雌激素靶向配体调控的高活性卤代喹啉-镧系系列抗肿瘤配合物

In order to improve the low activity and selectivity of lanthanide complexes, starting from the concept of target-ligand-metal interaction, by means of estrogen receptors(ERs) and halogen effect, we design and synthesize estrogen targeting halo-substituted quinolinol and isoquinoline ligands, which react with la(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Er(III) and Ce(III) lanthanide salts to afford a series of complexes. The composition and structure of these lanthainde complexes are characterized by various spectroscopic methods and single-crystal X-ray diffraction analysis. Through the in vitro inhibition proliferation experiments of lanthanide complexes on estrogen-sensitive ER(+) and estrogen-insensitive ER(-) cell lines including breast, uterine and ovarian, the lanthanide complexes (candidates) with high antitumor activity and good selectivity are screened. The in vivo antitumor activity of the candidates are tested on the murine breast cancer models ER(+)MXT-M-3,2 and ER(-)MXT(ovex). The influence of the candidates on cell cycle is investigated. The estrogen receptor binding affinity (RBA) to the candidates, and the interaction between the potential molecular target DNA and the candidates are investigated. The action mechanism of these lanthanide antitumor complexes is initially discussed. It is expected that this project will provide new thought to obtain highly active and selective lanthanide antitumor complexes regulated and controlled by estrogen targeting ligands.

针对镧系抗肿瘤配合物活性低、选择性低的问题，从靶向-配体-金属三者相互作用的理念出发,利用雌激素受体(ERs)和卤素效应,设计、合成雌激素靶向卤代喹啉和异喹啉作为调控配体，再与镧、镨、钕、钐、铕、钆、铒、铈等镧系金属配位获得系列配合物。通过多种谱学手段和单晶X-射线衍射分析表征所合成镧系配合物的组成和结构。再通过镧系配合物对雌激素敏感ER(+)和雌激素不敏感ER(-)乳腺癌、卵巢癌、子宫癌细胞株的抑制增殖作用的体外实验进行筛选，得到活性高、选择性好的雌激素-卤代喹啉、异喹啉镧系抗肿瘤配合物（候选化合物）。通过小鼠ER(+)MXT-M-3,2和ER(-)MXT(ovex)模型评价候选化合物的体内抗肿瘤活性。研究候选化合物对胞增殖周期的影响和对雌激素受体的结合亲合力及其与潜在靶分子DNA的相互作用，初步探讨其作用机制。可望为发现雌激素靶向配体调控的高活性、高选择性镧系抗肿瘤配合物提供新思路。

为了寻找高效低毒的金属抗肿瘤合物,利用雌激素受体和卤素效应,本项目设计、合成和表征了具有抗肿瘤活性的双卤代8-羟基喹啉、8-羟基喹啉衍生物、氧化异阿朴菲、氧化阿朴菲异喹啉生物碱等配体的金属配合物72个，其中镧系配合物13个。获得具有潜在雌激素受体介导靶向的金属配合物5个。对其中绝大部分金属配合物进行了细胞水平和分子水平的作用机制研究，发现这些金属抗肿瘤配合物具有多靶点多重作用机制的特点。完成了6个高活性金属配合物的体内抗肿瘤实验，发现具有开发前景的金属配合物3个。提出和初步实现活性成分+金属活性中心的设计思想，为发现新型抗肿瘤金属药物提供了新的模式。本项目共发表SCI收录论文30篇,其中JCRII区论文20篇,获中国授权发明专利6项。在国际化学与药学相关学术会议做大会报告1次，邀请报告5次；在全国性学术会议做邀请报告4次。培养博士毕业生2人,硕士毕业生4人。

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