Chemicals present in low quantity in natural product constitute an important source of chemical diversity. However, isolation of sufficient amounts of these low abundant constituents for structural modification has been a challenge for several decades and subsequently halts research on the utilization of this important source of chemicals to identify novel scaffolds for drug discovery and development. In order to address the difficulty of chemical modification of low abundant constituents in natural products, a novel combinatorial modification approach called one-pot synthesis was used to diversify a partially purified tanshinone mixture isolated from Danshen (Salvia miltiorrhiza). This led to the isolation of ten new imidazole-tanshinones [DST-(1-10)] and one oxazole-tanshinone (DST-11), the structures of which were characterized by spectroscopic methods in combination with single-crystal X-ray crystallographic analysis. vi Angiogenesis refers to the formation of new blood vessels from preexisting vasculature, and is essential in a series of physiologic processes such as embryonic development, wound healing and female reproductive cycle. Excessive or inefficient angiogenesis may lead to pathologic responses and diseases such as rheumatoid arthritis, diabetic retinopathy, tumor growth and metastasis as well as stroke, heart diseases and ulcers. The angiogenic activities of the new tanshinone derivatives (DSTs) were determined in an experimental model of chemical-induced blood vessels damage in zebrafish. Of all the tested DSTs, DST-10 with a diketone functionality at C-13 and C-14 exhibited the most potent vascular protective and restorative activity with an EC50 value of 0.026 μM. Moreover, the mechanism underlying the pro-angiogenesis effect of DST-10 in injuried blood vessels zebrafish probably involved the VEGF/FGF-Src-MAPK and PI3K-P38 signaling pathways as shown by gene expression analysis and a blocking assay with pathways-specific kinase inhibitors. Meanwhile, DST-10 had been showed significant pro-migration and pro-invasion effetcs in HUVECs, but also exhibited obvious anti-proliferation effects against MCF-7, MDA-231 and A549 cancer lines in vitro. Our results highlighted the potential of adopting a newly modified one-pot synthesis approach to enhance the chemical diversity and biological activities of constituents of natural products regardless of their abundance.

天然藥物中一些微量成分不僅豐富了化學多樣性，提供了寶貴的藥物資源， 而且具備不容忽視的優良藥效。然而，這些微量成分的提取分離工藝難度較大， 且較難獲得足夠的質量。其結構修飾更是受限已久，這些因素嚴重影響了微量化 合物作為新型前體藥物的開發。為了克服此類瓶頸，一種倍受諸多化學家推崇的 一鍋合成法被應用在大量及微量丹參酮的前期合成研究中，合成得到十個新型咪 唑丹參酮衍生物 DST-（1-10）和一個惡唑丹參酮衍生物 DST-11。利用光譜技術 結合 X-ray 單晶衍射法進行了結構鑒定。為後期的血管新生效果評價提供了物質 基礎。 血管新生是一個重要的生理過程，它涉及胚胎發育，創傷癒合和女性生理週 期等。血管新生的失調是諸多疾病的罪魁禍首，如血管新生過量將引發癌症、風 濕性關節炎，而在另一方面中風、心肌缺血以及傷口難以癒合都與血管新生不足 息息相關。 本課題利用 VRI 誘導的血管損傷斑馬魚模型篩選了十一種丹參酮衍生物的 血管新生活性，並與常見的丹參酮（丹參酮 IIA，隱丹參酮 和丹參酮 I）進行了 系統性比較。在所有十四種丹參酮類化合物中，在 C-13 和 C-14 位置上有二元酮 的 DST-10 表現出較強的保護血管效果，其 EC50值僅 0.026 μM。而且 DST-10 潛 在的血管新生作用機制通過即時定量 PCR 和特異性抑制劑實驗驗證出： DST-10 可能通過VEGF/FGF-Src-MAPK和PI3K-P38信號通路發揮作用。 與此同時DST-10 在人臍靜脈內皮細胞和三個癌細胞上分別進行了評價，DST-10 不僅對人臍靜脈 內皮細胞展示出明顯的促進遷移和侵入的效果，而且對 MCF-7，MDA-231，A549 三種癌細胞均展示了效果優越的抗增殖效果。我們的結果證實：利用一種新的一 鍋法合成，不僅能夠增強化學多樣性，提升生物活性，而且能夠克服自然界產物 中原材料稀缺的障礙，為以後合成新型化合物及利用其作為治療血管功能紊亂類 疾病提供了依據。