Quinolino-benzo-[5, 6]-dihydroisoquindolium compounds derived from berberine: A new class of highly selective ligands for G-quadruplex DNA in c- myc oncogene

• Published in: European journal of medicinal chemistry Vol. 46; no. 5; pp. 1906 - 1913
• Main Authors: Ma, Yan, Ou, Tian-Miao, Tan, Jia-Heng, Hou, Jin-Qiang, Huang, Shi-Liang, Gu, Lian-Quan, Huang, Zhi-Shu
• Format: Journal Article
• Language: English
• Published: PARIS Elsevier Masson SAS 01.05.2011; Elsevier
• Subjects: Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Berberine; Berberine - chemistry; Biological and medical sciences; Biophysical and biochemical evaluation; C- myc G-quadruplex; Cell Proliferation - drug effects; Cells, Cultured; Chemistry, Medicinal; DNA - drug effects; Down-Regulation - drug effects; Drug Screening Assays, Antitumor; G-Quadruplexes; General aspects; HL-60 Cells; Humans; Isoquinolines - chemical synthesis; Isoquinolines - chemistry; Isoquinolines - pharmacology; Life Sciences & Biomedicine; Ligands; Medical sciences; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-myc - antagonists & inhibitors; Proto-Oncogene Proteins c-myc - genetics; Quinolines - chemistry; Quinolino-benzo-[5, 6]-dihydroisoquindolium compounds; Reverse Transcriptase Polymerase Chain Reaction; Science & Technology; Stereoisomerism; Synthesis; Thermodynamics; Transcription, Genetic - drug effects; Transcription, Genetic - genetics; Berberine; C- myc G-quadruplex; Synthesis; Quinolino-benzo-[5, 6]-dihydroisoquindolium compounds; Biophysical and biochemical evaluation; DESIGN; Quinolino-benzo-[5,6]-dihydroisoquindolium compounds; TELOMERASE; TRANSCRIPTION; DOWN-REGULATION; QUINDOLINE DERIVATIVES; C-myc G-quadruplex; STABILIZING LIGANDS; ELEMENT; INHIBITORS; PROMOTER; BINDING; Organic cation; Selectivity; Modeling; Telomere; Guanine; Structure activity relation; Molecular model; Aromatic compound; Chemical synthesis; Protooncogene; Oxygen nitrogen heterocycle; Sequence specificity; Nucleotide sequence; Iminium compounds; Thermodynamic stability; Diamine; Biological fixation; DNA; myc Gene; Onc gene
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2011.02.020

A series of quinolino-benzo-[5, 6]-dihydroisoquindolium compounds ( 3a, 3f, 3g, and 3j) derived from alkaloid berberine were designed and synthesized as novel G-quadruplex ligands. Subsequent biophysical and biochemical evaluation demonstrated that the addition of pyridine ring and amino group into berberine improved the binding ability and selectivity towards G-quadruplex DNA in comparison with the previously reported 9- N-substituted berberine derivatives. Furthermore, qRT-PCR assay showed compound 3j led the down-regulation of c- myc gene transcription in leukemia cell line HL60, while little effect on normal cell line ECV-304, which was consistent with the behavior of an effective G-quadruplex ligand targeting c- myc oncogene. A series of quinolino-benzo-[5, 6]-dihydroisoquindolium derivatives (3 a, 3 f, 3 g, and 3 j) was designed, synthesized and evaluated as new G-quadruplex ligands. [Display omitted] ► A series of quinolino-benzo-[5, 6]-dihydroisoquindolium compounds derived from alkaloid berberine were synthesized. ► The addition of pyridine ring and amino group into berberine improved the binding ability and selectivity towards G-quadruplex DNA. ► Compound 3j led the down-regulation of c- myc gene transcription in leukemia cell line HL60, while little effect on normal cell line ECV-304.