n--(10h-indolo(3-2-b)quinolin-11-yl)-n-n-dimethylpropane-1-3-diamine and quindoline

The c-MYC oncogene is overactivated during Burkitt's lymphoma pathogenesis. Targeting c-MYC to inhibit its transcriptional activity has emerged as an effective anticancer strategy. We synthesized four series of disubstituted quindoline derivatives by introducing the second cationic amino side chain and 5-N-methyl group based on a previous study of SYUIQ-5 (1) as c-MYC promoter G-quadruplex ligands. The in vitro evaluations showed that all new compounds exhibited higher stabilities and binding affinities, and most of them had better selectivity (over duplex DNA) for the c-MYC G-quadruplex compared to 1. Moreover, the new ligands prevented NM23-H2, a transcription factor, from effectively binding to the c-MYC G-quadruplex. Further studies showed that the selected ligand, 7a4, down-regulated c-MYC transcription by targeting promoter G-quadruplex and disrupting the NM23-H2/c-MYC interaction in RAJI cells. 7a4 could inhibit Burkitt's lymphoma cell proliferation through cell cycle arrest and apoptosis and suppress tumor growth in a human Burkitt's lymphoma xenograft.

Topics: Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Burkitt Lymphoma; Cell Cycle Checkpoints; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; G-Quadruplexes; Humans; Indoles; Mice, Inbred NOD; Mice, SCID; Molecular Structure; Neoplasms, Experimental; Proto-Oncogene Proteins c-myc; Quinolines; Structure-Activity Relationship; Transcription, Genetic

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.

Topics: Alkaloids; Cell Line, Tumor; Cell Proliferation; Cell-Free System; Circular Dichroism; Dialysis; Enzyme Inhibitors; G-Quadruplexes; Humans; Indoles; Ligands; Methylation; Models, Molecular; Potassium; Quinolines; Structure-Activity Relationship; Telomerase; Telomere; Thermodynamics

Stabilization of G-quadruplex structures in the promoter region of certain oncogenes is an emerging field in anticancer drug design. Human c-myc gene is one of these oncogenes, and G-quadruplexes have been proven to be the transcriptional controller of this gene. In the present study, the interaction of quindoline derivatives with G-quadruplexes in c-myc was investigated. The experimental results indicated that these derivatives have the ability to induce/stabilize the G-quadruplexes in c-myc, which lead to down-regulation of the c-myc in the Hep G2 cell line. It was found that derivatives with terminal amino groups in their side chains would selectively bind to the isomers with the double nucleotide loops in the absence of K+. Molecular modeling studies revealed the binding mode between the derivatives and the G-quadruplexes is end-stacking at the 3'-position, and the positively charged side chain on the quindoline derivatives may contribute to the selectivity to certain loop isomers of topological quadruplexes as well as the improved stabilization action.

Topics: Alkaloids; Antineoplastic Agents; Base Sequence; Cell Line, Tumor; Cell Proliferation; Circular Dichroism; Dialysis; DNA; Guanine; Humans; Indoles; Isomerism; Models, Molecular; Nucleic Acid Conformation; Promoter Regions, Genetic; Proto-Oncogene Proteins c-myc; Quinolines; Static Electricity; Structure-Activity Relationship; Thermodynamics

A new series of quindoline derivatives (4a-j) were designed and synthesized to develop novel and potent telomerase inhibitors. The interaction of the G-quadruplex of human telomere DNA with these newly designed molecules was examined via circular dichroism spectroscopy and electrophoretic mobility shift assay (EMSA). The selectivity between the quindoline derivative (4a) and G-quadruplex or duplex DNA was investigated by competition dialysis. These new compounds as inhibitors of telomerase were also investigated through the utilization of modified telomerase repeat amplification protocol (TRAP) assay. The results revealed that the introduction of electron-donating groups such as substituted amino groups at the C-11 position of quindoline significantly improved the inhibitory effect on telomerase activity ((Tel)IC50 > 138 microM for quindoline, 0.44-12.3 microM for quindoline derivatives 4a-j). The quindoline derivatives not only stabilized the G-quadruplex structure but also induced the G-rich telomeric repeated DNA sequence to fold into quadruplex.

Topics: Alkaloids; Antineoplastic Agents; Circular Dichroism; Dialysis; DNA; Electrophoretic Mobility Shift Assay; Humans; Indoles; Ligands; Quinolines; Structure-Activity Relationship; Telomerase; Thermodynamics