I. 天然COX-2 抑制劑之結構修飾及活性研究; II. 高價碘對α,β-不飽和酮之氧化研究

I. Structural Modification and Activity of Natural COX-2 Inhibitors; II. Oxidation of α,β-Unsaturated Ketones with Hypervalent Iodine Reagent

李士霖(Su-lin Lee)

指導教授 ： 陳春雄

國立臺灣大學/醫學院/藥學研究所/碩士(2004年)

https://doi.org/10.6342/NTU.2004.00696

摘要

本論文分為 I. 天然COX-2抑制劑之結構修飾及活性研究， II. 高價碘對α,β-不飽和酮之氧化研究。

I. 天然COX-2抑制劑之結構修飾及活性研究
雖然非固醇類消炎藥物(NSAIDs)目前是最廣泛的消炎藥物，但是仍然還有腸胃毒性等耐受性的問題，這主要是因為上述藥物對於兩種環氧化酶(Cyclooxygenase, COX-1, COX-2)沒有選擇性的抑制，而且研究顯示只抑制可誘發性的第二型環氧化酶(Cyclooxygenase-2,COX-2)可以避免此副作用。因此有釵h的研究朝這方面來發展更安全更有效率的消炎藥物。
本研究主要是從天然物中找尋具有可以抑制COX-2活性的天然衍生物作為藥物設計的前導藥之模型，藉結構修飾及活性變化之研究及探討，希望能研發出具有臨床應用潛在性的藥物。
1. 先前有研究指出diarylheptanoid類的化合物oregonin (1)具有抑制COX-2的活性，而本實驗室也發現樺木科植物赤楊中具有這類的化合物。基於先前的研究以oregonin (1)作為前導藥，針對diarylheptanoid的3,5位置做不同的官能基修飾，進而研究結構變化與活性關係的探討。
以薑黃素(curcumin, 6)作為起始物，用不同條件的氫化反應可以得到各類還原態的產物。以diary- heptan-3-one為重要中間物，用還原性胺化反應製備出各diaryl-N-alkylheptan-3-amine。以上的產物的活性雖然大多不及oregonin (1)但還是可以用於研究結構活性關係。
2. 阿朴芬生物鹼具有抗心律不整、抑制乙醯膽鹼酶、抗發炎等活性。其部分結構特性與diarylbutanoid類似，因此擬製備其衍生物來研究這類化合物對於COX-2 之作用。
以波爾定鹼 (boldine, 56)做起始物，在N 6位置做開環反應可以得到次波爾定鹼 (secoboldine, 57)，再用還原胺化反應在二級胺上接上不同的苯醛，可以得到一系列的三級胺生物鹼化合物。以上化合物將來也會用於研究COX-2抑制劑的結構活性關係。
II. 高價碘對α,β-不飽和酮之氧化研究
先前已有文獻指出用lead(IV)acetate-borontrifluoride etherate (LTA/BF3-Et2O)做氧化劑，可以經由一步的重組氧化反應把α,β-不飽和酮(α,β-unsaturated ketones)氧化成β,γ-不飽和碳酸酯(β,γ-unsaturated carboxylic acid esters)衍生物。根據我們實驗室的研究，高價碘氧化劑也具有類似的氧化能力，而且具有低毒性、易取得、處理方便及具有特殊反應的特性。
以不同取代的芳香醛(arylaldehyde)跟丙酮縮合後可以得到α,β-不飽和酮，再用iodosobenzene diacetate做氧化劑氧化，可以成左滷o到β,γ-不飽和碳酸酯類化合物。根據實驗結果我們提出這個特殊氧化反應的重排反應機制。

關鍵字

高價碘氧化劑 ； 抑制劑 ； 薑黃素結構修飾 ； 第二型環氧化酶阿朴酚生物鹼結構修飾

並列摘要

This thesis contains two parts entitled as following:
I. Structural Modification and Activity of Natural COX-2 Inhibitors
II. Oxidation of α,β-Unsaturated Ketones with Hypervalent Iodine Reagent

