新型异斯特维醇D-环修饰杂环衍生物的合成及体外抗肿瘤活性研究
发布时间：2019-05-14 05:51
【摘要】：恶性肿瘤严重威胁人类的生命健康,化疗仍是治疗肿瘤的主要手段之一。但临床上抗肿瘤药物存在毒性大、易产生耐药性等缺点,因此开发高效、低毒的抗肿瘤药物是新药研发的热点。其中,对天然产物进行结构改造和修饰,是寻找新型抗肿瘤药物的有效途径。 本论文以四环二萜类化合物异斯特维醇(Isosteviol)为原料,通过酯化、Tollens反应、Grob重排、1,3-偶极环加成、亲核加成和缩合成环等反应,分别合成了五个系列共158个结构新颖的新型异斯特维醇D-环修饰的杂环衍生物,其中133个为未见文献报道的新化合物。所有目标化合物均经IR、1HNMR、13C NMR和HRMS等方法表征了其结构,其中18个新化合物经X-射线单晶衍射分析确定了其绝对构型；评价了异斯特维醇杂环衍生物的体外抗肿瘤活性。取得如下创新性研究成果： 1、从异斯特维醇1出发,经酯化、Tollens反应和氧化反应得到15-羟甲叉基异斯特维醇乙酯5,然后与肼缩合,选择性合成了异斯特维醇D-环(15,16位)并吡唑衍生物6；进而与不同取代的异硫氰酸苯酯反应,得到一系列取代苯氨基硫代甲酰基取代的吡唑衍生物7a-7u。 评价了该系列化合物对胃癌细胞SGC-7901、肺癌细胞A-549、宫颈癌细胞Hela和淋巴瘤细胞Raji的体外抗肿瘤活性。结果表明,所测化合物对Raji细胞的抑制活性最好；单取代比双取代的衍生物表现出较好的抑制活性,且对位单取代衍生物活性最好；大部分化合物对Raji细胞的活性明显高于阳性对照物顺铂；对甲氧基苯基衍生物7p表现出最好的抗肿瘤活性,对SGC7901、A549、 Raji和Hela细胞的IC50值分别为9.65μM、17.73μM、6.51μM和13.91μM。 2、从15a-羟甲基-16β-羟基异斯特维醇3出发,经磺酸酯化和Grob重排得到异斯特维醇开环衍生物9,再经醛肟化和1,3-偶极环加成反应得到异斯特维醇D-环并异嗯唑烷衍生物11,进而与不同取代的异硫氰酸苯酯反应,得到一系列结构新颖的取代苯氨基硫代甲酰基取代的异嗯唑烷衍生物12a-12u。 通过对上述4组肿瘤细胞的体外抗肿瘤活性测试,发现此类化合物对Raji细胞的抑制活性优于SGC7901,A549和Hela细胞的抑制活性；二取代苯基衍生物表现出较好的抑制活性,其中2,6-二甲基取代的化合物12t活性最好,对SGC7901、A549和Raji细胞的IC50值分别为27.38μM、41.56μM和19.72μM。 3、由异斯特维醇开环衍生物9衍生的各种取代苯腙13经分子内1,3-偶极环加成反应得到一系N-取代苯基修饰的异斯特维醇D-环并吡唑啉衍生物14a-14ad。 评价了各化合物对4组肿瘤细胞的体外抗肿瘤活性。实验结果表明,这类异斯特维醇吡唑啉衍生物对Raji细胞的抑制活性高于对A549、SGC7901和Hela等细胞的抑制活性；对于SGC7901细胞,苯环上含供电子取代基的衍生物比卤素取代的衍生物活性高；部分化合物对Raji细胞和A549细胞的抑制活性优于顺铂；其中苯环对甲基取代的化合物141的活性最好,对SGC7901、A549、Raji和Hela细胞的IC50值分别为29.39μM、13.67μM、3.91μM和29.14μM。 4、由15-羟甲叉基异斯特维醇乙酯5与不同取代的苯肼经环化缩合反应,区域选择性地合成了一系列N-取代苯基衍生的异斯特维醇D-环并吡唑衍生物16a-16ad。 评价了该系列化合物对4组肿瘤细胞的体外抗肿瘤活性,实验结果表明,所测化合物对Raji细胞的抑制活性最好；单取代衍生物中,间位甲基衍生物活性最好；在对Raji细胞的活性测试中,所有化合物都表现出优于顺铂的抑制活性；其中化合物2,4-二氯取代苯环衍生物16t的活性最好,对SGC790、A549、 Raji和Hela细胞的IC50值分别为2.71μM、3.18μM、1.09μM和13.52μM。 5、以异斯特维醇乙酯为原料,通过缩合、加成反应得到缩氨基硫脲衍生物19a-19u,再经氧化-环化得到一系列结构新颖的噻二唑啉衍生物20a-20u。 评价了所合成的化合物对四组肿瘤细胞的抑制活性,结果表明大部分所测化合物的活性较差,而部分化合物对Raji细胞的活性较好；苯环不含取代基的衍生物20a比缩氨基硫脲衍生物19a表现出较好的活性,对A549和Raji细胞的IC5o值分别为17.07μM和29.79μM；在单取代衍生物中,卤素衍生物活性较差,甲基、甲氧基和硝基衍生物中,只有对位取代衍生物表现出对Raji细胞较好的抑制活性,IC50值分别为25.75μM、32.43μM和27.65μM。
[Abstract]:Malignant tumor is a serious threat to human health, and chemotherapy is still one of the main methods to treat tumor. But the clinical anti-tumor medicament has the disadvantages of large toxicity, easy production of drug resistance and the like, therefore, the high-efficiency and low-toxicity anti-tumor medicament is a hot spot for the research and development of a new drug. In which, the structure modification and modification of the natural product are an effective way to find a novel anti-tumor medicament. In this paper, the four-ring dipolar compound isosteviol is used as the raw material, and the reaction of the esterification, the Kolens reaction, the Grob rearrangement, the 1,3-dipolar ring addition, the nucleophilic addition and the condensation synthesis ring and the like are reversed. At the same time, the novel heterocyclic derivatives of the novel isosteviol D-ring modified with a total of 158 structures