目前醫學上發現許多因素可以直接或間接地讓腫瘤細胞免於衰老甚至凋亡，造成腫瘤細胞持續增生並轉移至其他部位。其中腫瘤相關巨噬細胞 (TAMs) 就在癌症的擴散中扮演著重要的角色，腫瘤相關巨噬細胞的浸潤會使免疫系統中的T細胞被調節抑制，降低免疫系統清除腫瘤細胞的功能最終導致癌細胞繼續生長。集落刺激因子1受體 (CSF1R) 與其配體CSF1的表現已經在許多種腫瘤中得到證實，例如典型霍奇金氏淋巴瘤、乳腺癌、卵巢癌和肺癌等等。透過針對CSF1R訊號的傳遞進行抑制來減少腫瘤相關巨噬細胞是一種極具開發潛力的免疫療法，因此我們致力於開發具有抗癌效果和高選擇性的口服集落刺激因子1受體抑制劑 (CSF1R inhibitor)。
我們實驗室最近開發了先導化合物BPR1R062 (22)，但考量到其許多類藥性質仍有改進的空間，因此對其進行中間連接體和末端側鏈與活性關係之間的探討，期望透過結構的修飾增加化合物對CSF1R的抑制活性並使其在藥物動力學中有更好的表現。在對BPR1R062 (22) 進行一系列的結構最佳化後，得到了先導化合物85 (IC50 = 14.3 nM) 和86 (IC50 = 8.2 nM)，且化合物85在藥物動力學和骨髓源性巨噬細胞抑制實驗中皆有非常好的表現，另外為了提高化合物86的藥物口服吸收能力，我們也對其進行結構的修飾並成功的增加其溶解度。
另一方面為了加速衍生物的合成並用於研究末端側鏈對抑制活性的影響，我們開發了一套可信任的高通量平行合成平台，篩選出對CSF1R有良好抑制活性的化合物139 (IC50 = 10.8 nM)，未來可透過此方法快速且大量的合成更多衍生物。

A wide variety of factors cause tumor cells to evade apotosis and senescence, and thus lead to tumor growth and metastasis. Tumor-associated macrophages (TAMs) have a significant effect in multiple human malignancies, its infiltration is correlated to mediate T cell to reduce the immunity and make tumor progression. Expression of colony stimulating factor 1 receptor (CSF1R) and its ligand CSF1 has been documented in several human malignancies including classical Hodgkin’s lymphoma, breast, ovarian, and lung cancer. Targeting CSF1R is a potential immunotherapy to reduce TAMs, so we’ve been committed to developing orally available and highly selective CSF1R inhibitors that exhibited immunomodulatory anti-tumor efficacy.
BPR1R062 (22), the lead compound discovered by our laboratory recently, its drug-like properties still have room for improvement, so we performed structure activity relationship studies utilizing different types of linkers and terminal moieties to improve CSF1R inhibition and to promote pharmacokinetic properties. After a series of structural optimizations of BPR1R062 (22), lead compound 85 (IC50 = 14.3 nM) and 86 (IC50 = 8.2 nM) were obtained, compound 85 showed good performance in both pharmacokinetics study and bone marrow derived macrophage inhibition study. In addition, in order to improve the drug absorption capacity of compound 86, we also modified its structure and successfully increased its solubility.
On the other hand, in order to accelerate the synthesis of drug derivatives and to study the effect of terminal moiety on inhibitory activity, we developed a trusted high-throughput parallel synthesis (HTPS) platform via urea formation and found compound 139 with IC50 of 10.8 nM. In the future, more derivatives can be synthesized rapidly through this method.

壹、緒論 1
1.1 前言 1
1.2 癌症的治療 2
1.3 蛋白質激酶(Protein kinase) 4
1.3.1 激酶運作方式 4
1.3.2 激酶抑制劑 5
1.4 免疫激酶 (Immuno kinase) 8
1.5 癌症免疫治療 (Cancer immunotherapy) 12
1.6 集落刺激因子1受體 (Colony stimulating factor 1 receptor, CSF1R) 15
1.6.1 CSF1R 結構 16
1.6.2 CSF1R 活化過程 16
1.6.3 CSF1R 訊息傳遞路徑 17
1.7 CSF1R 與癌症免疫療法 19
1.7.1 腫瘤相關巨噬細胞 (Tumor-associated macrophage, TAMs) 19
1.7.2 CSF1 / CSF1R 與M1 / M2 的關係 20
1.8 與CSF1 / CSF1R 相關的疾病 20
1.9 CSF1R 激酶抑制劑 22
貳、研究動機 27
2.1 具喹唑啉核心結構之CSF1R抑制劑最佳化 - BPR1R062 之開發歷程 27
2.2 研究構想 29
2.2.1 改變中間連接體 (5,6-Bicyclic ring linker variation) 30
2.2.2 改變末端側鏈 (Terminal moiety variation) 31
2.2.3 增加BPR1R062系列化合物水溶解度 31
2.2.4 BPR1R062系列末端側鏈最佳化與流程優化 32
2.2.5高通量平行合成平台 (High-throughput parallel synthesis, HTPS) 32
2.3 生物活性測試分析 35
2.3.1 酵素抑制活性測試 (Enzyme assay) 36
2.3.2 細胞株生長抑制測試 (Cell assay) 37
2.3.3 微粒體代謝穩定性測試 (Microsomal stability assay) 38
2.3.4 骨髓源性巨噬細胞抑制測試 (Bone marrow-derived macrophage assay) 38
2.3.5 藥物動力學測試 (Pharmacokinetics study, PK) 39
2.3.6 溶解度測試 (Solubility test) 40
參、結果與討論 41
3.1 不同五六環中間體對活性的影響 41
3.1.1 喹唑啉核心結構合成 41
3.1.2 末端側鏈合成 42
3.1.3 五六環衍生物合成-尿素結構 (38 - 41) 43
3.1.4 五六環衍生物合成-醯胺結構 43
3.2 引入具有優異活性潛力之側鏈 48
3.2.1 兩種重要的中間體合成 49
3.2.2 衍生物85-88之合成 49
3.2.3 衍生物85-88之活性分析 50
3.2.4 衍生物85-88之藥物動力學測試 52
3.2.5 先導化合物85 和 86 之溶解度測試 55
3.2.6 先導化合物 85 之 BMDM 測試 & Kinase Profiling 測試 57
3.3 末端側鏈對 CSF1R 抑制活性的影響 58
3.4 改善衍生物86之水溶解度對抑制活性的影響 62
3.4.1直接加上水溶性基團對活性的影響 62
3.4.2 改變分子平面性對活性的影響 65
3.5 高速平行合成平台 69
3.5.1核心中間體合成 69
3.5.2 平行合成方法 70
3.5.3 平行合成平台可信度 72
3.5.4 平行合成結果與活性分析 73
3.6 吲哚系列衍生物光譜解析 77
肆、總結 82
4.1 先導化合物BPR1R062結構修飾最佳化 82
4.2 未來展望 85
伍、實驗部分 86
5.1 一般實驗方法 86
5.2 化合物合成步驟與光譜資料 87
陸、參考資料 162
附錄ㄧ、化合物之核磁共振光譜圖 168
附錄二、化合物之編號對照表 223
附錄三、生物活性測試方法 225
附錄四、論文口試投影片 229

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