I. Structural Modification and Activity of Natural COX-2 Inhibitors
Although the NSAID are the most widely used and prescribed drugs world-wide for the treatment of inflammation, problems still remained concerning their tolerability, in particular, gastrointestinal irritation. The latter symptom is caused by the nonselective inhibition of both cyclooxygenases, COX-1 and COX-2, it has been demonstrated that selective COX-2 inhibitors could avoid such side effect. Hence, a lot of efforts have been made on the development of selective COX-2 inhibitors to achieve safer and efficacious anti-inflammatory agents.
The purpose of this research is to explore the potential new drug leads by structural modification of several natural products that possess bioactivity against COX-2.
1. Recently oregonin (1), a diarylheptanoid, was reported to have activity against COX-2. Our previous studies found that Alnus formosana also contain such type of compounds. Based on origonin as a lead compound, a series of modifications on the 3, 5 position of diarylheptanoid structure have been carried out that provide various structures for study in SAR.
Starting from curcumin (6), various kind of reductive state products were prepared by catalytic hydrogenation with different reaction conditions. Target product diaryl-N-alkylheptan-3-amines were prepared by diary-heptan-3-one through reductive amination. The preliminary bioactivity analysis of these products against COX-2 showed lower activity compared with oregonin (1), but the results still provide us informations regarding SAR and lead optimization.
2. Aprophine alkaloids possess anti-arrhythmic, anti-cholinesterase, and anti-inflammatory activities. Based on their similar structural pattern with diaryheptanoids, some chemical modifications will be carried out to provide some compounds similar to diarybutanoids, for further study in bioactivity against COX-2.
Starting from boldine (56), secoboldine (57) was prepared by ring opening at N6 position. Then the resulting secondary amine, secoboldine (57), was treated with various substituted benzaldehydes, to form a series of diarybutanoid-like tertiary amine alkaloids. These products will be tested and explored for their SAR.

II. Oxidation of α,β-Unsaturated Ketones with Hypervalent Iodine Reagent
Literatures reported that lead (ΙV) acetate-borontrifluoride etherate (LTA/BF3-Et2O) can transform α,β-unsaturated ketone to β,γ-unsaturated carboxylic acid ester through an one-step oxidative rearrangement reaction. Our research along this line indicated that hypervalent iodine (III) reagents can also affect the same reaction. Hypervalent iodine (III) reagents have some unique properties, including low toxicity, ready availability, and easy handling, and can be applied to many useful transformations.
Thus, α,β-unsaturated ketones were prepared by base-catalized aldol condensation between substituted arylaldehydes and acetones. Using iodosobenzene diacetate as oxidants, the resulting α,β-unsaturated ketones will be transformed to β,γ-unsaturated carboxylic acid esters. We also proposed a mechanism for the rearrangement concerning this particular oxidation.

並列關鍵字

hypervalent iodine oxidant ； aporphine alkaloid structure modification ； COX-2 inhibitor ； curcumin structure modification

參考文獻

1. Vane, J. R. Pharmacology - Towards A Better Aspirin. Nature 1994, 367, 215-216.

2. Subbaramaiah, K. and Dannenberg, A. J. Cyclooxygenase 2: a molecular target for cancer prevention and treatment. Trends Pharmacol. Sci. 2003, 24, 96-102.

3. McKenna, F. COX-2: Separating myth from reality. Scandinavian Journal of Rheumatology 1999, 28, 19-29.

4. Frolich, J. C. A classification of NSAIDs according to the relative inhibition of cyclooxygenase isoenzymes. Trends in Pharmacological Sciences 1997, 18, 30-34.

5. Xie, W. L.; Chipman, J. G.; Robertson, D. L.; Erikson, R. L.; and Simmons, D. L. Expression of A Mitogen-Responsive Gene Encoding Prostaglandin Synthase Is Regulated by Messenger-Rna Splicing. Proceedings of the National Academy of Sciences of the United States of America 1991, 88, 2692-2696.