were synthesized, of which 133 were the new compounds not reported in the literature. The structure of all the target compounds was characterized by IR, 1HNMR, 13C NMR and HRMS. The absolute configuration of 18 new compounds was determined by X-ray single crystal diffraction analysis. In vitro anti-tumor activity of the heterostrol heterocyclic derivative was evaluated. Sex. The following innovative research has been made: Fruit:1, starting from the isosterol 1, carrying out esterification, the following reaction and the oxidation reaction to obtain the 15-hydroxy-methyl-isosterol ethyl ester 5, and then carrying out condensation and selective synthesis of the isosteviol D-ring (15,16-position) and carrying out the reaction. bio6; in turn, reacting with a different substituted phenyl isothiocyanate to obtain a series of substituted phenylamino-thiomethyl-based substituted phenyl derivatives 7a -7u. The in vitro of the series of compounds on the gastric cancer cells SGC-7901, lung cancer cells A-549, cervical cancer cell Hela and lymphoma cell Raji was evaluated. The results showed that the inhibitory activity of the compound on Raji cells is the best; the mono-substituted bi-substituted derivatives show better inhibitory activity, and the para-substituted derivatives have the best activity; the activity of most of the compounds on Raji cells is obviously higher than that of the positive The control was cisplatin; the best antitumor activity was exhibited on the methoxyphenyl derivative 7p, and the IC50 values for SGC7901, A549, Raji and Hela cells were 9.65. mu.M, 17.73. mu.M, 6.51. mu.M, and 13, respectively. .91. mu.M.2, from 15a-hydroxymethyl-16-hydroxy-iso setting out the ring-opening derivative 9 of the isosteviol by the esterification of the sulfonic acid and the Grob, and then carrying out the addition reaction of the aldehyde oxime and the 1,3-dipolar ring to obtain the isosteviol D-ring and the isobuxane derivative 11, the phenyl thiocyanate reaction is carried out to obtain a series of novel and novel substituted benzene amino-thiomethyl-base-substituted heterohmxane derivatives, 12a-12u. The inhibition activity of these compounds on Raji cells was better than that of SGC7901, A549 and Hela cells by the in vitro anti-tumor activity test of the 4 groups of tumor cells. A better inhibitory activity was shown, of which 2,6-dimethyl-substituted compound 12t had the best activity, the IC50 values for SGC7901, A549 and Raji cells were 27.38. m u.M, 41.56. m M鍜，
本文编号：2476477
