title: Design, Synthesis, and Evaluation of Isaindigotone Derivatives To Downregulate c-myc Transcription via Disrupting the Interaction of NM23-H2 with G-Quadruplex.
abstract: Transcriptional control of c-myc oncogene is an important strategy for antitumor drug design. G-quadruplexes in the promoter region have been proven to be the transcriptional down-regulator of this gene. The transcriptional factor NM23-H2 can reactivate c-myc transcription by unwinding the G-quadruplex structure. Thus, down-regulation of c-myc transcription via disrupting G-quadruplex-NM23-H2 interaction might be a potential approach for cancer therapy. Here, a series of new isaindigotone derivatives were designed and synthesized based on our previous study. The abilities of these derivatives on interacting with G-quadruplexes or NM23-H2, and disrupting G-quadruplex-NM23-H2 interaction were evaluated. Among these derivatives, 19d and 22d showed remarkable abilities on disrupting G-quadruplex-NM23-H2 interaction. They exhibited significant effects on c-myc-relating processes in SiHa cells, including inhibiting the transcription and translation, inhibiting cellular proliferation, inducing apoptosis, and regulating cell cycle. Our findings provided the basis for the anticancer strategy based on c-myc transcriptional regulation via small molecules disrupting G-quadruplex-protein interaction.
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.|Institute for Translation Medicine, Qingdao University , Shandong 266021, People's Republic of China.
authors.forename: Chan
authors.initials: C
authors.lastname: Shan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.|School of Bioscience and Bioengineering, South China University of Technology , Guangzhou 510006, People's Republic of China.
authors.forename: Jin-Wu
authors.initials: JW
authors.lastname: Yan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Tong
authors.initials: T
authors.lastname: Che
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Zhou-Li
authors.initials: ZL
authors.lastname: Huang
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Ai-Chun
authors.initials: AC
authors.lastname: Chen
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Pei-Fen
authors.initials: PF
authors.lastname: Yao
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Jia-Heng
authors.initials: JH
authors.lastname: Tan
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Ding
authors.initials: D
authors.lastname: Li
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Tian-Miao
authors.identifier: 0000-0002-8176-4576
authors.initials: TM
authors.lastname: Ou
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Lian-Quan
authors.initials: LQ
authors.lastname: Gu
authors.affiliation: School of Pharmaceutical Sciences, Sun Yat-sen University , Guangzhou 510006, People's Republic of China.
authors.forename: Zhi-Shu
authors.identifier: 0000-0002-6211-5482
authors.initials: ZS
authors.lastname: Huang
mesh_terms: D000470:Alkaloids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects*; D015195:Drug Design; D005260:Female; D054856:G-Quadruplexes / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D054778:NM23 Nucleoside Diphosphate Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D015533:Transcriptional Activation / Q000187:drug effects; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D000470:Alkaloids; D000970:Antineoplastic Agents; D054778:NM23 Nucleoside Diphosphate Kinases; D016271:Proto-Oncogene Proteins c-myc; D011799:Quinazolines; C440668:isaindigotone; C517940:NME2 protein, human