兰州大学机构库 >化学化工学院
两种大戟科植物中二萜的发现及其生物活性研究
Alternative TitleDiterpenoids from Two Euphorbiaceae Plants and Their Biological Activities
张兰军
Subtype博士
Thesis Advisor高坤
2023-08-30
Degree Grantor兰州大学
Place of Conferral兰州
Degree Name理学博士
Degree Discipline化学
Keyword红雀珊瑚 Pedilanthus tithymaloides 绿玉树 Euphorbia tirucalli 假白榄烷型二萜 Targeted discovery 定向发现 Jatrophanes diterpenoids 跨环环化反应 Cyclization 多药耐药逆转活性 Multidrug resistance reversal activit P 糖蛋白 Pgp
Abstract

在亿万年的演化过程中,天然产物对物种的生存至关重要,因为它们通过调节关键蛋白酶在物种体内具有重要的生物学功能。当前的生物都是由共同祖先演化而来的,因此人类体内用于调节生命活动的某些酶可能与植物体内用于调节相似生命活动的酶相同,这也是天然产物能够治疗人类疾病的关键原因。因此,天然产物一直是新药开发的主要来源。二萜是一类重要天然产物,而大戟科植物是二萜的主要来源。大戟科二萜因其新颖的分子结构和广泛的生物活性,引起了国内外天然产物化学家、全合成化学家和药物化学家的极大关注。

为了寻找结构新颖和活性显著的二萜类化合物,本论文选取了两种大戟科的药用植物红雀珊瑚(Pedilanthus tithymaloides)和绿玉树(Euphorbia tirucalli),对它们的二萜类成分进行了系统的提取分离和结构鉴定,共获得122个天然化合物,其中天然二萜类78个,包括新结构二萜48个和新骨架二萜4个。另外,对量大的大环二萜化合物进行了结构修饰,共获得合成的衍生物25个,其中新化合物21个,包括2个新颖骨架的衍生物。最后,对所获得的部分二萜化合物进行了抗癌、抗炎和多药耐药逆转活性评价,筛选到了几个活性良好的分子。

从红雀珊瑚乙醇提取物的总二萜组分中采用定向分离策略高效分离得到假白榄烷型大环二萜55个,其中天然的新结构二萜42 个,新骨架二萜3个。它们的结构通过波谱解析、NMR计算、DP4+概率分析和ECD计算等方法得以确定,个别化合物经由仿生合成以及X-ray 单晶衍射得到验证。化合物 Pt-1-Pt-3是一类结构新颖的5/6/8稠合的三环骨架,即三环[10.3.0.02,9]十五烷体系。同时我们提出了一个该类骨架的生源假说,该生源假说的关键步骤是ene环化反应,反应中的六元环过渡态进一步通过DFT计算得到验证。此外,通过路易斯酸构建碳正离子等方案,得到了1个结构新奇的类天然产物,即大环跨环环化的5/6/5/5稠合的四环二萜新骨架化合物,同时得到关氧环的二萜衍生物;对量大的天然二萜进行了水解和氧化等修饰得到了其它一系列假白榄烷二萜衍生物。结构修饰的衍生物共25个,其中新结构21个。最后,对所获得的部分二萜化合物进行了抗癌、抗炎和多药耐药逆转活性评价。对活性突出的化合物Pt-3初步研究了其产生多药耐药逆转活性的机制,机制实验表明化合物Pt-3是通过抑制P-糖蛋白(P-glycoprotein, Pgp)的功能,从而逆转肿瘤细胞的多药耐药性。

从绿玉树甲醇提取物中分离得到了67个化合物,其中二萜类化合物23个,新化合物6个,这6个新化合物是罕见的巴豆烷型二萜糖苷类化合物,其中化合物Et-3是一种罕见的5/7/5/4四环天然新骨架。化合物Et-6是一种不常见的吡喃葡萄糖基修饰的巴豆烷型二萜糖苷。它们的结构通过1D和2D NMR、MS和酸水解来确定。活性研究表明,化合物Et-1-Et-5在非细胞毒性浓度为10 μM时,逆转了肿瘤细胞的多药耐药性,逆转倍数为17.4~64.6。机制结果表明,化合物Et-3抑制了Pgp转运蛋白的功能,从而逆转了肿瘤细胞的耐药性。

论文还综述了从大戟科植物中分离到的假白榄烷型二萜和其环化衍生物的的结构分布、结构鉴定的方法、假白榄二萜的全合成、大环跨环环化的仿生合成及其生物活性和天然产物中定向分离的策略。

本论文研究不仅丰富了二萜类化合物的结构多样性,也为大戟科药用植物的活性成分及其构效关系的研究、活性先导化合物的发现以及潜在新药的筛选提供相关的科学依据,并为进一步开发大戟科药用资源及多药耐药逆转创新药物研究提供了理论依据和物质基础。

