title: Synthesis and evaluation of quindoline derivatives as G-quadruplex inducing and stabilizing ligands and potential inhibitors of telomerase.
abstract: 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.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510275, People's Republic of China.
authors.forename: Jin-Lin
authors.initials: JL
authors.lastname: Zhou
authors.forename: Yu-Jing
authors.initials: YJ
authors.lastname: Lu
authors.forename: Tian-Miao
authors.initials: TM
authors.lastname: Ou
authors.forename: Jun-Min
authors.initials: JM
authors.lastname: Zhou
authors.forename: Zhi-Shu
authors.initials: ZS
authors.lastname: Huang
authors.forename: Xiao-Feng
authors.initials: XF
authors.lastname: Zhu
authors.forename: Cui-Juan
authors.initials: CJ
authors.lastname: Du
authors.forename: Xian-Zhang
authors.initials: XZ
authors.lastname: Bu
authors.forename: Lin
authors.initials: L
authors.lastname: Ma
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.forename: Yue-Ming
authors.initials: YM
authors.lastname: Li
authors.forename: Albert Sun-Chi
authors.initials: AS
authors.lastname: Chan
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D002942:Circular Dichroism; D004247:DNA / Q000737:chemistry*; D003956:Dialysis; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry; D008024:Ligands; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D007211:Indoles; D008024:Ligands; D011804:Quinolines; C016712:quindoline; D004247:DNA; D019098:Telomerase