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研究生： 張欽安
Teoh, Chin-Ang
論文名稱： 探討5-羥基葵酸鈉對紫杉醇引發周邊神經病變的神經保護效果之構效關係
Structure-Activity Relationship Study of Sodium 5-Hydroxydecanoate as a Novel Neuroprotective Agent against Paclitaxel-Induced Peripheral Neuropathy
指導教授： 洪欣儀
Hung, Hsin-Yi
學位類別： 碩士
Master
系所名稱： 醫學院 - 臨床藥學與藥物科技研究所
Institute of Clinical Pharmacy and Pharmaceutical sciences
論文出版年： 2020
畢業學年度： 108
語文別： 英文
論文頁數： 115
中文關鍵詞： 5-羥基葵酸鈉 、神經保護 、紫杉醇引發周邊神經病變
外文關鍵詞： 5-Hydroxydecanoate, 5-HD, Neuroprotection, Paclitaxel-Induced Peripheral Neuropathy, CIPN
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    • 如今，隨著化療技術的進步，癌症病患的存活率大幅提升。因此，化療所引發的嚴重副作用如周邊神經病變，大幅影響病患接受化療後的日常生活。此外，周邊神經病變的產生也經常限制了化療的劑量，進而影響化療的治療效果。因為紫杉醇 (Paclitaxel)具有良好的抗癌活性，所以在臨床上紫杉醇為常用的化療藥物。然而，接受紫杉醇治療的病人可能伴隨著不可逆的周邊神經系統的損傷，使其在化療後的生活品質受到嚴重影響。目前在臨床上並無任何有效的治療或預防手段來應對紫杉醇引發的周邊神經病變，僅能減緩病人的部分症狀。近期一項高通量神經保護劑篩選研究 (high content screening) 中發現了5-羟基葵酸鈉 (5-HD) 對於紫杉醇所引發周邊神經病變具有良好的神經保護效果。為了能夠更加了解 5-HD 的神經保護功效，我們設計了一個5-HD構效關係 (SAR) 的探討。在這項研究中，透過化學合成的方式，成功合成出21個5-HD衍生物。這21個衍生物包含了以下5-HD的結構變化：羟基的位置，直鏈烷骨架的長度，氧化態，官能基以及骨架結構。其中，化合物1至化合物20已完成體外神經保護活性的篩選。在體外神經保護活性的篩選結果中，化合物12與20具有比5-HD更優秀的神經保護效果而化合物18則具有神經毒性。因此，我們進一步去探討化合物12與20在體內的神經保護效果。結果顯示預防性給予化合物12與20 (2.5 mg/kg及5 mg/kg) 皆在周邊神經病變的動物模型中有效緩解紫杉醇引發的機械性痛覺超敏並恢復其受損的熱靈敏度至正常水平。此外，化合物12與20對於小鼠的基礎活動力與體重並無明顯負面影響，說明化合物12與20對小鼠無明顯的毒性。由此可證，化合物12與20為具有潛力的神經保護候選藥物，未來我們會以此初步結果進行更多5-HD結構的修飾，並試圖找出其神經保護活性的機轉，尋求治療紫杉醇引發的周邊神經病變的候選化合物。

    Advances in chemotherapy increase the life span of cancer patients; therefore, severe chemotherapy side effects, such as peripheral neuropathy (PN), pronouncedly affected the patient’s life. PN not only is a major dose-limiting factor of paclitaxel treatment but also impacts patient’s quality of life due to the impairments of sensory and motor neurons which may be irreversible. In clinical, neither treatment nor prevention strategy is available for paclitaxel-induced PN. Only symptomatic treatment is given. A recent high content screening in rodents reported sodium 5-hydroxydecanoate (5-HD) showed a significant neuroprotective effect against paclitaxel-induced PN. To better understand the scope of 5-HD as a neuroprotective agent against paclitaxel-induced PN, a structure-activity relationship (SAR) study of 5-HD was conducted. In this study, 21 structural analogs of 5-HD were synthesized. These structural analogs were designed based on the manipulations of: (i) hydroxy group positions, (ii) hydrocarbon side chain length, (iii) oxidation states, (iv) functional groups and (v) backbone diversities. A total number of 20 5-HD analogs (compound 1−20) were tested for their neuroprotective effect. Among all the screened analogs, one compound showed neurotoxicity and two compounds showed remarkable neuroprotective effects. Compound 18 (1 μM) jeopardized the paclitaxel-induced neurite outgrowth damages of drosal root ganglion (DRG) neurons. On the other hand, compound 12 and compound 20 showed outstanding in vitro neuroprotective effects. Treatment with compound 12 (1 μM) and compound 20 (10 nM) prior to paclitaxel exposure (1 μM) protected DRG neurons from damages. In addition, both compounds showed statistically significant (p < 0.05) with the positive control group (treated with 1000 nM of 5-HD) at the concentration above. In animal behavior test, mice treated with both compounds alleviated mechanical allodynia and regained thermal sensitivity, in comparison to the paclitaxel treated only group. No significant body weight loss was found in the mice treated with compound 12 and 20. Interestingly, unlike 5-HD, both compounds showed no negative effect on mice’s locomotor activity. As a result, compound 12 and 20 may be a better neuroprotective agent candidate than 5-HD for the prophylaxis of paclitaxel-induced PN. In the future, the design and synthesis of 5-HD structural analogs will be continued and the screening criteria of the neuroprotective drugs will be further optimized.

