毛萼乙素及5/7/6环系紫杉烷二萜的结构修饰及抗肿瘤活性研究
文献类型：学位论文
| 作者 | 赵昱 |
| 学位类别 | 博士 |
| 答辩日期 | 2007-01-22 |
| 授予单位 | 中国科学院昆明植物研究所 |
| 授予地点 | 昆明植物研究所 |
| 导师 | 赵勤实 |
| 关键词 | 毛萼乙素 紫杉烷 化学反应 活性 构效关系 |
| 其他题名 | MODIFICATION AND ANTITUMOR ACTIVITY OF ERIOCALYXIN B AND TAXOIDS WITH 5/7/6 RING SYSTEM |
| 学位专业 | 植物学 |
| 中文摘要 | 本论文由五章组成。第一章报道了毛萼乙素及其衍生物的化学和构效关系研究。第二章中，对taxayunnansin A的化学反应，尤其是一个由Red-Al引发的重排反应进行了探讨。在第三章中，报道了我们以taxchinin A 和brevifoil为底物合成了一类新颖的活性二萜，并对它们的构效关系进行了详细研究。在第四章中，介绍了对中国红豆杉 (Taxus Chinensis) 的化学成分研究。在最后一章中，对紫杉醇及其衍生物的发展历史，构效关系研究成果和目前的药物化学研究进展进行了综述。 第一章 毛萼乙素的化学反应和构效关系讨论 毛萼乙素是从毛萼香茶菜 (Isodon eriocalyx var. laxiflora)的叶子中首次分离得到的，随后发现，该化合物以0.84%的高含量存在于毛萼香茶菜的叶子中。由于具备显著的活性和新奇的作用机制，毛萼乙素被看作是一个极具发展前景的抗肿瘤化合物。因此对其进行系统的结构修饰，化学反应和构效关系研究，进而深入了解该化合物的活性，优化并寻找更多活性和水溶性更好的衍生物将是一个十分有意义的课题。在本章中，我们详细报道了对毛萼乙素的化学反应和构效关系研究的结果。其中，对毛萼乙素进行的结构修饰主要包括：还原分子中A环和D环的α,β-不饱和结构单元，对分子中6-羟基-7-半缩酮结构进行系列修饰，以及将毛萼乙素转化为其3,20-环氧类型和6,7-断裂类型的衍生物。我们对合成的22个衍生物用5个细胞株 (K562, OVCA2780, A549, DU145 和 MCF-7)进行了活性筛选。结果表明，其中一些化合物 (9–19, 25) 对各细胞株表现出不同程度的活性，IC50范围在0.27至11.9 μg/mL。构效关系研究证明：(1) D环五元环外不饱和酮和A环α,β-不饱和酮是毛萼乙素的活性中心，其中D环是主要的活性中心，A环是次要的活性中心。 (2) 6位和7位的自由羟基对增加毛萼乙素活性起重要作用。但，在六位连接上一些恰当的基团，可继续保持优异活性。(3) 为保持最佳活性，7,20-环氧结构要较3,20-环氧结构更为理想。(4) 毛萼乙素6,7-断裂衍生物25在K562, A549 和 MCF-7细胞株上表现出了显著的活性，这应是该分子内螺环内酯单元和α,β-不饱和结构单元相互协同，共同作用的效果。然而，将25的醛基氧化为羧基得到26后，发现其活性完全丧失，这一结果表明6位的羧基彻底破坏了整个化合物的活性，尽管分子内A环不饱和酮，D环环外不饱和酮，及内酯环结构依然存在。除此之外，我们还合成一个水溶性极佳的化合物28，但遗憾的是，在目前的活性筛选实验中，该化合物在体内体外的测试中，均未表现出活性。 第二章 Taxayunnansin A化学反应研究 抗癌药物紫杉醇，由于其独特的结构，新奇的作用机制和显著的临床效果，一直以来都是各国科学工作者的研究热点。为寻找到更多的类似活性化合物，研究者们对紫杉醇的构效关系进行了详细研究，并合成了大量的衍生物。但，这些研究长期以来一直集中在6/8/6环系的紫杉烷二萜上，而对5/7/6环系紫杉烷二萜的研究和报道则非常少。为了充分利用红豆杉的宝贵资源，并寻找到更多类型的活性紫杉烷二萜，我们研究组决定对5/7/6/环系的紫杉烷二萜进行详细研究。Taxayunnansin A 由于在红豆杉枝叶中的高含量，被选做母体化合物。我们设计对其进行系列修饰以期寻找到新的活性化合物。在本章中，我们详细报道了对taxayunnansin A进行的去酯基反应研究。特别是，我们发现了一个由Red-Al引发的意想不到的13-oxo-taxayunnansin A重排反应，得到了5个结构简化的产物，并对该重排反应进行了详细研究，推测并证明了一个包括自由基裂解和负氢离子转移的反应历程。一般情况，Red-Al仅被当做温和的还原剂使用，反应历程为负氢离子转移，据我们所知，这是首次报道由Red-Al引发的自由基消除重排反应。除此之外，使用MsCl试剂，我们成功的完成了将taxayunnansin A转化为一个新颖的天然紫杉烷二萜13,15-epoxy-13-epi-taxayunnasin A的反应，并推测该反应有可能就是该新化合物的生物合成路线。 第三章 Taxchinin A, Brevifoil 衍生物的合成，细胞毒活性和构效关系研究 为充分利用红豆杉植物的宝贵资源，我们研究组致力于对该种植物中含量丰富且较少引起关注的5/7/6环系紫杉烷二萜进行结构修饰并寻找活性化合物。做为该工作的一部分，我们希望对从中国红豆杉中分离到的另外两个含量大的化合物taxchinin A和brevifoil进行化学和活性研究。对taxchinin A和brevifoliol化学反应研究，发现该类5/7/6型紫杉烷二萜的一些特有化学反应。通过对taxchinin A和brevifoliol的2－3步修饰，合成21个衍生物，活性筛选发现了一系列含α,β-不饱和酮结构单元的活性紫杉烷二萜。构效关系研究证明：(1) 六元环外不饱和酮是活性中心而A环的α,β-不饱和酮结构单元对活性没有任何作用，据我们所知，这一发现尚属首次报道。(2) 13位为硅醚取代的衍生物14和13位桥醚取代的化合物18的活性始终最好。13位取代基对活性的重要作用极有可能在于协同分子中六元环外不饱和酮将化合物刚化到一个合适的活性构象。(3) 在分子内引入其它的双键，构建大共轭结构对活性没有明显的帮助。(4) 2位乙酰基可以增强该类化合物的活性。(5) 该类活性紫杉烷二萜对A549，K562和HL-60细胞株表现出选择性。 第四章 中国红豆杉化学成分研究 中国红豆杉 (Taxus chinensis) 属于红豆杉科 (Taxaceae) 红豆杉属 (Taxus) 植物。中国红豆杉中含有丰富的紫杉烷类化合物。由于枝叶容易收集而不破坏植物资源，我们对采自四川省凉山州的中国红豆杉枝叶的化学成分作进行了研究。通过各种分离手段和技术，从其乙醇提取物中共分离鉴定了13个化合物，包括5个新的紫杉烷二萜，5个已知的紫杉烷二萜和3个木脂素。 第五章 综述 回顾了重要抗癌药物紫杉醇的发展历史。总结了紫杉醇及其衍生物的构效关系研究成果。对近期紫杉烷类化合物的药物化学进展进行了综述。 |
