含氮芥双-(亚苄基)环烷酮的合成、晶体结构及其体外光动力抗肿瘤活性

为构建光动力治疗与化疗协同抗肿瘤先导化合物,基于药效团拼合原理,设计合成了含氮芥双-(亚苄基)环烷酮化合物3a~3c及对比的双-(亚苄基)环烷酮化合物3d~3f,并经核磁共振波谱仪(NMR)、高分辨质谱HRMS(ESI-MS)、X射线衍射仪(XRD)及傅里叶变换红外光谱仪(FTIR)等技术手段对其进行了结构和性质表征。采用噻唑蓝(MTT)法考察了他们对A549(人肺腺癌细胞)和Hep G2(人源肝癌细胞)的光毒性。结果表明,大部分化合物对两株受试细胞株表现出了一定的光毒性,尤以化合物3a对Hep G2光毒性的半抑制率(IC50)达到2. 0 nmol/m L,值得进一步研究。运用Gaussian09软件,在B3LYP和6-311G+基组水平上对化合物3a和3d进行了量子化学计算并得到其优化构型和分子轨道能量,从前沿轨道能量分析了化合物的结构特征和抗肿瘤活性的构效关系。

Synthesis,Crystal Strutures and Phototoxicity in Vitro of Nitrogen Mustard-Linked Bis(arylmethylidene)cycloalkanones

In order to build photodynamic therapy and chemotherapy synergy anticancer leading compounds, three novel nitrogen mustard-linked bis(arylmethylidene)cycloalkanone compounds 3a~3c and other three bis(arylmethylidene)-cycloalkanone compounds 3d~3f were designed and synthesized based on principle of efficacy hybridization. Their structures were characterized by nuclear magnetic resonance spectroscopy(NMR), high resolution mass spectrometry(ESI-MS), X-ray diffraction(XRD) and Fourier transform infrared spectrometer(FTIR). Their in vitro phototoxicity were investigated by thiazolyl blue tetrazolium bromide(MTT) method against A549(human lung adenocarcinoma) and HepG2(human hepatoma) cell lines. The preliminary data indicates that most of these compounds exhibit moderate to potent phototoxicity against both tumor cell lines. In particular, compound 3a is worthy of further study with an IC₅₀ of against HepG2 at 2.0 nmol/mL. Compounds 3a and 3d were simulated at B3LYP 6-311G+ level with Gaussian09 program. Their optimized geometries and the energy of frontier molecular orbitals are obtained. Furthermore, the relationship between the structural features and phototoxicity were analyzed based on the energy of frontier molecular orbitals.