酸浆苦素结构与肠吸收特性关系及其机制的研究

Physalins are highly oxidized steroidal lactone constituents of Physalis and possess a number of interesting biological properties, including highly anti-tumor and anti-inflammatory activities. Despite the fact that research has gathered their structural identification, pharmacology, and synthesis, their absorption and metabolism in the body have not been reported. Our previous studies found that physalins have very low bioavailability in rats as well as structure-dependent absorption properties, which hindered further exploitation. How to increase their bioavailability is a big challenge for the exploitation of these compounds. This project proposes the use of the structure transformation strategy and the gastrointestinal incubation system to obtain the series derivatives of physalins and the use of LC-DAD-MS/MS to establish a qualitative and quantitative analysis platform. It then proposes the development of in-vitro and in-vivo absorption models to study these compounds’ absorption properties and corresponding mechanisms. Finally, the study proposes molecular properties analysis, comparative molecular field analysis, and an analysis of the physalins’ intestinal absorption properties to clarify the relationship between their structures and intestinal absorption properties in order to reveal molecular absorption properties and key domains. This study will provide theoretical and experimental bases for designing and developing physalin-related drug candidates with more efficacious and higher bioavailability.

酸浆苦素是酸浆属植物中一类具有良好抗肿瘤、抗炎等活性的高度氧化的环麦角甾烷类化合物。前人研究多集中于其结构鉴定、活性筛选、化学合成等方面，而我们前期对其吸收、代谢的研究发现，酸浆苦素在大鼠体内生物利用度低，且吸收具有结构依赖性，阻碍了该类化合物的进一步开发。如何提高其生物利用度是目前开发此类化合物面临的一大挑战。本项目拟在前期工作基础上，运用结构转化策略和胃肠孵育体系获得酸浆苦素的系列衍生物，采用液质联用技术建立其定性、定量分析平台；通过构建体内外转运、吸收模型，研究该类化合物体内吸收特性及相应机制；并采用分子特性计算、比较分子场分析等方法，结合酸浆苦素肠吸收特性，阐明其结构与肠吸收特性的关系，揭示影响其肠吸收特性的分子特征及关键结构域，为设计、开发兼具高效和适宜生物利用度的酸浆苦素类候选药物提供理论和实验依据。

酸浆苦素（Physalins）是酸浆属植物中一类具有良好抗肿瘤、抗炎等活性的高度氧化的环麦角甾烷类化合物。我们前期的研究发现，physalins在大鼠体内生物利用度低，为了探明此现象的原因，本项目首先从锦灯笼提取物中制备了physalin A， physalin B，isophysalin B，physalin D ，physalin H和physalin L等单体；采用液质联用技术建立physalins在不同基质中的定性、定量分析平台。其次，运用环孢素和丙磺舒分别作为PgP及MRP2的抑制剂，干预SD大鼠对灌胃给予physalins以及在体肠灌流模型对physalins在大鼠各肠段的吸收，结果显示PgP及MRP2抑制剂对physalins的吸收没有显著影响；通过对physlins在大鼠胃肠道、全血及肝微粒体中的稳定性研究发现，其在人工胃肠液中稳定性良好，但在肠道菌群孵育液、全血及肝微粒体中的稳定性较差。以上研究结果说明：存在较大的肝肠首过效应是physalins生物利用度低的主要原因。最后，对physalin B和physalin D静脉给予SD大鼠后的组织分布、代谢和排泄情况进行了研究，结果发现，physalin B在大鼠体内主要靶向分布于肺组织，且浓度远远高于其他脏器；并进一步对physalin B抗肺癌活性及相关机制进行了研究，结果表明，physalin B可抑制 CDC2/cyclin B1复合物表达，诱导A549细胞发生细胞周期阻滞，进而抑制A549细胞增殖，通过影响线粒体的功能，最终导致A549细胞发生凋亡。本项目的研究结果可对进一步提高physalins的成药性，指导制剂的研发和疾病的治疗具有较好的指导意义。