新型雌激素受体拮抗剂呋喃并[3,2-g]色烯类化合物的设计、合成及其构效关系研究

Estrogen receptor antagonists are the main drug for the clinical treatment of breast cancer, ovarian cancer, uterine cancer and other estrogen-related malignancies. According to the binding three-dimensional structure of available estrogen receptor-ligand complexes, using the computer-aided drug design software including molecular docking software, some furo[3,2-g]chromene derivatives with as a novel heterocyclic scaffold were designed and synthesized, and the biological screening showed these compounds exhibiting the significant anti-tumour activity discovered in our laboratory..Based on our previous work, by using molecular design and virtual screening, this project proposes to design and synthesize a novel series of furo[3,2-g]chromene derivatives as the target compounds. Accompanied by the experimental results of antagonistic binding between estrogen receptor and furo[3,2-g]chromene derivatives and in vitro and in vivo anti-tumour screening, the structure-activity relationships will be explored and summarized. The final target of this project will result in discovery of lead compounds, the further development of lead compounds or active compound and discovery of new chemical entities.

雌激素受体（ER）拮抗剂是目前临床上治疗乳腺癌、卵巢癌、子宫癌等与雌激素有关的恶性肿瘤的主要药物。我们根据已知的ER与配体结合的三维结构，利用计算机辅助药物设计软件，采用分子对接技术设计并合成了一系列呋喃并[3,2-g]色烯类化合物，通过体内外生物活性筛选，发现了呋喃并[3,2-g]色烯类化合物具有显著的抗肿瘤活性。我们拟通过分子设计和虚拟筛选，同时考虑到目标化合物的理化性质与合成可行性，设计并合成一些新型呋喃并[3,2-g]色烯类化合物作为目标化合物，通过雌激素受体拮抗实验和体内外生物活性筛选，探索其构效关系，为进一步活性化合物的深入研究和创制新药奠定基础。

本项目在前期工作基础上，采用分子对接和分子模拟方法，对2-芳酰基-3-芳基-6,7-二氢-5H-呋喃并[3,2-g]色烯类化合物进行结构修饰与改进，共合成了14余种呋喃并[3,2-g]色烯类化合物、12种卤代-2-芳甲酰基苯并呋喃类化合物、10种呋喃并[3,2-g]喹啉类化合物和22种呋喃并苯并呋喃类化合物，并对这些化合物进行了结构表征；通过对所合成目标化合物进行了抗肿瘤活性筛选，根据活性筛选结果，初步阐述了其构效关系；初步探讨了部分目标化合物的雌激素受体拮抗活性及抗肿瘤活性作用机理。发表相关学术论文3篇（其中SCI收载2篇），获得美国授权专利1项，申请中国专利4项。研究成果为进一步的化合物设计及活性化合物的深入研究奠定了基础。