Syntheses and evaluation of acridone-naphthalimide derivatives for regulating oncogene PDGFR-β expression.
Syntheses and evaluation of acridone-naphthalimide derivatives for regulating oncogene PDGFR-β expression.
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DOI：
10.1016/j.bmc.2021.116042
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发表时间：
2021-02
影响因子：
3.5
通讯作者：
Meiling Zhang;Zuzhuang Wei;Xue Gong;Xiaoya Li;Shuangshuang Kang;Jing Wang;Bobo Liu;Zhishu Huang;Ding Li
中科院分区：
文献类型：
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作者：
Meiling Zhang;Zuzhuang Wei;Xue Gong;Xiaoya Li;Shuangshuang Kang;Jing Wang;Bobo Liu;Zhishu Huang;Ding Li
血小板衍生生长因子受体β(PDGFR-β)的表达上调与多种肿瘤的发生发展密切相关，已成为抗肿瘤治疗的靶点。我们已经合成和研究了一种吖啶酮类化合物B19，它可以选择性地结合和稳定癌基因-myc启动子I-基序，从而下调FC-myc的转录和翻译，但其对肿瘤细胞凋亡的作用有待改进。在本研究中，我们合成了多种含有已知抗癌荧光发色团的B19衍生物，以增强抗癌活性。通过筛选，我们发现吖啶酮-萘酰亚胺衍生物WZZ02可以选择性地稳定PDGFR-β启动子G-四链体并破坏其相应的I-基序结构的稳定，而与其他癌基因启动子G-四链体和I-基序没有明显的相互作用。WZZ02以剂量依赖的方式下调PDGFR-β基因的转录和翻译，这可能是由于上述相互作用所致。WZZ02可以显著抑制肿瘤细胞的增殖，诱导细胞凋亡和周期停滞。WZZ02在MCF-7移植瘤模型中显示出肿瘤生长抑制活性，这可能是由于其与PDGFR-β启动子G-四链体和I-基序的结合作用。我们的结果表明，WZZ02作为双G-四链体/I-基序结合蛋白对癌基因的复制和转录都是有效的，有望成为进一步开发的具有更高效力和选择性的先导化合物。1，8-萘二甲酰亚胺衍生物的广泛性质有助于通过各种荧光物理和化学方法进一步深入研究WZZ02的作用机理，从而有助于进一步了解PDGFR-β基因启动子G-四链体和I-基序的功能。
Upregulation of platelet-derived growth factor receptor β (PDGFR-β) 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 derivativeB19, which can selectively bind to and stabilize oncogenec-mycpromoter i-motif, resulting in down-regulation ofc-myctranscription and translation, however its effect on tumor cells apoptosis requires improvement. In the present study, we synthesized a variety ofB19derivatives containing a known anti-cancer fluorescent chromophore naphthalimide for the purpose of enhancing anti-cancer activity. After screening, we found that acridone-naphthalimide derivativeWZZ02could selectively stabilize PDGFR-β promoter G-quadruplex and destabilize its corresponding i-motif structure, without significant interaction to other oncogenes promoter G-quadruplex and i-motif.WZZ02down-regulated PDGFR-β gene transcription and translation in a dose-dependent manner, possibly due to above interactions.WZZ02could significantly inhibit cancer cell proliferation, and induce cell apoptosis and cycle arrest.WZZ02exhibited tumor growth inhibition activity in MCF-7 xenograft tumor model, which could be due to its binding interactions with PDGFR-β promoter G-quadruplex and i-motif. Our results suggested thatWZZ02as 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 ofWZZ02through various fluorescent physical and chemical methods, which could help to further understand the function of PDGFR-β gene promoter G-quadruplex and i-motif.