癌症是仅次于心血管疾病的人类死亡的第二大原因。近十年来，多种类型的抗肿瘤药物（尤其是小分子多靶点酪氨酸激酶抑制剂/TKI）相继上市，为临床医师对付恶性肿瘤提供了更多的选择。然而，目前临床用抗肿瘤药物普遍存在较多副作用、治愈率较低以及耐药性逐年增加等缺陷，发现和开发具有全新结构骨架和/或作用机制的新药是解决这些问题的根本途径，而对已知药物进行结构修饰则不失为一种更为现实的新药研发方向。

近年研究发现，非甾体类抗炎药/ NSAIDs（尤其是阿司匹林）可以预防多种肿瘤的发生（甚至可能成为癌症治疗的辅助药物），而向NSAIDs的结构中引入NO或/和H₂S供体片段可改善其抗肿瘤活性。例如，被称为“超级阿司匹林”的NOSH-阿司匹林系列化合物（同时释放NO和H₂S）其对多种肿瘤细胞的IC₅₀值为nM级。借鉴这一思想，我们试图对其他NSAIDs也进行相似的结构修饰。本研究将首次向ATB-429（一种含有H₂S供体片段的5-氨基水杨酸衍生物）中引入不同的NO片段，同时向其5-位氨基上引入芳香脲基，设计合成三类不同结构的ATB-429衍生物。期望能筛选出有苗头的抗肿瘤化合物，为本课题组开展该领域的研究打下基础。

IMB-1506是本课题组近期筛选得到的一个全新结构的抗肿瘤先导物（芳基喹啉-乙胺丁醇杂合体）。本品具有良好的体外广谱抗肿瘤活性，如对A549（肺癌）、HepG2（肝癌）、DU145（前列腺癌）和乳腺癌细胞（MCF-7）的体外活性均优于舒尼替尼（第一个被美国FDA批准的TKI）。作为对IMB-1506的第一轮结构修饰，本研究将立足于对其中的乙胺丁醇片段进行改造，设计合成一系列IMB-1506衍生物。通过体外活性的初步评价，期望能筛选出该位置上的最佳取代基，为后续的IMB-1506结构修饰奠定基础。

本论文研究工作分为以下两个部分：

一、设计合成了一系列结构新颖的含有NO供体片段的ATB-429衍生物。在初步评价目标物及某些中间体（30 µM）对六种肿瘤细胞生长抑制率的基础上，进一步评价了部分化合物对这些肿瘤细胞的IC₅₀值。结果发现，含有氧化呋咱片段的化合物具有明确的体外抗肿瘤活性。其中，化合物7-9对HT-29、PANC1的活性 (IC₅₀: 0.256 - 3.024 μM)、8a,b对MCF-7的活性 (IC₅₀: 2.677 - 3.051 μM ) 以及8a对DU145的活性（IC₅₀: 1.270 μM )均优于对照药凡德他尼（IC₅₀: 1.925 - 4.107 μM）。相关研究结果发表于Bioorg. Med. Chem. Lett. 2016, 26: 2355–2359。

二、设计了四个系列结构新颖的IMB-1506衍生物，但由于时间关系，本研究仅基本完成了第一个系列（对乙胺丁醇片段的修饰）的合成工作。目标物的体外抗肿瘤活性正在评价中，结果值得期待。本部分工作的完成将为IMB-1506的后续结构修饰奠定基础。

通过以上研究工作，本论文共合成了70个化合物，未见文献报道的新化合物58个，包括目标化合物30个。新化合物经¹H NMR和MS确证，部分目标化合物还经HRMS，¹³C NMR进一步确证。

Cancer is the second leading cause of death worldwide after the cardiovascular disease. Over recent decade, multiple types of antitumor-drugs (especially small molecule multi-targeted tyrosine kinase inhibitor / TKI) were launched successively and provided more treatment options for cancers in the clinic. However, the existing defects of antitumor drugs such as too much side effects, low cure rate and increased drug-resistance restricted their use in the clinic. The discovery and development of new drugs with new structure skeleton and/or mechanism are the fundamental way to solve these problems, while structural modification of known drugs is regarded as a more realistic direction of drug research and development.

Recently, nonsteroidal anti-inflammatory drugs (NSAIDs), in particular aspirin, were found to exhibit cancer prevention activity, might be developed to complementary medicines for the treatment of cancers. The introduction of nitric oxide (NO) - or hydrogen sulfide (H₂S)-donation segments to NSAIDs could improve the NSAIDs antitumor activity. For example, the NOSH-aspirin derivatives (releasing NO and H₂S simultaneously) known as "super aspirin" showed nanomolar (IC₅₀) antitumor activity to a variety of tumor cells. Inspired by this design, we planned to modify other NSAIDs in a similar manner. In this study, some NO-donation segments was firstly introduced to ATB-429 (a 5-amino salicylic acid derivative containing a H₂S-donation fragment), and 5-amino position of ATB-429 was also investigated by introduction of aryl ureido moieties. Thus, three series of ATB-429 were designed and synthesized. Our primary object was to identify potent and novel antitumor compounds so as to lay a foundation for the further study.

IMB-1506, an aryl quinoline-ethambutol hybrid, having a potent broad-spectrum antitumor activity (in vitro), was discovered by our group recently. It displayed better activity than Sunitnib (the first TKI approved by USA FDA) against A549, HepG2, DU145 and MCF-7 cells in vitro. As the beginning optimization of our lead compound, a series of IMB-1506 with the modification on the ethambutol fragment of IMB-1506 was designed and synthesized. We expected to identify the best substitution on this segment through preliminary in vitro evaluation, and lay a foundation for subsequent structural modification of IMB-1506.

This dissertation could be divided into the following two chapters:

Firstly, a series of novel ATB-429 (an anti-inflammatory candidate) derivatives containing a NO-releasing moiety were designed, synthesized and evaluated for their in vitro activity against six human cancer cell lines. Our results reveal that phenylsulfonylfuroxan-based derivatives have considerable antitumor activity, and compounds 7-9 (IC₅₀: 0.256 - 3.024 μM) against HT-29 and PANC-1, 8a,b (IC₅₀: 2.677 - 3.051 μM) against MCF-7 and 8a (IC₅₀: 1.270 μM) against DU145 are more active than Vandetanib (IC₅₀: 1.925 - 4.107 μM). The relevant results have been published on Bioorg. Med. Chem. Lett. 2016, 26: 2355–2359.

Secondly, four series of novel IMB-1506 derivatives were designed. Due to time constraints, this study only completed the synthesis of the first series (modifications on the ethambutol fragment). The in vitro anti-tumor activity of target compounds is under evaluation, and the results are expected to be attractive. This work will undoubtedly be the foundation for subsequent structure modification of IMB - 1506.

In this dissertation, totally 70 compounds have been synthesized, 58 (including 30 target compounds) of them are structurally novel. All the compounds were characterized by ¹H NMR and MS, some of the target compounds were further confirmed by HRMS and ¹³C NMR.