3,5-1H-雙芳基吡唑衍生物之合成暨抑制SK-OV-3卵巢癌細胞生長之構效關係研究

Synthesis of 3,5-1H-Diarylpyrazole Derivatives and Structure-Activity Relationship Study of Growth Inhibition Against SK-OV-3 Ovarian Cancer Cells

廖浩涵(Hao-Han Liau)

指導教授 ： 蕭永政

淡江大學/理學院/化學學系碩士班/碩士(2009年)

https://doi.org/10.6846/TKU.2009.00741

摘要

本論文中我們設計了3,5-雙芳基-1H-吡唑化合物，一個簡單的分子骨架來做為抗癌的試劑。以簡單的合成方法，將苯乙酮化合物和醯氯化合物在甲苯中以六甲基二矽基胺基鋰合成1,3-雙酮化合物。之後把反應得到的混合物經過萃取和濃縮的處理，不再進一步的純化，直接在乙醇中和聯胺反應得到3,5-雙芳基-1H-吡唑化合物。再以相同的合成方法，將反應中的聯胺改為羥胺，合成了3,5-雙苯基異噁唑化合物的結構異構物混合物，且發現這個反應的化學選擇性會受到其苯環上的取代基影響。
在抑制SK-OV-3卵巢癌細胞生長的實驗中，藉由改變3,5-雙苯基-1H-吡唑化合物的官能基來觀察其結構與抑制SK-OV-3卵巢癌細胞生長的關係。由實驗結果發現3,5-雙苯基-1H-吡唑化合物做為SK-OV-3卵巢癌細胞生長抑制劑的最佳化結構：其一邊苯環上須有拉電子基，另一邊的苯環上則須為推電子基。推電子基如甲氧基在3號位置最佳，若4號位置上有氫鍵供給者像是羥基或胺基時，其抑制SK-OV-3卵巢癌細胞生長的能力可得到不錯的效果。
當我們將3,5-雙苯基-1H-吡唑化合物一邊的苯基改為1,1’-聯苯基時，其抑制SK-OV-3卵巢癌細胞的效果更好。由實驗結果發現固定3,5-雙芳基-1H-吡唑化合物一邊為1,1’-聯苯基時的最佳化結構：當苯環上有取代基使得吡唑結構中氮上的氫可以固定在靠近1,1’-聯苯基的氮上，可提升抑制SK-OV-3卵巢癌細胞生長的效果。此外，苯環上的4號位置上為氫鍵供給者時，其抑制SK-OV-3卵巢癌細胞生長的效果會下降。綜合實驗結果，發現化合物64(第53頁)和68(第55頁)為抑制SK-OV-3卵巢癌細胞生長的效果最好的3,5-雙芳基-1H-吡唑化合物，其IC50分別為0.6 ± 0.14 μM和0.5 ± 0.14 μM。

關鍵字

吡唑 ； 構效關係 ； SK-OV-3卵巢癌細胞

並列摘要

In this dissertation, we synthesized a series of 3, 5-diaryl-1H-pyrazole derivatives containing a simple molecular scaffold for the study of growth inhibitory effect in cancer cells. We took advantage of a practical synthetic route to synthesize these derivatives as shown in the followings: The 1,3-diketone intermediate was prepared by the treatment of acetophenone and benzoyl chloride in the presence of lithium bis(trimethylsilyl)amide (LiHMDS) in toluene solution. Without further purification, 1,3-diketone intermediate was treated with hydrazine and heated at reflux in ethanol solution to afford the desired products. In a similar manner, two isomers of isoxazoles were obtained by treatment of 1,3-diketone with hydroxylamine in ethanol solution. In addition, the selectivity of two isomers was dependent of substituted groups on the aromatic ring.
The growth inhibitory effect of all tested compounds was examined in the SK-OV-3 ovarian cancer cells. The results indicated that the most potent growth inhibition could be observed as one aromatic ring bearing an electron-withdrawing group while the another containing an electron-donating group in the 3,5-diaryl-1H-pyrazole scaffold. Moreover, as an electron-donating group such as methoxy group (48, IC50 = 15 ± 2 μM, page 48) located at 3-position as well as a hydrogen bond donor such as hydroxyl (77, IC50 = 10 ± 2 μM, page 52) and amino groups (78, IC50 = 18 ± 2 μM, page 52) at 4-position exhibited better growth inhibitory effects.
Surprisingly, as one aromatic group attached to the pyrazole core was replaced with a 1,1’-biphenyl group, an improved growth inhibitory effect on SK-OV-3 cells was observed. We found that 79 (2-OH on the benzene ring, IC50 = 10 ± 1 μM, page 55) maintaining the tautomerism of pyrazole in which NH closed to the 1,1’-biphenyl group revealed a better growth inhibitory as compared to its counterpart 66 (2-OMe, IC50 = 34 ± 3 μM, page 55). Meanwhile, as a hydrogen bond donor such as hydroxyl group at 4-position (80, 4-OH, IC50 = 27 ± 4 μM, page 55) exhibited a poor growth inhibitory effect in comparison with its counterpart (64, 4-OMe, IC50 = 0.6 ± 0.14 μM, page 53). Taken together, we have synthe-sized a series of 3, 5-diaryl-1H-pyrazole derivatives that exhibited some interesting structure activity relationships in the study of growth inhibi-tion of SK-OV-3 ovarian cancer cells. To further improve their physical properties such as water solubility as drug-like compounds, structural modifications of 3,5-diaryl-1H-pyrazole-based anticancer agents could be further explored in the near future.

並列關鍵字

pyrazole ； Structure-Activity Relationship ； SK-OV-3

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