| 摘要: | 隨著預期壽命的上升，癌症所造成的死亡率更加明顯，因此，許多研究人員專注於癌症研究。核糖核苷酸還原酶(ribonucleotide reductase, RR)是由 RRM1 和RRM2 組成的酵素。RR 在體內扮演催化核糖核苷轉化為脫氧核糖核苷，後者為DNA 合成原料，近年發現 RR 在部分癌症有過度表達的情況，使其具有成為良好的抗癌藥物的潛力。目前已上市的 RR 抑制劑中，gemcitabine 最為廣為使用，被用在胰腺癌的一線治療和乳腺癌的二線治療。然而，傳統的 RR 抑制劑是不可逆的，並且會導致由 DNA 鏈終止引發的嚴重副作用。
Dr. Chris Dealwis 的實驗室使用 Schrödinger 軟體篩選由 350,000 種化合物組成的 Cincinnati 資料庫，得到第一個 RRM1 高選擇可逆抑制劑 NSAH (8)。基於對接(docking)研究結果，發現水楊酰肼(salicyl hydrazide)結構與 hRRM1 中的半胱氨酸(cysteine)具有相互作用進而形成抑制活性。鑒於上述結果，本次實驗通過稠環系統拆解(dissociation of fused-ring system)與生物等效性(bioisosterism)的策略修飾連結(linkage)和 2-萘酚(2-naphthol)兩部分，並進行 SAR 研究討論。實驗結果顯示，所合成的 20 個化合物(9a-22)，大部分都具有較 NSAH 更好的結合親和力。在細胞研究中，16 顯示對 Panc1 細胞抑制活性較 NSAH 提升 2 倍，IC50 值為 0.393 μM，同樣也表現在其他癌細胞株，這為抗胰腺藥物的開發開闢了道路。
α-和 β-微管蛋白會聚合形成微管，後者對許多細胞生理功能是必不可少的，諸如：胞器移動、訊息傳導。有絲分裂等。而抗微管蛋白劑具有阻斷有絲分裂能力，隨後誘導細胞凋亡發生，對於癌細胞具有強烈毒性，使得這類抑制劑在臨床中廣為使用，例如長春花生物鹼，紫杉醇和秋水仙鹼。苯並咪唑(benzimidazole)為藥物中常見的活性結構，而本次實驗為了保留具有抗癌活性的 combretastatin A4 的 Z-構型，在先前研究結果中引入 benzimidazole，達到鎖定 Z-構型，設計出一系列 1,2-diarylbenzimidazole 衍生物。本研究先使用在亞硫酸鈉存在下使鄰苯二胺(o-phenylenediamine)與各種苯甲醛反應得到benzimidazole，這與傳統上通過鄰苯二胺與烷基腈(alkylnitrile)的縮合或在疊氮化鈉存在下 2-鹵代苯胺(2-halophenylamine)與苯甲醛的反應明顯不同。隨後利用銅介導的 Chan-Lam 反應與各種芳基硼酸進行芳基化反應，生成所設計的1,2-diarylbenzimidazole。
As life expectancy increases, the rate of death from cancer is more obvious. Therefore, many researchers focus on cancer research. Ribonucleotide reductase (RR) is an enzyme consisting of RRM1 and RRM2. RR catalyzes the conversion of ribonucleotides into deoxyribonucleotide and is found overexpressed in cancer cell. Nowadays, RR inhibitors such as gemcitabine are used as a first line treatment of pancreatic cancer and second line treatment of breast cancer. However, those traditional RR inhibitors are irreversible, and lead to severe side effects caused by DNA chain termination activity.
Dr. Dealwis’ lab screened the Cincinnati library consisting of 350,000 compounds in silico using the Schrödinger software suite. Based on the docking study, the salicyl hydrazide group was reserved showing an interaction with cysteine in hRRM1. Instead, the linkage and 2-naphthol group were modified by strategies of ring dissociation and bioisosterism to conduct SAR study. As a result, twenty compounds (9a-22) were synthesized and most of them showed better binding affinity than NSAH. In cellular study, 16 shows two-fold potent against Panc1 cells with an IC50 value of 0.393 μM which opens an avenue to development of anti-pancreatic agents.
In addition, α- and β-tubulins polymerize into microtubules which are essential to cell transport, signaling, mitosis, and so on. Blocking the progression of mitosis and prolonging activation of the mitotic checkpoint induces apoptosis. There are numerous anti-tubulin agents used in clinics, for examples, Vinca alkaloids, the taxanes, and colchicine.
Benzimidazole is a common heterocycle that is comprehensively found in bioactive molecules. To retain Z-geometry of combretastatin A4, which contributes anticancer activity, a series of 1,2-diarylbenzimidazoles were deigned. This study utilized copper-mediated Chan-Lam reaction to afford designed compounds, which is different from traditional syntheses of benzimidazole through condensation of ophenylenediamine with alkylnitrile and reaction of 2-halo-phenylamine with benzaldehyde in the presence of sodium azide. Accordingly, o-phenylenediamine was reacted with various benzaldehydes in the presence of sodium sulfite, and the resulting 2-aryl benzimidazoles underwent Chan-Lam arylation with various arylboronic acids to generate designed 1,2-diarylbenzimidazoles. |
