Annonaceous acetogenins 是新種類的天然物， 他們具有多種生物活性， 包含了細胞毒素 (cytotoxic)、抗癌(antitumor)、抗瘧疾(antimalarial)、抑制免疫力(immunosuppressive)、殺蟲劑 (pesticidal) 和antifeedant agent。其活化機制涉及到(1)抑制血漿細胞膜內的NADH 氧化.. (2)抑制粒線體的 NADH-ubiquinone 還原.。 這類天然物中最具有抗癌活性的化合物bullatacin，其全合成需要十幾個步驟。經由電腦分子模擬bullatacin 的結構，發現生物活性與羥基及骨架上的氧原子有關，但與THF 環的存在與否無關，因此Wu et al.發現化合物47 比adriamycin 及化合物36 對於HT-29 cell line 更具有抑制效果。 5 O O OH OH 5 O O OH bullatacin 3 5 O O OH OH 5 O O OH 47 5 O O OH OH 5 O O 36 另外有文獻報告指出Annonaceous acetogenins 可藉由其長鏈中的氧原子與二價金屬離子 (Ca2+,Mg2+)鍵結形成錯合物(complex)，而此錯合物能有效溶解在細胞膜形成ionophore，導致Ca2+累積在cytosol 進而活化其他transcriptional factors，最後誘導癌細胞死亡，例如:細胞自毀(apoptosis)，換句話說：形成ionophore 能力越好，抗癌的活性就越好。 因此本計畫欲結合以上兩個觀點，藉由合成化學建構出不同官能基之bullatacin 類似物(60, 61, 62)，其骨架上含有兩個氮原子及一到三個的胺基 (NH2)，進而觀察這些衍生物之不同官能基對於形成ionophore 能力以及抗癌活性有何關聯，希望藉此找到更好的抗癌藥物。
Annonaceous acetogenins, a relatively new class of natural products so far only found in Annonaceae, have been attracting wordwide attention in recent years because of their potent biological activities including cytotoxic, antitumor, antimalarial, immunosuppressive, presticidal, and antifeedant agent.1 Their modes of action are related to the inhibition against either NADH oxidase in plasma membrane or mitochondrial NADH-ubiquinone reductase. The isolation, structure elucidation and synthesis of these compounds have been a area of active research during the past decade.2 More than 400 compounds have been isolated up to date; the most potent molecule possess central 10-carbon fragments comprising two adjacent 2,5-disubstituted tetrahydrofuran subunits flanked by secondary carbinols.3 (trans╱ threo╱trans) of bis-THF core stereochemistries compounds 1-4 are shown in Figure 1. Their structural similarity suggests that they could be derived from a common precursor.
