含硼小分子固醇调控元件结合蛋白抑制剂的合成及其体外抗肿瘤活性研究

目的设计、合成固醇调控元件结合蛋白(SREBP)抑制剂BF-175的衍生物,并对其稳定性和体外抗肿瘤活性进行研究。方法以水杨醛为起始原料,通过6步反应合成了一系列含硼小分子SREBP抑制剂,通过高效液相色谱法分析其稳定性,并采用RT-PCR实验评价其抗肿瘤活性。结果合成了9个含硼小分子SREBP抑制剂,并通过NMR和MS对其进行表征。其药学稳定性均优于BF-175。RT-PCR检测表明目标化合物可以抑制人子宫内膜腺癌细胞(AN3CA)中SREBP靶基因硬脂酰辅酶A去饱和酶-1(SCD-1)的表达,其中化合物7g的活性高于BF-175。结论含硼小分子SREBP抑制剂具有较好的抗肿瘤活性,为此类药物的作用机制研究奠定了基础。

Synthesis of boron-containing sterol regulatory element binding protein inhibitors and their antitumor activities in vitro

Objective To study the four week repeated dose toxicity of recombinant human erythromycin injection(CHO cells) in cynomolgus monkey. Methods Eighteen monkeys were randomly divided into three groups (six each, half male and half female) to receive the dose of 0, 500, 1 500 IU/kg of EPO by sc injection three times a week for four weeks. On dosing termination, one third of the animals in each group were left to observe four weeks recovery. Daily observation of animal appearance and sign, behavior and mental state were carried out. And body weights, body temperature, ophthalmology, ECG, hematology, clinical chemistry, T lymphocyte subset and histopathology were examined in different points in administration period and recovery period. Results No abnormalities were found in the exarninations of clinical symptoms, body weight, body temperature, opthalmology, ECG, coagulation index, clinical chemistry and gross anatomy. RBC, RET, HGB, HCT and PLT were observed signifieantly increased and LYMPH obviously decreased in high and medium dose groups after four weeks dosing as compared to control group. RET and PLT returned to normal level and RBC, HGB and HCT remained at a high level after four weeks recovery. The proportion of CD3⁺T cells decreased significantly in high dose groups and returned to normal level after 4 weeks recovery, the mild erythroid hyperplasia of femur were abserved in high dose group in three animals after 4 weeks dosingon histopathology exarnination. Conclusion The dose of 15 00 IU/kg of Recombinant human erythromycin injection (CHO cells) for 4 weeks shows no obvious toxic effect in cynomolgus monkey. The changes of hematology and pathology are related to their pharmacological effects.