摘要
本文以计算化学方法来解决天然产物化学中存在的一些在现有实验条件下难以解决的问题。本文将从三个不同的层次进行阐述：第一个层次是天然产物的结构鉴定,通过计算天然产物的圆二色谱确定其绝对构型；第二个层次是活性天然产物的发现,运用虚拟筛选方法发现活性天然产物并进一步研究其生物活性效应；第三个层次是天然产物的反应机理研究,通过理论计算推测天然产物在生物体内的合成机理。
绝对构型的确定是目前天然产物结构鉴定中的难点之一。目前仅有X射线衍射、化学修饰等少数方法可以使用,这些方法对化合物的要求非常苛刻,前者需要质量非常好的晶体结构,后者需要进行复杂的化学修饰。对于具有复杂骨架结构、得到数量又少的天然产物而言,这些要求往往很难满足。而基于计算化合物圆二色谱的方法不需要晶体结构,只需要做出化合物的圆二色谱即可以确定其绝对构型。本文对一种新型倍半萜内酯化合物和一种新型倍半萜二聚物的圆二色谱分别进行理论计算,结合实验结果确定了它们的绝对构型。
活性天然产物的发现是目前天然产物化学研究的热点之一。相对于传统方法而言,虚拟筛选技术可以大大提高活性化合物的发现效率,加快研究其生物活性效应。本文应用虚拟筛选技术,针对抗癌靶标基质金属蛋白酶(MMPs)和抗疟靶标恶性疟原虫半胱氨酸酶(FP-2)分别发现了若干个具有较好的活性的天然产物。随后,我们挑选一个活性较好的MMPs抑制剂进行了细胞实验,发现该天然产物不仅可以抑制MMP-2和MMP-9活化态的表达,同时还能抑制癌细胞MDA-MB-231的转移。此外,本文还对FP-2体外活性最好的抑制剂做进一步的体内药效学评价,发现该天然产物通过腹腔注射给药方式对染虫小鼠有良好的体内抗疟活性,其减虫率最高达到64%；通过对其体内作用过程的跟踪和定位,得到了该化合物作用靶点的影像和质谱实验证据,从而发现它能特异性地在滋养体阶段进入疟原虫体内,这个结果也为进一步的靶标定位提供了线索。
天然产物生源反应机理研究是实现生物合成的重要理论基础。本文的理论计算为目前实验上还较难进行研究的生源合成机理提供了一种理论验证方法。本文通过对反应物的前线轨道和反应过渡态分析,推测出本文所研究的新型倍半萜二聚物的二聚反应机理为DA反应机理；并分析了该倍半帖类化合物二聚过程中产生选择性的原因,如空间位阻会影响其立体选择性,超共轭效应会影响其区域选择性。这些结果对经典DA反应机理做出了补充,同时也为理解复杂天然产物中DA反应机理提供了参考。
This thesis focuses on some problems existing in natural products chemistry, which remains unsolved under current experimental conditions. We will provide some computational chemistry methods to solve these problems from three perspectives. Firstly, we determine absolute configurations for natural products through calculating compound derived electronic circular dichroism (ECD) spectra data. Secondly, virtual screening is used to identify the bioactive hits from natural products. Thirdly, we investigate the synthetic mechanism of the natural products in the bioprocess based on the frontier molecular orbits theory.
It is difficult to determine the absolute configurations for natural products. Currently, only a few methods can be used, such as X ray single crystal diffraction, chemical derivatization. However, these methods are not applicable to complicated natural products, for it is hard to acquire crystal structures of these compounds which are also hard to be synthesized, while absolute configurations can be identified only through comparing computational spectra and experimental ones. Thus the method which just calculates the compound derived ECD spectra adopted in our work is more realizable and reliable. In particular, we calculate the ECD spectra of a sesquiterpene lactone and a sesquiterpene dimmer to determine the absolute configurations for them by comparing the computational results with the experimental ones respectively.
As for virtual screening applications, we identify several natural products hits with potent inhibitory activities against matrix metalloproteinases (MMPs) and facipain-2(FP-2), respectively. Among them, a MMPs inhibitor shows superior inhibitory effect on the expression of MMP-2and active-MMP-9, as well as suppresses the wound-healing migration of MDA-MB-231cancer cells efficiently. Besides, a FP-2inhibitor exhibits potent antimalarial activity in the model of infected mice by intraperitoneal injection, and the highest reduction rate of the malaria parasites is64%. Moreover, according to the target images and the mass spectrometry data, we find that the compound could enter the cells of the malaria parasites in the trophozoite stage specifically. These results can help us know more about mechanisms of the natural products to interact with the target.
Understanding the synthesis mechanism of the natural products is an important foundation for biosynthesis. We also provide a solution to elucidate certain biogenic synthesis mechanisms, which are difficult to be confirmed under current experimental conditions. Through analyzing the frontline orbits and transition states, we conclude that the dimerization reaction of the novel sesquiterpene dimer is a DA reaction, and the stereoselectivity of the reaction is caused by the steric hindrance, while the regioselectivity is caused by the hyperconjugation effects. These results refine the traditional DA reaction mechanism, and help us to understand the mechanism in a thorough way.
引文
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