吉非替尼工艺研究

吉非替尼是一种新型的分子靶向抗肿瘤药物,为表皮生长因子受体酪氨酸激酶抑制剂,可通过阻断酪氨酸激酶信号传导通路抑制肿瘤的生长,从而起到抗肿瘤作用,临床中适用于治疗既往接受过化学治疗或不适于化疗的局部晚期或转移性非小细胞肺癌(NSCLC)。本文以6-乙酰氧基-7-甲氧基-4-羟基喹唑啉(GFT-1)为原料,经氯代反应制备6-乙酰氧基-7-甲氧基-4-氯喹唑啉(GFT-2),这一步合成了本路线中最重要的中间体,GFT-2与3-氯-4-氟苯胺环合制备4-(3-氯-4-氟苯基氨基)-7-甲氧基喹唑啉-6-基乙酸酯盐酸盐(GFT-3),再经水解反应获得7-甲氧基-6-羟基-4-(4-氟-3-氯苯胺基)喹唑啉(GFT-4),GFT-4与N-(3-氯丙基)吗啉缩合反应获得抗肿瘤药物吉非替尼,总收率约50.5%。该合成路线反应步骤少,收率高,且反应条件温和,对环境污染小,实验员操作环境友好,适于工业化生产。吉非替尼及其中间体均经核磁、液相色谱、熔点等手段进行结构表征。     

吉非替尼合成研究进展

吉非替尼是一种新型抗肿瘤药物。本文综述了吉非替尼的合成方法及每种合成方法所用的原料、中间产物和过程。     

Targeted Co-Delivery of Gefitinib and Rapamycin by Aptamer-Modified Nanoparticles Overcomes EGFR-TKI Resistance in NSCLC via Promoting Autophagy

Acquired drug resistance decreases the efficacy of gefitinib after approximately 1 year of treatment in non-small-cell lung cancer (NSCLC). Autophagy is a process that could lead to cell death when it is prolonged. Thus, we investigated a drug combination therapy of gefitinib with rapamycin—a cell autophagy activator—in gefitinib-resistant NSCLC cell line H1975 to improve the therapeutic efficacy of gefitinib in advanced NSCLC cells through acute cell autophagy induction. Cell viability and tumor formation assays indicated that rapamycin is strongly synergistic with gefitinib inhibition, both in vitro and in vivo. Mechanistic studies demonstrated that EGFR expression and cell autophagy decreased under gefitinib treatment and were restored after the drug combination therapy, indicating a potential cell autophagy–EGFR positive feedback regulation. To further optimize the delivery efficiency of the combinational agents, we constructed an anti-EGFR aptamer-functionalized nanoparticle (NP-Apt) carrier system. The microscopic observation and cell proliferation assays suggested that NP-Apt achieved remarkably targeted delivery and cytotoxicity in the cancer cells. Taken together, our results suggest that combining rapamycin and gefitinib can be an efficacious therapy to overcome gefitinib resistance in NSCLC, and targeted delivery of the drugs using the aptamer-nanoparticle carrier system further enhances the therapeutic efficacy of gefitinib.     

气相色谱-质谱联用法测定对甲苯磺酸脂类基因毒性杂质的方法学验证

用气相色谱-质谱联用法对吉非替尼中的对苯磺酸酯类(对甲苯磺酸甲酯、对甲苯磺酸乙酯、对甲苯磺酸异丙酯)的含量进行测定。该方法对对甲苯磺酸甲酯、对甲苯磺酸乙酯的检出限均为0.50 mg/kg,对甲苯磺酸异丙酯的检出限为1.2 mg/kg;三种化合物在5~200 ng/m L的浓度范围内均成良好的线性关系,相关系数R20.99;回收率在88.3%~111.6%之间;相对标准偏差(n=6)4.67%,符合检测要求。该方法可以很好的应用于吉非替尼中对苯磺酸酯类杂质的检测。     

吉非替尼联合立体定向放疗一线治疗高龄肺腺癌的临床研究

Objective: The aim of our study was to evaluate the efficacy and safety of gefitinib combined with γ-ray stereotactic radiotherapy for senile patients with adenocarcinoma of lung as the first-line regimen. Methods: The 153 senile patients with adenocarcinoma of lung were divided into 4 groups according to the therapy method. Group A was the 35 patients treated with gefitinib combined with γ-ray stereotactic radiotherapy. Group B was the 45 patients treated with γ-ray stereotactic radiotherapy.Group C was the 42 patients treated with gefitinib. Group D was the 31 patients treated with best supportive therapy.The patients received gefitinib of 250 mg/d from the first day until disease progression or other reasons. The patients were treated six times every week. Results: All the patients were examined by enhanced double helix CT at the second month. The tumor response rate (RR) of group A was 68.6% (24/35). Disease control rate (DCR) was 88.6% (31/35). The median survival year survival rate was 40.0% (14/35). The main side effects included skin rash and diarrhea. The RR of group B was 51.1% survival rate was 15.6 % (7/45). The RR of group C was 40.5 % (17/42). DCR was 61.9% (26 /42). MST was 10.3 months overall 1-year survival rate was 0. The short-term therapeutic effects (RR) of group A was higher than group C (P = 0.014 <0.05, χ2 = 6.053) but has no significant difference with group B (P = 0.116 > 0.05, χ2 = 2.477). The long-term therapeutic effects (overall 1-year survival rate) of group A was higher than group B (P = 0.014 < 0.05, χ2 = 6.077) but has no significant difference with group C (P = 0.642 > 0.05, χ2 = 0.216). Conclusion: Gefitinib combined with γ-ray stereotactic radiotherapy is feasible and effective for treatment in senile patients with adenocarcinoma of lung as the first-line regimen.     

喹唑啉类抗癌药物的合成研究进展

综述了喹唑啉类已经上市的三种典型的抗癌药物(吉非替尼、厄洛替尼和拉帕替尼)的几条主要的合成路线,并且对这些合成路线进行了简单的评价。     

吉非替尼合成工艺研究

文章对新型抗肿瘤药物,表皮生长因子受体(EGFR)酪氨酸激酶抑制剂吉非替尼的合成进展进行了综述,并讨论了各路线优缺点及可行性。