背景和目的：在粒線體電子傳遞鏈已知為細胞中產能的最重要過程，在傳遞過程中主要包括了四個複合體(complexes I, II, III, and IV)，其中complex I (NADH:ubiquinone oxidoreductase) 為高能分子NADH 進入電子傳遞鏈的入口。而細胞中可以轉換出ATP 的高能分子除了NADH 外另一個則是FADH2，而complex II 則是FADH2高能分子的入口處，在細胞中NADH 扮演了主要提供能量的角色，而FADH2 則較為少量且次要。Pterulon為真菌Pterula sp 82618 所代謝出來具有抗其他真菌的代謝物質，根據研究發現此化合物具有抑制complex I 酵素活性，部分屬於complex I 抑制劑的化合物已被應用於農業上作為殺蟲劑方面的用途。近年來在一些報告中發現這類抑制劑對正常細胞的細胞毒性相當得低(IC50 = 36 M)但卻可以有效的抑制癌細胞的生長，雖然完整的機制尚未清楚膫解但已知主要的途徑是藉由抑制促進癌細胞生長的酵素ODC(orthine decarboxylase，是癌細胞中特有的酵素) 的活性而達到抑制癌細胞生長的目的。方法：本研究主要是利用經全合成的天然物pterulone 及其衍生物對純化出來的細胞粒線體電子傳遞鏈中complex I 酵素活性的抑制效果進行探討。結果：由本研究結果中發現目前所合成的這些化合物其抑制酵素活性的效果仍未達理想，即抑制酵素活性IC50仍是太高介於4~55 (M 之間接近於pterulone 的抑制活性與rotenone 的0.5 nM 相差甚遠。結論：因此還需再進行結構式的修改後再利用酵素活性的測試以篩選出更好的化合物。

Background and Purpose: Complex-I is the first of fivefive large enzyme complexes in respiratorychain located in the inner mitochondrial membrane. This enzyme forms the electron transport chain thatcarries electrons fromNADHtomolecular oxygen during oxidative phosphorylation. There are a wide varietyof natural and synthetic inhibitors of complex Iwhich have foundmultiple applications. Recently, it has beenshown that inhibition of complex-I causes a concomitant reduction in the activity of orthine decarboxylase(ODC) . Orthine decarboxylase (ODC) is responsible for the biosynthesis of polyamine growth factorsrequired for cellular proliferation, and induction of ODC activity has been associated with tumor promotion.Since the overexpression of ODC in tumor cells contributes to aberrant proliferation, the ability of complex Iinhibitors to reduce ODC activity makes them promising candidates as next-generation antitumor agents.The fungalmetabolites pterulone (1) and its analogue 2were isolated fromfermentations of a Pterula sp. 82168specimen andMycena galopus, respectively. Pterulone (1) exhibited significant antifungal activity, and it is ahighly potent inhibitor of complex I with an IC50 value of 36 M. Although the pharmacological profile of 2has not yet been reported, compound 2 is structurally related to 1; therefore, it is believed that 2 will exhibitsimilar biological activities as pterulone (1) . The goal of this study was to identify novel lead complex Iinhibitors through a structure-activity relationship (SAR) study based on compound 2. These leadcompounds synthesized through this SAR study may be more amenable to further synthetic modification asrequired for optimization of physical and pharmacological properties. Methods: This was a total synthesispathway to synthesize the pterulone and its datives. The bioactivity of these compounds were evaluated bythe inhibition activity to complex-I. Results: The sevenseven compounds have been synthesized in thisstudy, and they exhibit IC50 values of between 4 and 55 M; thus, they are much less potent compared withrotenone (IC50 = 0.5 nM) . The antagonistic effects of the analogues examined herein showed only smallimprovements compared to pterulone (IC50 = 36 M) . Conclusion: From this preliminary SAR study, thedata suggest that the binding environment for these inhibitors is composed of a hydrophobic amino acid, andthe dimensions of the binding site are large enough to tolerate a large halogen group. A detailed study on thebinding domain by varying the inhibitors is currently underway.