Design, synthesis, and antiproliferative effect of 2,9‐bis[4‐(pyridinylalkylaminomethyl)phenyl]‐1,10‐phenanthroline derivatives on human leukemic cells by targeting G‐quadruplex

Abstract

Current multiagent chemotherapy regimens have improved the cure rate in acute leukemia patients, but they are highly toxic and poorly efficient in relapsed patients. To improve the treatment approaches, new specific molecules are needed. The G‐quadruplexes (G4s), which are noncanonical nucleic acid structures found in specific guanine‐rich DNA or RNA, are involved in many cellular events, including control of gene expression. G4s are considered as targets for the development of anticancer agents. Heterocyclic molecules are well known to target and stabilize G4 structures. Thus, a new series of 2,9‐bis[(substituted‐aminomethyl)phenyl]‐1,10‐phenanthroline derivatives (1a–i) was designed, synthesized, and evaluated against five human myeloid leukemia cell lines (K562, KU812, MV4‐11, HL60, and U937). Their ability to stabilize various oncogene promoter G4 structures (c‐MYC, BCL‐2, and K‐RAS) as well as the telomeric G4 was also determined through the fluorescence resonance energy transfer melting assay and native mass spectrometry. In addition, the more bioactive ligands 1g–i were tested for telomerase activity in HuT78 and MV4‐11 protein extracts.

G-quadruplexes in helminth parasites

“…The synthesis of G4 ligands tested against S. mansoni was previously described ( 35–37 ). Stock solutions were prepared at 10 mM in DMSO.…”

New 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazoline and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinoline Derivatives: Synthesis and Biological Evaluation as Novel Anticancer Agents by Targeting G-Quadruplex

“…The solutions were incubated for 16 h at 4 °C before analysis. K d were calculated as already described [ 29 ].…”

“…In the course of our research devoted to the design and the discovery of novel heterocycles for cancer chemotherapies [ 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ], we previously designed and prepared two series of new substituted 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthrolines A and diquinolinyl-pyridines B ( Figure 1 ) designed to bind to DNA G-quadruplexes [ 25 , 28 ], and endowed with interesting and promising activity towards human leukemia cells. In this context, and through considering the pharmacological activities of these previous series A and B on human leukemia cells [ 25 , 28 ], we undertook the design and the synthesis of a new series of 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazoline and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinoline derivatives 12 , 13 (series C), novel structural analogues of these latter series A and B.…”

Targeting Proliferation Signals and the Cell Cycle Machinery in Acute Leukemias: Novel Molecules on the Horizon

“…In the meantime, the development of novel heterocycles binding to DNA G-quadruplexes has led to the synthesis of a series of new substituted 2,9-bis [(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives, showing a selective activity against human leukemia cells over normal PBMCs [ 107 ]. This was the starting point for the synthesis of a new series of 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives [ 95 ]. Among them, compounds 1g – i provided the most promising results in terms of activity against AML cell lines, stabilization of c-MYC, BCL-2 and K-RAS promoter G-quadruplexes and inhibition of telomerase activity.…”