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Syntheses and evaluation of acridone-naphthalimide derivatives for regulating oncogene PDGFR-ß expression.
Zhang, Meiling; Wei, Zuzhuang; Gong, Xue; Li, Xiaoya; Kang, Shuangshuang; Wang, Jing; Liu, Bobo; Huang, Zhi-Shu; Li, Ding.
Afiliação
  • Zhang M; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China.
  • Wei Z; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China.
  • Gong X; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China.
  • Li X; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China.
  • Kang S; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China.
  • Wang J; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China.
  • Liu B; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China.
  • Huang ZS; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China.
  • Li D; School of Pharmaceutical Sciences, Sun Yat-sen University, 132 Waihuan East Road, Guangzhou 510006, PR China. Electronic address: liding@mail.sysu.edu.cn.
Bioorg Med Chem ; 34: 116042, 2021 03 15.
Article em En | MEDLINE | ID: mdl-33561716
Upregulation of platelet-derived growth factor receptor ß (PDGFR-ß) has been found to be associated with development of various types of cancers, which has become an attractive target for anti-tumor treatment. Previously, we have synthesized and studied an acridone derivative B19, which can selectively bind to and stabilize oncogene c-myc promoter i-motif, resulting in down-regulation of c-myc transcription and translation, however its effect on tumor cells apoptosis requires improvement. In the present study, we synthesized a variety of B19 derivatives containing a known anti-cancer fluorescent chromophore naphthalimide for the purpose of enhancing anti-cancer activity. After screening, we found that acridone-naphthalimide derivative WZZ02 could selectively stabilize PDGFR-ß promoter G-quadruplex and destabilize its corresponding i-motif structure, without significant interaction to other oncogenes promoter G-quadruplex and i-motif. WZZ02 down-regulated PDGFR-ß gene transcription and translation in a dose-dependent manner, possibly due to above interactions. WZZ02 could significantly inhibit cancer cell proliferation, and induce cell apoptosis and cycle arrest. WZZ02 exhibited tumor growth inhibition activity in MCF-7 xenograft tumor model, which could be due to its binding interactions with PDGFR-ß promoter G-quadruplex and i-motif. Our results suggested that WZZ02 as a dual G-quadruplex/i-motif binder could be effective on both oncogene replication and transcription, which could become a promising lead compound for further development with improved potency and selectivity. The wide properties for the derivatives of 1,8-naphthalimide could facilitate further in-depth mechanistic studies of WZZ02 through various fluorescent physical and chemical methods, which could help to further understand the function of PDGFR-ß gene promoter G-quadruplex and i-motif.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor beta de Fator de Crescimento Derivado de Plaquetas / Naftalimidas / Acridonas / Antineoplásicos Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptor beta de Fator de Crescimento Derivado de Plaquetas / Naftalimidas / Acridonas / Antineoplásicos Tipo de estudo: Clinical_trials / Prognostic_studies Limite: Animals / Female / Humans Idioma: En Ano de publicação: 2021 Tipo de documento: Article