| 英文摘要 | This dissertation consists of five chapters altogether. The first chapter reported the chemistry and strcuture–activity relationship of eriocalyxin B and its analogues. The second chapter described the chemical reaction of taxyunnansin A, especially an unexpected rearrangement of 13-oxo taxayunnansin A initiated by Red-Al. In third chapter, a novel class of abeo-taxoids with potent cytotoxicity has been prepared from non-cytotoxic and readily available taxoids, taxchinin A and brevifolil, in only two or three steps. The structure–activity relationship (SAR) of this series of compounds has been discussed thoroughly and the chemical behavior of taxchinin A and brevifolil has been reported. In fourth chapter the isolation and identification of chemical constituents from Taxus Chinensis has been described. In last chapter, the history of development, SAR and current advance in the medicinal chemistry of taxoids have been reviewed. Chapter 1.The Chemistry and Structure–Activitity Relationship of Eriocalyxin B and Its Analogues Eriocalyxin B was firstly isolated from the leaves of Isodon eriocalyx var. laxiflora in 1982, and had the highest content of 0.84% in the dried leaves of the plant. It was regarded as the promising candidate for new anticancer agent because of its potent activity and novel mechanism of action. Therefore, systematical modification and SAR studies on eriocalyxin B are important for understanding this interesting compound and searching for drug candidate. In this chapter we described the modification of eriocalyxin B and discussion of SAR. The modification on eriocalyxin B mainly included reduction of α,β-unsaturated ketones in ring A and D, modification on the 6-hydroxyl-7-hemiacetal unit and chemical conversion of eriocalyxin B to its 3,20-epoxy or 6,7-seco derivatives. The cytotoxicity of obatianed twenty-two derivatives were evaluated against five tumor cell line (K562, OVCA2780, A549, DU145 and MCF-7). Some derivatives (9–19, 25) showed different activity against the tumor cells with IC50 values varied from 0.27 to 11.9 μg/mL. From the SAR study, the following conclusions can be drawn as that (1) α,β-unsaturated ketone units in ring A and D are the active sites, in which the unit in ring D appears to be more important for the activity, (2) the hydroxyl groups at C-6 and C-7 play important role in enhancing the activity, while some appropriate modifications at C-6 is well tolerant for the activity, (3) 7,20-epoxy moiety is more optimal for the cytotoxicity than corresponding 3,20-epoxy one, and (4) The 6,7-seco type derivative 25 