5-N-Methylated Quindoline Derivatives as Telomeric G-Quadruplex Stabilizing Ligands: Effects of 5-N Positive Charge on Quadruplex Binding Affinity and Cell Proliferation

Abstract

A series of 5-N-methyl quindoline (cryptolepine) derivatives (2a- x) as telomeric quadruplex ligands was synthesized and evaluated. The designed ligands possess a positive charge at the 5- N position of the aromatic quindoline scaffold. The quadruplex binding of these compounds was evaluated by circular dichroism (CD) spectroscopy, fluorescence resonance energy transfer (FRET) melting assay, polymerase chain reaction (PCR) stop assay, nuclear magnetic resonance (NMR), and molecular modeling studies. Introduction of a positive charge not only significantly improved the binding ability but also induced the selectivity toward antiparallel quadruplex, whereas the nonmethylated derivatives tended to stabilize hybrid-type quadruplexes. NMR and molecular modeling studies revealed that the ligands stacked on the external G-quartets and the positively charged 5- N atom could contribute to the stabilizing ability. Long-term exposure of human cancer cells to 2r showed a remarkable cessation in population growth and cellular senescence phenotype and accompanied by a shortening of the telomere length.

The G-quadruplex ligand, SYUIQ-FM05, targets proto-oncogene c-kittranscription and induces apoptosis in K562 cells

“…We evaluated the cell growth arrest effect of SYUIQ-FM05 on the K562 cell line based on the inhibitory proliferation effect of SYUIQ-FM05 on HL60 and CA46 cells (Lu et al, 2008). SYUIQ-FM05 inhibited the proliferation of cells from hematological malignancy in a dose-dependent manner.…”

“…These ligands, including N′- (7-fluoro-5-N-methyl-10H-indolo[3,2-b]quinolin-5-ium)-N,N-dimethylpropane-1,3-diamine iodide (SYUIQ-FM05, Figure 1B), induce growth arrest in HL60 and CA46 cells through an inhibition of telomerase activity (Lu et al, 2008). N-(3-(Dimethylamino)propyl)-7-fluoro-10H-indolo [3,2-b] quinolin-11-amine (SYUIQ-F05, Figure 1C), another quindoline derivative, down-regulates the expression of the proto-oncogene, c-myc, by stabilizing the nuclear hypersensitivity element III 1 upstream of the c-myc promoter in Hep G2 hepatocellular carcinoma and Ramos and CA46 Burkitt's lymphoma cell lines (Ou et al, 2007).…”

“…N-(3-(Dimethylamino)propyl)-7-fluoro-10H-indolo [3,2-b] quinolin-11-amine (SYUIQ-F05, Figure 1C), another quindoline derivative, down-regulates the expression of the proto-oncogene, c-myc, by stabilizing the nuclear hypersensitivity element III 1 upstream of the c-myc promoter in Hep G2 hepatocellular carcinoma and Ramos and CA46 Burkitt's lymphoma cell lines (Ou et al, 2007). SYUIQ-FM05 is a 5-N-methyl quindoline derivative that exerts remarkable effects on cell growth arrest and cellular senescence and inhibits telomere elongation in leukemia cells (Lu et al, 2008). SYUIQ-FM05 inhibits the transcription of the bcl-2 gene by stabilizing the promoter quadruplex in HL60 cells (Wang et al, 2010).…”

“…Because SYUIQ-FM05 possesses higher bioactivity compared to other 5-N-methyl quindoline derivatives (Lu et al, 2008), we investigated its effects on c-kit transcription and the RAS/MEK/ERK pathway, which may be responsible for its anticancer potency in c-Kit-positive chronic myelocytic leukemia (CML) K562 cell line. (SYUIQ-FM05) was synthesized using a previously reported method (Lu et al, 2008) with slight modifications. The melting point was 230-232°C.…”

Structure-Based Approaches Targeting Oncogene Promoter G-Quadruplexes

“…For example, cationic porphyrins , quindoline and berberine derivatives (Ou et al 2007;Lu et al 2008;Ma et al 2008), and trisubstituted isoalloxazines (Bejugam et al 2007) have been demonstrated to interfere with the oncogenic transcription in vitro. Quarfloxin, developed by Cylene Pharmaceuticals, entered clinical trials due to its ability to interact with G-quadruplexes in vivo (Duan et al 2001).…”