新型环丙烷缩氨基脲类化合物的合成及抗癫痫、抗肿瘤活性评价

Synthesis and pharmacological evaluation of novel cyclopropane-containing semicarbazones derivatives as potential anticonvulsant and antitumor agents

目的设计合成新型缩氨基脲类化合物,探讨结构中同时含有海因和缩氨基脲片段时其抗癫痫和抗肿瘤活性。方法依据拼合原理,将具有抗癫痫活性的环丙烷海因结构与缩氨基脲类结构结合起来并据此合成系列衍生物;采取通用的抗癫痫药物筛选模型[最大电惊厥实验(MES)、皮下注射戊四唑实验(sc PTZ)和神经毒性实验(Neurotoxocity)]进行抗癫痫活性评价;应用MTT法测试目标物对不同细胞株的潜在抗肿瘤细胞活性。结果与结论合成了19个目标化合物,其中Ⅰa~Ⅰl及Ⅱa~Ⅱh未见文献报道;在抗癫痫测试中,化合物Ⅱa~Ⅱd在100 mg·kg-1剂量下抗惊厥效果明显,Ⅱb、Ⅱc及Ⅱd在300 mg·kg-1时有拮抗戊四氮的作用;除了Ⅲ、Ⅵ、Ⅰi、Ⅰj外的化合物均有严重的神经毒性;化合物Ⅱd对He La细胞系抑制最好,其IC50值为23.7μmol·L^(-1),化合物Ⅰd对Hep G2细胞系的IC50值为26.7μmol·L^(-1)。

Epilepsy is a chronic brain disorder characterized by excessive temporary neuronal discharge and affects about 1% of the world＇ s population.The urgent demands for novel antiepileptic drugs（AEDs） will be long-standing for the complexity and severity of epilepsy and the side effects of the currently marketed AEDs.Over last decade,anticonvulsant drug development has become one of the most active research areas in medicinal chemistry.According to combination principles,we found a way to mash up hydantoin core with semicarbazone.In other words,some atoms in those agents would be not only a part of the hydantoin core but also a member of the semicarbazone group.They would also be evaluated for their anticonvulsant activities by maximal electroshock shock（MES） models subcutaneous and pentylenetetrazole（sc PTZ） seizure models both of which are based on the tests of mice.Rotarod toxicity method was used to study the acute neurotoxicity profile of selected compounds.The preliminary anticancer activity was tested by the MTT assay.Nineteen novel target compounds Ⅰa-Ⅰl and Ⅱa-Ⅱh were synthesized.The physiological activity of the newcompounds is not due to cyclopropane structure.The activity experimental study showed thatⅡa-Ⅱd contained the lowest median effective dose（ED50） of 100 mg·kg-1in MES test,and Ⅱb-Ⅱd the lowest ED50 of 300 mg·kg-1in sc PTZ test.In addition to compounds Ⅲ,Ⅵ and Ⅰi-Ⅰj,all compounds had severe neurotoxicity.In the mechanism of drug action and drug side effects,among these compounds,IC50 value of compound Ⅱd against He La was 23.7 μmol·L^-1; IC50 value of compound Ⅰd against Hep G2 was26.7 μmol·L^-1.However,they did not showactivities against the other cell lines which had been tested.These promising data suggested that the newcompounds can be a newclass of anticonvulsant and antitumor agents with high effectiveness and lowtoxicity for the treatment of epilepsy.