Other Abstract

The generation of natural products is crucial for the survival of a species due to their significant biological functions in modulating key protein enzymes. Over billions of years of natural evolution, today's species have evolved from a common ancestor. Consequently, certain enzymes that regulate life activities in humans might also regulate similar activities in plants. This similarity is the primary reason why natural products are utilized in the treatment of human diseases. Natural products with complex and diverse structures have served as a fruitful source for the discovery and development of new drugs. Diterpenoids are an important class of natural products. Diterpenoids derived from the Euphorbiaceae family are major chemical components and exist as a variety of different core frameworks. Moreover, the diterpenoids isolated from Euphorbiaceae species possess a broad range of biological activities. Each member of this diterpene subfamily exhibits an intriguing and complex molecular scaffold as well as being biologically significant, attracting now great attention from the organic chemistry community.

As part of a program to search for unique and significant bioactive diterpenoids, the isolation, structural characterization, and biological activities of the diterpenoids from two medicinal plants, Pedylanthus tithimaloides and Euphorbia tirucalli, were investigated. A total of 122 compounds were obtained from the above two medicinal plants through isolation, most of which are diterpenoids (78 diterpenoids, of them 48 new diterpenoids and 4 novel skeletons diterpenoids). To more diverse diterpenoid structures of subsequent screening activities,25 diterpenoid derivatives including 21 new ones were obtained through structural modifications of major compounds. Finally, the antitumor, anti-inflammatory and multidrug resistance reversal activities of some compounds were evaluated, and the specific results are summarized as follows:

55 diterpenoid derivatives were isolated from the total diterpenoid fraction of the ethanol extract of Pedylanthus tithimaloides, including 42 new compounds. Their structures were elucidated via an extensive analysis of HRESIMS, NMR, quantum-chemical calculation, DP4+ probability, and X-ray crystallographic data. Compounds Pt-1-Pt-3 describe an unusual 5/6/8 fused tricyclic with a unique tricyclic[10.3.0.02,9]pentadecane framework. A hypothetical biosynthetic pathway was proposed, which further supported the ene cyclization of 5/12 bicyclic diterpenoids to 5/6/8 tricyclic diterpenoid. The ene reaction mechanism was further examined through density functional theory (DFT) calculations. The synthesis experiment results showed that the jatrophane diterpenoid forms the intermediate of carbocation and then undergoes the series cyclization of carbocation, under the Lewis acid, and a natural-like new framework type diterpenoid was obtained. In addition, other novel oxycycloditerpenoids were also found. A series of new jatrophane diterpenoid derivatives were obtained by hydrolysis and oxidation of jatrophane diterpenoids. Finally, some diterpenoids were evaluated for their anticancer, anti-inflammatory and multidrug resistance reversal activities. The mechanism results indicated that compound Pt-3 inhibited the P-glycoprotein (Pgp) transporter function, thus reversing the drug resistance.

67 compounds were isolated from the methanol extract of Euphorbia tirucalli, including 23 diterpenoids and 6 new compounds. Compounds Et-1-Et-6 are rare examples of the tigliane-type diterpenoid glucosides. Compound Et-3 is a rare 5/7/5/4 tetracyclic natural skeleton. Compound Et-6 is the first example of an unusual glucopyranosyl-modified tigliane-type diterpenoid glucoside. Their structures were determined by a combination of 1D and 2D NMR, MS, and acid hydrolysis. Compounds Et-1-Et-5 reversed multidrug resistance in cancer cells with the fold-reversals ranging from 17.4 to 64.6 at the noncytotoxic concentration of 10 μM. The mechanism results indicated that compound Et-3 inhibited the P-glycoprotein (Pgp) transporter function, thus reversing the drug resistance.

In this thesis, the jatrophane diterpenoids and their cyclized derivatives with biological activities, which were isolated from Euphorbiaceae plants, and the total synthesis of jatrophane diterpenoids were summarized. In addition, the strategies for targeted isolation from natural products are summarized.

Our research results could further enrich the natural product library of diterpenoids and provide relevant study of the active constituents from the Euphorbiaceae medicinal plants, their structure-activity relationships, discovery of active lead compounds, and on the screening of potential new drugs. In addition, all studies could also provide new ideas for the research and development of traditional Chinese medicine.

Subject Area天然产物化学
MOST Discipline Catalogue理学 - 化学
URL查看原文
Language中文
Other Code262010_120190903811
Document Type学位论文
Identifierhttps://ir.lzu.edu.cn/handle/262010/538057
Collection化学化工学院
Affiliation
兰州大学化学化工学院
Recommended Citation
GB/T 7714
张兰军. 两种大戟科植物中二萜的发现及其生物活性研究[D]. 兰州. 兰州大学,2023.
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