【作者】 陈卓；

【导师】 徐玉芳；

【作者基本信息】 华东理工大学 ， 应用化学， 2011， 博士

【摘要】 本论文基于苊并[1,2-b]吡咯和萘酰亚胺母体结构,设计合成了三系列新型抗肿瘤药物先导,详细研究了它们的抗肿瘤性能及作用机理,发现了它们有别于已报道的该类衍生物的全新的作用靶点,例如成纤维细胞生长因子受体(FGFR1)、溶酶体膜通透性(LMP)等。第一系列化合物为苊并[1,2-b]吡咯衍生物。通过在苊并[1,2-b]吡咯的3位引入多种硫醇和／或9位引入各种多种酯类,设计合成了20个新结构目标化合物。10种肿瘤细胞的细胞毒性测试结果表明该系列化合物具有很强的抗肿瘤活性,IC50值为10-6—10-8M。代表性化合物2a-b酪氨酸激酶抑制活性普筛结果表明,它们对FGFR1有较强选择性。进一步研究证实该系列化合物中的8-氧-8H-苊并[1,2-b]吡咯-9-甲酸酯类衍生物2a-d对FGFR1有较强抑制作用,IC50值达到0.019-0.077μM。而其烯丙基硫醇衍生物同样具有良好的的FGFR1抑制作用,IC50值在0.2-0.6μM。它们对FGFR1抑制活性与抗肿瘤活性的构效关系一致。计算机模拟分子对接表明2a-b能与FGFR1的ATP位点结合。这是苊并[1,2-b]吡咯衍生物第一次用作FGFR1抑制剂。第二系列化合物为多靶点萘酰亚胺类抗肿瘤剂。通过在萘酰亚胺的2位和6位分别引入长烷链和多胺结构,设计合成了8个新结构目标化合物,同时设计合成了4个对照化合物。5种肿瘤细胞的细胞毒性测试结果表明该系列化合物具有较强的抗肿瘤活性,IC50值为10-5—10-6。圆二色谱、荧光广谱等实验结果表明,该系列化合物与DNA几乎没有直接作用,但是kDNA解链环实验证实在非细胞体系中该系列化合物具有一定的topoⅡ抑制活性。此外,LMP实验证实该系列化合物中的7b-d具有较好的LMP作用,这和与其它同类类似物相比表现出的抗肿瘤性能优势一致。细胞色素c释放和Annexin V-FITC双染实验证实：化合物7a-d和8a-d能高效诱导细胞通过线粒体途径凋亡。本章工作提出了一种新型多靶点药物设计思想,并进行了初步验证。第三系列化合物为萘酰亚胺—大环多胺加合物。通过在萘酰亚胺的2-位和6-位分别引入大环多胺和不同长度的烷链,设计合成了5个目标化合物。5种肿瘤细胞的细胞毒性测试表明该系列化合物具有较强的抗肿瘤活性,IC50值为10-5—10-6M。圆二色谱和DNA解螺旋实验表明,萘酰亚胺—大环多胺加合物与DNA的直接作用比较温和,kDNA解链环实验证实在非细胞体系中萘酰亚胺—大环多胺加合物具有较强的topoⅡ抑制活性。在上述实验中我们还发现,烷链长度可以调节化合物和上述靶点的作用强度。Annexin V-FITC双染实验证实：萘酰亚胺—大环多胺加合物有较强的诱导肿瘤细胞凋亡的作用。更多还原

【Abstract】 In the dissertation, three series of acenaphtho[1,2-b]pyrrole or naphthalimide derivatives were designed and synthesized. They were evaluated of their antitumor potency and confirmed of their mechanism of action. Comparing with their analogs reported before, several compounds were proved to possess novel molecular targets like fibroblast growth factor receptor 1 (FGFR1), lysosomal membrane permeabilization (LMP).In the first section, the antitumor activities of acenaphtho[1,2-b]pyrrole derivatives were studied. Twenty target compounds were designed and synthesized by introduction of sulfur, nucleophiles at 3-position, and/or by esterification with bromide/iodide at the 9-position. This novel series of acenaphtho[1,2-b]pyrrole derivatives were discovered as FGFR1 inhibitors with submicormolar to double digital nanomolar IC50 values and exhibited outstanding growth inhibition property in vitro with micromolar to double digital nanomolar IC50 values. The structure-activity relationship (SAR) studies showed that acenaphtho[1,2-b]pyrrole-carboxylic acid esters (2a-d) possess distinguished FGFR1 inhibition activity, e.g. compound 2b showed IC50 values of 19 nM. The thiol derivatives of the esters (3a-h) could also be great FGFR1 inhibitors with submicromolar IC50 values which varied with 3-position substitution. Additionally, compounds 2a-b were validated for their excellent selectivity against diverse kinases, like VEGFRs and PDGFRs. The antiproliferative results were quite consistent with their FGFR1 inhibition activities, especially for compound 2a-d and 3a-h. Molecular docking simulation demonstrated that compounds 2a-b occupied the ATP-binding domain. After all, these are the first examples of FGFR1 inhibitors based on acenaphtho[1,2-b]pyrrole scaffold.In the second section, the antitumor activities of multitarget naphthalimide derivatives were studied. Eight novel compounds were designed and synthesized by functionalizing the naphthalimide core at the 2-and 6-positons with polyamines and long alkyl chains. Besides,4 compounds were synthesized as reference. Majority of compounds 7a-d and 8a-d potently inhibited the growth of the five tested cancer cell lines with IC50 values ranging from 2 to 10μM and are more active than Amonafide. These compounds were tested for their interactions with DNA and their cell-free topo II inhibition activities, which demonstrated these compounds were weak DNA binders but modest topoⅡinhibitors. Furthermore, compounds 7b-d were found to notably induce LMP, and exhibited better antiproliferative activity comparing with their single-target analogs. All the newly-synthesized compounds were demonstrated to efficiently induce apoptosis via a mitochondrial pathway. Accordingly, a new paradigm was suggested for the design of novel multitarget anticancer drugs.In the third section, the antitumor activities of naphthalimide-cyclam conjugates with alkyl chains were studied. Five novel compounds were designed and synthesized by functionalizing the naphthalimide core at the 2-and 6-positons with cyclam and alkyl chains. They exhibited potent growth inhibition property in vitro with the IC50 values of 1005-10-6 M. These compounds were demonstrated to be quite modest DNA binders according to circular dichroism (CD) spectra and DNA relaxation assay, but quite potent topoⅡinhibitors in cell-free system due to kDNA decatenation assay. Besides, the length of alkyl chains could be utilized to adjust the binding of the compounds towards DNA and topoⅡ. All the newly-synthesized compounds were demonstrated to efficiently induce apoptosis.更多还原