethylamino analogues, possibly due to specific hydrogen bond interactions with the G-quadruplex loops.

AB - A series of 4,7-diamino-1,10-phenanthroline derivatives carrying positively charged side chains has been synthesized, and their G-quadruplex interaction evaluated by circular dichroism (CD) and surface plasmon resonance (SPR). In absence of side chains, 4,7-diamino-1,10-phenanthroline exhibits a weak but significant G-quadruplex stabilizing effect, compared to no stabilization by 1,10-phenanthroline. We hypothesize that this effect is due to increased basicity of the phenanthroline nitrogens and protonation or ion chelation to form a central positive charge which stack on the G-tetrad above the central ionic column. Introduction of positively charged side chains results in compounds with appreciable G-quadruplex stabilizing properties and high aqueous solubility, with the longer side chains giving more potent compounds. Ligands carrying guanidine side chains in general show higher quadruplex stabilizing activity and distinctly slower kinetic properties than their amino and dimethylamino analogues, possibly due to specific hydrogen bond interactions with the G-quadruplex loops.

U2 - 10.1016/j.bmc.2009.09.055

DO - 10.1016/j.bmc.2009.09.055

M3 - Journal article

SN - 0968-0896

VL - 17

SP - 8241

EP - 8246

JO - Bioorganic & Medicinal Chemistry

JF - Bioorganic & Medicinal Chemistry

IS - 24

ER -