活性成分结构修饰和构效关系研究 (Modification and SAR on active compounds)----中国科学院昆明植物研究所

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赵勤实研究组

研究成果

活性成分结构修饰和构效关系研究 (Modification and SAR on active compounds)

文章来源: | 发布时间：2012-02-11 | 作者: | 浏览次数： | 【打印】【关闭】

　　作为新药研究候选化合物，天然化合物往往不是十全十美的。尽管一些天然化合物可以直接作为候选药物，大绝大多数化合物需要做结构修饰及构效关系研究以筛选出效价更好的化合物。同时通过结构修饰产生的一列化合物有助于对药物作用机制和靶点的认识。在过去的六年中本研究组对毛萼乙素、紫杉烷二萜，景洪哥那香素等天然产物开展了广泛结构修饰及构效关系研究。

　　Natural products have long been excellent source of novel active agents that may serve as the leads and scaffolds for elaboration into efficacious drugs. According to a review of New Chemical Entities (NCE) from 1940 to 2006, approximately 65% of drugs were delivered from natural products, or mimicked them in one form or another. Through the medicinal chemistry approach, natural products can be modified synthetically to improve their pharmacological profiles.

　　During the past five years, the modification, structure-activity relationship (SAR), and drug discovery from natural product have been studied. Erioclyxin B, taxoids, cheliensisin A, and so on were selected as starting material because of their potent bioactivity, unique structure or high content in plants.

1. 毛萼乙素结构修饰及构效关系研究 (Modification and SAR on eriocalyxin B)

　　对毛萼香茶菜（Isodon eriocalyx var. laxiflora )中的活性成分毛萼乙素展开研究。合成了22个毛萼乙素衍生物。细胞毒活性筛选和构效关系研究确认了毛萼乙素的活性中心及影响活性的各项因素。

　　Eriocalyxin B (1) was regarded as the promising candidate for new anticancer agent because of its potent activity, high content and novel mechanism of action. Systematic modification was performed on eriocalyxin B and twenty-two derivatives were synthesized and evaluated for cytotoxicity against five tumor cell lines. The SAR revealed that α,β-unsaturated ketone at ring D and A are the leading active sites. The OH-6 and OH-7 are the important enhancement factors for the cytotoxicity. 7,20-epoxy structure is more suitable for keeping a good activity than the corresponding 3,20-epoxy structure. Transformation of 1 to its 6,7-seco derivative (19) resulted in a good activity, while its 6,7-seco-20-carboxyl derivative (20) show no activity. This suggested the carboxyl group might destroy the activity, which was firstly reported . These results have been published in theEuropean Jouranl of Medicinal Chemistry.

2. 5/7/6型紫杉二萜衍生物研究(Synthesis, cytotoxic activity, and SAR analysis of derivatives of abeo-taxoids)

　　对从中国红豆杉中分离得到的5/7/6型紫杉烷二萜进行了结构改造，合成了一系列的具有α,β-不饱和酮的紫杉烷二萜衍生物，通过活性筛选发现了具备显著抗肿瘤活性的化合物。对该系列化合物构效关系进行了深入分析，并利用计算机辅助药物设计方法(QSAR)，搭建了一个可靠性和预测性高的模型,该模型将作为一个有力的工具，用于其它类似化合物的设计和活性预测。

　　Taxchinin A, one of the major taxoids contained in the leave of Taxus. Chinesis, possesses novel abeo-taxane skeleton. With taxchinin A as starting material, twenty-one derivatives were synthesized and evaluated for cytotoxicity against human non small lung cancer (A549) cell line. Nine derivatives showed potent activity with IC₅₀ values from 0.48 to 6.22 μM. The observed SAR of these derivatives shows that exocyclic unsaturated ketone at ring C is the key structural element for the activity, while the α,β-unsaturated ketone positioned at ring A have no effect for the activity. Further investigation on the SAR utilized a CoMFA method was carried out. The resulting 3D QSAR model provides an valuable tool to design more cytotoxic compounds. These results have been published in Bioorganic & Medicinal Chemistry.

　3. GC-51结构修饰及构效关系研究(Modification and SAR analysis On GC-51 )

　　GC-51是李朝明研究员从天然植物中分离到的单体化合物，该化合物对肝癌有显著的药理活性，对人的骨髓细胞无抑制作用，作用机制为诱导细胞凋亡。但该化合物面临水溶性不佳，化学不稳定性等问题，为解决上述问题，发展潜在的药物先导化合物，本研究组体统合成大量GC-51衍生物，并进行了系统细胞毒评价，发现了一系列活性表现良好，化学稳定性提高的衍生物，并进行了系统的构效关系总结。

　　Cheliensisin A is a natural styryl-lactone isolated from Goniothalamus cheliensis Hu in considerably large quantity with putative anticancer activities. However, its poor water solubility and chemical instability have precluded cheliensisin A as a potential drug candidate. To explore the strategy to overcome these problems, 21 novel derivatives of cheliensisin A with different substitutions at C-7 and C-8 positions were designed and synthesized. Inhibition of proliferation against five tumors cell lines indicates that eight new derivatives with embedment of oxazole or oxazoline exhibit improved cytotoxicity on SK-BR-3 and PANC-1, and compounds 2d and 2gshow 5-8 folds higher potency than cisplatin. HPLC investigation of representative compounds indicates that oxazole and oxazoline analogs exhibit much improved chemical stability than their natural parent. These results were published in the European Jouranl of Medicinal Chemistry.