possessed potent activity against K562, A549 and MCF-7 which might be due to the synergism between the spirolactone part and the α,β-unsaturated ketone moiety in the molecule. While its derivative 26 showed no activity against five cell lines. This result revealed that carboxyl group could destroy activity of 25 despite the presence of α,β-unsaturated ketone moiety. Moreover we also synthesized a derivative (28) with good water-solubility, while unfortunately 28 demonstrated no in vivo and in vitro activity in our present bioactivity evaluation. Chapter 2. The Chemistry of Taxayunnansin A The unique structure complexity, novel mechanism of action, and clinical importance of the antitumor agent paclitaxel continues to elicit a great deal of SAR studies for the development of more potent analogues. However most of these studies focused on the paclitaxel skeleton (6/8/6 ring system) the reports of derivativers from taxoids with a skeleton of 5/7/6 ring-system are few. In order to access more paclitaxel-like compounds, we initiated a program toward the synthesis of derivatives with a 5/7/6 taxoids ring system. Taxayunnasin A, possessing a skeleton of 5/7/6 ring-system with oxetane ring, is chosen as starting material for its abundance in the branches and leaves of Taxus chinensis. We hope to modify this compound to find new lead compounds. Deesterification of taxayunnansin A were thus investigated for further modification on the compound. When 13-oxo taxayunnansin A was treated with Red-Al, an unexpected rearrangement reaction took place, and five novel compounds with a structurally simplified skeleton were obtained. The possible mechanism of the reaction includes free radicals fragmentation and hydride transfer simultaneously. In general, Red-Al was used as hydride transfer. To the best of our knowledge, this is the first example of Red-Al initiating free radical elimination process for the taxoids skeleton. Moreover the chemical conversion of taxayunnansin A to a new natural taxoid 13,15-epoxy-13-epi-taxayunnasin A was accomplished in quantity with employment of MsCl, which was proposed to be the biosynthetic route of 13,15-epoxy-13-epi-taxayunnasin A. Chapter 3. Synthesis, Cytotoxicity and Structure–Activity of the Taxoids from Taxchinin A and Brevifoil As part of our group’s program toward the synthesis of derivatives with a 5/7/6 ring system, taxchinin A and brevifoil, possessing a skeleton of 5/7/6 ring-system with 4(20) double bond, are chosen as another parent compounds for further investigaion for their abundance in the branches and leaves of Taxus chinensis. The unprecedented chemical behavior for 11-(15→1)-abeo-Taxanes were discorverd in the course of our chemical study on taxchinin A and brevifolil. Twenty-one