Design, Synthesis, and Evaluation of 2,9‐Bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline Derivatives as G‐Quadruplex Ligands

Abstract

Genomic sequences able to form guanine quadruplexes (G4) are found in oncogene promoters, in telomeres, and in 5'- and 3'-untranslated regions as well as introns of messenger RNAs. These regions are potential targets for drugs designed to treat cancer. Herein, we present the design and syntheses of ten new phenanthroline derivatives and characterization of their interactions with G4-forming oligonucleotides. We evaluated ligand-induced stabilization and specificity and selectivity of ligands for various G4 conformations using FRET-melting experiments. We investigated the interaction of compound 1 a (2,9-bis{4-[(3-dimethylaminopropyl)aminomethyl]phenyl}-1,10-phenanthroline), which combined the greatest stabilizing effect and specificity for G4, with human telomeric sequences using FRET, circular dichroism, and ESI-MS. In addition, we showed that compound 1 a interferes with the G4 helicase activity of Saccharomyces cerevisiae Pif1. Interestingly, compound 1 a was significantly more cytotoxic toward two human leukemic cell lines than to normal human blood mononuclear cells. These novel phenanthroline derivatives will be a starting point for further development and optimization of potent G4 ligands that have potential as anticancer agents.

Design, synthesis, and antiprotozoal evaluation of new 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives

“…The intermediate bis ‐[2,9‐(formylphenyl)]‐1,10‐phenanthrolines 5a–c were prepared by a double Suzuki–Miyaura cross‐coupling reaction of 2,9‐dichloro‐1,10‐phenanthroline with 2‐, 3‐, or 4‐formylphenylboronic acids in the presence of Pd(PPh 3 ) 4 as a catalyst and in the presence of potassium (or sodium) carbonate . Condensation of primary amines with dialdehydes 5a–c afforded the di‐imines 6a–s , which were immediately reduced into the 2,9‐ bis ‐[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthrolines 1a–s using sodium borohydride as reductive agent in refluxing methanol as previously described by our team …”

“…As similar phenanthroline derivatives showed interesting effects as G‐quadruplex sequence stabilizing ligands, we investigated whether the newly synthesized compounds bound to P. falciparum telomeric sequences as we reasoned that this might be the mechanism of antiprotozoan effects. Interestingly, Plasmodium telomeres contain a repeated degenerate motif of 5′ GGGTTYA 3′ (where Y may be T or C), which is quite different from the human telomeric one ( 5′ GGGTTA 3′ ) .…”

“…In the course of our work devoted to discovery of new heterocyclic compounds for use in anticancer chemotherapy, we prepared a series of substituted 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives (Figure , 1 ) designed to bind to DNA G‐quadruplexes . As these 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthrolines possess the structural parameters required for an antimalarial activity, we decided to synthesize new substituted 1,10‐phenanthroline compounds (Figure ) taking into account our experience in the field of the synthesis of new antiprotozoal heterocyclic compounds .…”

Design, Synthesis and Biological Evaluation of New Substituted Diquinolinyl-Pyridine Ligands as Anticancer Agents by Targeting G-Quadruplex

“…The quinoline ring is one of the most useful scaffolds found in numerous natural products and pharmaceuticals with an extensive range of biological activities. This framework is also present in many well-known potent G-quadruplex ligands such as Phen-DC3, pyridostatin or 360A [ 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. By considering previously reported G-quadruplex DNA binding ligands with a large flat aromatic surface and positively charged lipophilic lateral chains, herein we have designed pyridine di-quinoline core with the possibility to attach to various carboxamide side chains ( Figure 1 ).…”

“…The large planar aromatic surface of a terminal G-quartet provided a rationale for the development of planar G4 ligands such as macrocyclic porphyrin [ 22 , 23 , 24 , 25 ] or telomestatin derivatives [ 26 , 27 , 28 , 29 , 30 ], polyaromatic fused molecules which include acridines [ 31 , 32 , 33 ], phenanthrolines [ 34 , 35 , 36 , 37 ], quinolones [ 38 ], quinones [ 39 ] etc. Based on these chemical structures a number of G4 binding small molecules have been developed during the last two decades [ 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Many of these ligands are selective for G4 structures over duplex DNA, but the design of a ligand specific for a given G4 structure is still challenging.…”