喹唑啉杂合体的抗肺癌活性研究进展

An insight into the therapeutic potential of quinazoline hybrids against lung cancer

关键词:  喹唑啉  杂合体  肺癌  耐药  构-效关系  作用机制

Key words:  quinazoline  hybrids  lung cancer  drug resistance  structure-activity relationship  mechanism of action

摘要:

肺癌是世界范围内最常见的恶性肿瘤,其发病率和死亡率居高不下,严重威胁人类的生命健康。化疗对肺癌的治疗至关重要,近几十年来,随着新型抗肺癌化疗药物的不断问世,肺癌患者的总体存活率和生活质量得到了极大的改善。然而,化疗药物存在着诸如耐多药性和全身毒性等缺陷,极大的限制了其临床应用。喹唑啉衍生物是潜在的表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKI),对多种癌症尤其是肺癌具有良好的活性。其中,以厄洛替尼、吉非替尼、埃克替尼、阿法替尼和达克替尼为代表的多个喹唑啉衍生物已作为抗肺癌药物广泛应用于临床。因此,喹唑啉母核是寻找新型抗肺癌药物的热点药效团。特别值得一提的是,喹唑啉杂合体可同时作用于肺癌细胞的多个靶点,具有提高抗肺癌疗效、克服耐药性和降低毒副作用的潜力,引起了药物化学家的广泛关注。本文综述了自2021年以来所发展的具有抗肺癌活性的喹唑啉杂合体的最新研究进展,着重探讨了此类杂合体的抗肺癌构-效关系和作用机制,为进一步研究提供参考。

Abstract:

Lung cancer, with high morbidity and mortality, is the most common malignant tumor worldwide, posing a serious threat to human life and health. Chemotherapy is of great significance in the treatment of lung cancer, and in recent decades, the overall survival rate as well as the quality of life of lung cancer patients have been significantly improved due to the great achievements in the development of novel chemotherapeutic interventions. However, multidrug resistance and systemic toxicity are surmountable obstacles for effective therapy. Quinazoline derivatives are potential epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and exhibit promising activity against various cancers, especially lung cancer. Among them, several quinazoline derivatives represented by erlotinib, gefitinib, icotinib, afatinib, and dacomitinib have already been widely applied in clinical practice for lung cancer therapy. Accordingly, quinazoline derivatives occupy a prominent place in the current anti-lung cancer chemotherapeutic arsenal. Particularly, quinazoline hybrids can act on multiple targets in lung cancer cells simultaneously, thereby having the potential to improve the anti-lung cancer efficacy, overcome drug resistance, and reduce side effects. This review emphasizes the current landscape of quinazoline hybrids with therapeutic potential against lung cancer, along with structure-activity relationships and modes of action, covering articles published from 2021 onwards, aiming to provide references for further research.