taxoids were synthesized from taxchinin A and brevifolil in only two or three steps. Bioactive evaluation identified a novel class of bioactive taxoids. From the SAR study, the following conclusions can be drawn as that (1) the α,β-unsaturated ketone moiety at ring C was the active center, while the α,β-unsaturated ketone moiety at ring A have no contribution to the activity, which, to the best of our knowledge, was firstly reported, (2) 13-TBDMS-5-oxo-taxchinin A (14) and 13, 15-epoxy-13-epi-5-oxo-taxchinin A (18) showed most potent activity against all tested tumor cell lines. The substituent at C-13 may act as the conformational modifier, rigidifying bioactive conformation to remarkably enhance the activity, (3) introduction more double bonds in the molecule gave no remarkable advantage on potency, (4) the acetate at C-2 could enhance the activity, (5) this class of active taxoids presented potent activity in A459, HL-60 and K562 cell lines. Chapter 4. Study on Chemical Constituents of Taxus chinensis Taxus chinensis belongs to genus Taxus of Taxaceae, is considered as a promising source of taxane-type diterpenoids. Because they can be collected without destruction of the trees, we have further investigated the chemical constituents of the branches and leaves from Taxus chinensis collected in Liangshan prefecture of Sichuan province. As a consequence, thirteen compounds were isolated and identified from this species, including five new taxane diterpenoids, five known taxane diterpenoids and three lignans. Compounds from the branches and leaves of T. chinensis are listed as follow. 1. Baccatin III (1) 2. 10-Deacetyl-baccatin III (2) 3. 10-Deacetyltaxol (3) 4. 10-Deacetylcephalomannine (4) 5. Taxumairol C (5) 6. 2-Deacetyltaxumairol C (6)* 7. 7,9,13-Trideacetyl-14β- benzoyl taxuspine K (7)* 8. 7,13-Dideacetyl-9,10-debenzoyl-7β,9α-p-hydroxylbenzlidenedioxytaxchinin C (8)* 9. 7,13-Dideacetyl-2,9,10-debenzoyl-2-tigloyl-7β,9α-p-hydroxylbenzlidenedioxy- Taxchinin C (9)* 10. 2-Debenzoyl-10-benzoyl-7β,9α-p-hydroxylbenzlidenedioxytaxuyunnanine L (10)* 11. Secoisolariciresinol (11) 12. Secoisolariciresinol-4,4′-mono-acetonide (12) 13. Dihydrodehydrodiconiferyl alchol (13) Chapter 5. Review In this review, the history of development of the important anticancer drug taxol is dercribed. The SAR of taxol and its derivatives has been summarized. And the current advances in the medical chemistry of taxoids were presented. |
| 语种 | 中文 |
| 公开日期 | 2011-10-25 |
| 页码 | 186 |
| 源URL | [http://ir.kib.ac.cn/handle/151853/158]  |
| 专题 | 昆明植物研究所_昆明植物所硕博研究生毕业学位论文 |
| 推荐引用方式 GB/T 7714 | 赵昱. 毛萼乙素及5/7/6环系紫杉烷二萜的结构修饰及抗肿瘤活性研究[D]. 昆明植物研究所. 中国科学院昆明植物研究所. 2007. |
入库方式： OAI收割
来源：昆明植物研究所
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