【作者】 应华洲；

【导师】 胡永洲；

【作者基本信息】 浙江大学 ， 药物化学， 2008， 博士

【摘要】 恶性肿瘤是严重威胁人类健康的重大高发疾病之一,虽然目前临床上抗肿瘤药物较多,但存在毒性大、效果不佳、易产生多药耐药等缺点,因此研究高效低毒的抗肿瘤药物是新药研发中一项迫切的任务。其中,对天然产物进行结构修饰,是寻找新型抗肿瘤药物的一条有效途径。姜黄素和类黄酮是两类具抗肿瘤活性的天然产物,具抗瘤谱广、低毒、抗多药耐药等优点,近年来深受科研工作者关注。本文在分析姜黄素及其类似物构效关系及本课题组前期的工作基础上,根据药效团和骨架迁越原理设计了新型姜黄素类似物——其结构特点:以1,4-二烯-3-戊酮链连接两个芳环,其中至少一个芳环的5位具碱性侧链。根据这一设计思想,共合成新化合物24个,并对目标分子进行了体外抗肿瘤活性筛选,结果表明,所合成的化合物普遍具有较好的抑制肿瘤细胞增殖活性,多数化合物IC₅₀值小于10μg/mL,明显优于先导物姜黄素。对目标分子进行了计算机辅助的ADME预测,结果表明此类化合物可能吸收良好,且血浆蛋白结合率亦较姜黄素高,提示此类化合物有良好的生物利用度。在作者攻读硕士期间发现的一类具发展潜力的黄烷酮衍生物——2,4-二芳基-苯并二氢吡喃[4,3-d]-⊿^1,9b-1,2,3-噻二唑啉的基础上,本文利用生物电子等排原理,保留黄烷酮骨架,拼入膦二唑或硒二唑环,分别设计合成了4-芳基-3,4-二氢苯并吡喃[3,4-d][1,2,3]膦二唑14个,2,4-二芳基-2,3,3a,4-四氢苯并吡喃[3,4-d][1,2,3]膦二唑12个和4-芳基-4H-苯并吡喃[4,3-d][1,2,3]硒二唑14个。上述40个黄烷酮衍生物的体外抗肿瘤筛选表明,多数化合物具有一定的抗肿瘤活性,部分化合物对5种细胞株均具有较好的抑制增殖作用,其中化合物3-5n的IC₅₀值均小于10μg/mL。对受试化合物的体外抗肿瘤活性实验结果分析可发现,此类化合物的活性明显依赖于苯环上的取代基。计算机辅助的ADME预测结果表明,除了2,4-二芳基-2,3,3a,4-苯并四氢吡喃[3,4-d][1,2,3]膦二唑类化合物以外,其它化合物均可能吸收良好。所合成化合物的作用机制和毒性研究正在进行中。在探索膦二唑类化合物的合成过程中,我们发现了以黄烷酮-4-缩氨基脲为原料,与POCl₃-SOCl₂反应再经EtOH或MeOH处理即可获得4-芳基-3,4-二氢苯并吡喃[3,4-d][1,2,3]膦二唑衍生物的新方法;并发现以黄烷酮-4-芳腙代替黄烷酮-4-缩氨基脲,采用同样的方法可合成2,4-二芳基-2,3,3a,4-苯并四氢吡喃[3,4-d][1,2,3]膦二唑衍生物。探讨研究了该类反应的反应条件和适用性,确定了最优的POCl₃-SOCl₂比例和反应温度。此方法的发现,填补了这两类化合物合成的空白。此外,我们还意外发现了黄烷酮、苯肼和PO（OCH₃）₃经“一锅煮”可合成1,3,5-三芳基吡唑;以脂肪肼代替苯肼,可用于合成3,5-二芳基吡唑。此方法的确立,为3,5-二芳基吡唑的合成提供了一种更为简便的途径。更多还原

【Abstract】 Cancer causes significant morbidity and mortality and is a major public health problem worldwide.The research of new antitumor drugs is of great significance since most of the currently available drugs had the disadvantages of high toxicity,low effection and multidrug resistance against subset of solid tumors.Structure modification of natural products is an old process but give a new hope for antitumor drug discovery.Curcumin and flavonoids are two kinds of natural products with antitumor activity and have been paid more attention for recent years.Based on SAR of curcuminoids and the previous work of our group,a series of novel curcumin analogues were designed and synthesized according to pharmacophore and scaffold hopping principle.Structurally,the new analogues are 1,5-diarylpentadienones which possess one nitrogen-containing substitution at the position 5 on one of the aromatic ring.24 new compounds were synthesized.All of them were screened for antiproliferation activity against two human tumor cell lines in vitro,and the result showed that most of the new analogues exhibit more antiproliferation activity than that of curcumin,with IC₅₀ values below 10μg/mL.The ’drug-like’ properties of them were analyzed by Discovery Studio 2.0.The results suggest that most of them may be well absorbed by intestine and have good bioavailability.Another part work of this dissertation is a research of novel flavonoid derivatives.2,4-diarylchromane[4,3-d]-（?）^1,9b-1,2,3-thiadiazolines had been synthesized and found as antiproliferative compounds in our previous work.As a continuation of our study,according to the bioisosteric principle,the similar compounds,4-aryl-3,4-dihydrochromeno[3,4-d][1,2,3]diazaphosphole,2,4-diaryl-2, 3,3a,4-tetrabydro-chromeno[3,4-d][1,2,3]diazaphospholes and 4-phenyl-4H-chromeno [4,3-d][1,2,3]selenadiazoles were designed and synthesized.The pharmacological research showed a number of these analogues had significant antitumor activity against five human tumor cell lines in vitro.The highly potent derivative 3-5n,exhibits antiproliferative activity against all the tested human tumor cell lines with IC₅₀ values below 10μg/mL.The ADME properties were analyzed by Discovery Studio 2.0.The results suggest most of the above compounds may be well absorbed by intestine and have good bioavailability except 2,4-diaryl-2,3,3 a,4-tetraby dro chromeno[3,4-d][1,2,3]di azapho spholes.A novel method was found for synthesis of 4-aryl-3,4-dihydro-and 2,4-diaryl-2,3,3 a,4-tetrabydrochromeno[3,4-d][1,2,3]diazaphospholes,by the reaction of chromone-4-hydrazones with POCl₃-SOCl₂ and ethanol（or methnol） in turn.The optimization procedures were also reported in detail.In addition,we also found a new method for synthesis of 1,3,5-triarylpyrozoles or 3,5-diarylpyrozoles by one-pot reaction of flavonones,PO（OCH₃）₃ with arylhydrazines or alkylhydrazines,respectively.This method provided a facile and efficient approach for preparation of 3,5-diarylpyrozole derivatives.更多还原