    中文摘要……………………………………………………………………………….. I Abstract………………………………………………………………………………...II Acknowledgements……………………………………………………………….. III Index………………………………………………………………………………........ V Abbreviations………………………………………………………………………….VIII Table Index……………………………………………………………………………..IX Figure Index…………………………………………………………………………… X Scheme Index…………………………………………………………………………XIII 1. Introduction…………………………………………………………………….1 1.1. Cancer and chemotherapy……………………………………………….1 1.2. Adverse effects of chemotherapy……………………………………3 1.2.1. Bodyweight loss……………………………………………………….3 1.2.2. Myelosuppression………………………………………………………3 1.2.3. Renal dysfunction………………………………………………………4 1.2.4. Peripheral Neuropathy………………………………………………4 1.3. Paclitaxel and paclitaxel-induced peripheral neuropathy……8 1.3.1. Paclitaxel therapy……………………………………………………….8 1.3.2. Paclitaxel-induced peripheral neuropathy…………………10 2. Research Motives and Study Aims……………………………………13 3. Method……………………………………………………………..................15 3.1. Chemistry……………………………………………………………..............15 3.1.1. Series A: Manipulation of hydroxy group positions…….15 3.1.2. Series B: Manipulation of hydrocarbon backbone lengths……16 3.1.3. Series C: Manipulation of oxidation states……………………………17 3.1.4. Series D: Manipulation of functional groups…………………………18 3.1.5. Series E: Manipulation of backbone diversities…………………….19 3.2. Biology……………………………………......................................................20 3.2.1. Primary dorsal root ganglion (DRG) cell culture……………………20 3.2.2. In vitro neuroprotective screening assay………………………………20 3.2.3. Immunofluorescence and automated image acquisition………21 3.2.4. Animal behavioral tests and drug administration………………….21 3.2.5. Statistical analysis……………………………………............................ 23 4. Results……………………………………......................................................24 4.1. Chemistry……………………………………..................................................24 4.1.1. Series A: Manipulation of hydroxy group positions……………….24 4.1.2. Series B: Manipulation of hydrocarbon backbone lengths…….25 4.1.3. Series C: Manipulation of oxidationstates…………………………….27 4.1.4. Series D: Manipulation of functional groups…………………………29 4.1.5. Series E: Manipulation of backbone diversities…………………….31 4.2. In vitro neuroprotective effect screening results………………………….34 4.3. In vivo animal behavioral test………………………………………………………38 4.3.1. Von Frey test……………………………………......................................38 4.3.2. Warm water tail immersion test…………………………………………….38 4.3.3. Bodyweight measurement…………………………………………………....41 4.3.4. Locomotor activity measurement……………………………………….…42 5. Discussion…………………………………………………...................................43 5.1. Chemistry…………………………………………………... ………..........43 5.2. Biology…………………………………………………... ………………….......47 6. Conclusion and Future works…………………………………………………….49 7. Experimental Section………………………………………………………......51 7.1. General consideration…………………………………………………..……...51 7.1.1. Reagent and solvent………………………………………………….............51 7.1.2. Preparation of solutions………………………………………………….......51 7.1.2.1. p-anisaldehyde TLC staining solution…………………………………51 7.1.2.2. KMnO4 TLC staining solution……………………………………........51 7.1.2.3. NaOH solution (1.0 M) ………………………………………………...51 7.1.2.4. Jones reagent (2.5 M) …………………………………………………..51 7.2. Chromatography…………………………………………………..........................52 7.2.1. Thin-layer chromatography (TLC) ………………………………………….52 7.2.2. Column chromatography…………………………………………………….52 7.3. Analytical instruments…………………………………………………............52 7.3.1. Nuclear Magnetic Resonance Spectrometer (NMR) ………………..52 7.3.2. Infrared Spectrometer (FT/IR)……………………………………………….52 7.3.3. Low-resolution Mass Spectrometer (LRMS)…………………………...53 7.4. Synthetic procedures…………………………………………………......................53 References……………………………………………………………………………...67 Supplementary data …………………………………………………………………..74

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