低氧激活偶氮苯类AGT抑制剂的合成及还原性研究

Synthesis and Reduction Activity Evalution of Hypoxia-activated Azobenzene AGT Inhibitors

O^6-烷基鸟嘌呤-DNA烷基转移酶(AGT)是一种重要的DNA修复酶,AGT在保护正常细胞DNA不受烷化剂损伤的同时,也能够修复抗癌烷化剂对肿瘤细胞DNA的损伤,进而导致抗肿瘤药物的耐药性。设计合成了一类具有肿瘤低氧靶向性的AGT抑制剂,合成化合物能够特异性地在肿瘤低氧环境中被还原,释放AGT抑制剂——O^6-3-氨基苄基鸟嘌呤(ABG);而在常氧条件下不能被激活,不能发挥AGT抑制作用。因此,合成化合物可与氯乙基亚硝基脲等烷化剂联合用药,通过靶向性地抑制肿瘤低氧区域中AGT的活性,提高肿瘤细胞对抗癌烷化剂的敏感性。设计合成了4种以偶氮甲苯衍生物为低氧激活基团的O^6-烷基鸟嘌呤衍生物。经过体外实验模拟实体瘤中的低氧环境,确证了4种化合物均能够选择性地在低氧条件下被还原为AGT抑制剂——ABG;4种目标化合物的还原活性为:(E)-6-((3-((4-(二丙基氨基)苯基)二氮烯基)苄基)氧基)-9H-嘌呤-2-胺>(E)-6-((3-((4-(乙基氨基)苯基)二氮烯基)苄基)氧基)-9H-嘌呤-2-胺>(E)-6-((3-((4-(二乙基氨基)苯基)二氮烯基)苄基)氧基)-9H-嘌呤-2-胺>(E)-6-((3-((4-(甲基氨基)苯基)二氮烯基)苄基)氧基)-9H-嘌呤-2-胺,为开发新型靶向性抗肿瘤药物以及设计高效低毒的联合用药策略提供了新的思路。

O6-Alkylguanine-DNA alkyltransferase(AGT)is an important DNA repair enzyme.AGT can lead to drug resistance of chemotherapy by repairing DNA damages of tumor cells,while it also protects normal cell DNA from the damages induced by alkylating agents.A series of AGT inhibitors with tumor hypoxia targeting were designed and synthesized,which could be specifically reduced in tumor hypoxic environments,releasing an AGT inhibitor———O6-3-aminobenzylguanine(ABG).The compounds cannot be activated to exert AGT-inhibiting activity under normoxic conditions.Therefore,the compounds can be used in combination with alkylating agents,such as chloroethylnitrosourea,to increase the sensitivity of the tumor cells to chemotherapy by targetingly inhibiting the AGT activity in tumor hypoxia areas.Four O6-alkylguanine derivatives with azotoluene moiety as hypoxia-activating groups were designed and synthesized.After in vitro experiments to simulate the hypoxic environment in solid tumor,it was confirmed that the four compounds can be selectively reduced to AGT inhibitor(ABG)under the hypoxic conditions,and the reductive activity of the four target compounds was(E)-6-((3-((4-(dipropylamino)phenyl)diazenyl)benzyl)oxy)-9H-purin-2-amine>(E)-6-((3-((4-(ethylamino)phenyl)diazenyl)benzyl)oxy)-9H-purin-2-amine>(E)-6-((3-((4-(diethylamino)phenyl)diazenyl)benzyl)oxy)-9H-purin-2-amine>(E)-6-((3-((4-(methylamino)phenyl)diazenyl)benzyl)oxy)-9H-purin-2-amine.It provided new ideas for the development of novel tumor targeting chemotherapy and for the design of anti-tumor combination strategies with high-efficacy and low-toxicity.