[Abstract]:Malignant tumor is a serious threat to human health, and chemotherapy is still one of the main methods to treat tumor. But the clinical anti-tumor medicament has the disadvantages of large toxicity, easy production of drug resistance and the like, therefore, the high-efficiency and low-toxicity anti-tumor medicament is a hot spot for the research and development of a new drug. In which, the structure modification and modification of the natural product are an effective way to find a novel anti-tumor medicament. In this paper, the four-ring dipolar compound isosteviol is used as the raw material, and the reaction of the esterification, the Kolens reaction, the Grob rearrangement, the 1,3-dipolar ring addition, the nucleophilic addition and the condensation synthesis ring and the like are reversed. At the same time, the novel heterocyclic derivatives of the novel isosteviol D-ring modified with a total of 158 structures were synthesized, of which 133 were the new compounds not reported in the literature. The structure of all the target compounds was characterized by IR, 1HNMR, 13C NMR and HRMS. The absolute configuration of 18 new compounds was determined by X-ray single crystal diffraction analysis. In vitro anti-tumor activity of the heterostrol heterocyclic derivative was evaluated. Sex. The following innovative research has been made: Fruit:1, starting from the isosterol 1, carrying out esterification, the following reaction and the oxidation reaction to obtain the 15-hydroxy-methyl-isosterol ethyl ester 5, and then carrying out condensation and selective synthesis of the isosteviol D-ring (15,16-position) and carrying out the reaction. bio6; in turn, reacting with a different substituted phenyl isothiocyanate to obtain a series of substituted phenylamino-thiomethyl-based substituted phenyl derivatives 7a -7u. The in vitro of the series of compounds on the gastric cancer cells SGC-7901, lung cancer cells A-549, cervical cancer cell Hela and lymphoma cell Raji was evaluated. The results showed that the inhibitory activity of the compound on Raji cells is the best; the mono-substituted bi-substituted derivatives show better inhibitory activity, and the para-substituted derivatives have the best activity; the activity of most of the compounds on Raji cells is obviously higher than that of the positive The control was cisplatin; the best antitumor activity was exhibited on the methoxyphenyl derivative 7p, and the IC50 values for SGC7901, A549, Raji and Hela cells were 9.65. mu.M, 17.73. mu.M, 6.51. mu.M, and 13, respectively. .91. mu.M.2, from 15a-hydroxymethyl-16-hydroxy-iso setting out the ring-opening derivative 9 of the isosteviol by the esterification of the sulfonic acid and the Grob, and then carrying out the addition reaction of the aldehyde oxime and the 1,3-dipolar ring to obtain the isosteviol D-ring and the isobuxane derivative 11, the phenyl thiocyanate reaction is carried out to obtain a series of novel and novel substituted benzene amino-thiomethyl-base-substituted heterohmxane derivatives, 12a-12u. The inhibition activity of these compounds on Raji cells was better than that of SGC7901, A549 and Hela cells by the in vitro anti-tumor activity test of the 4 groups of tumor cells. A better inhibitory activity was shown, of which 2,6-dimethyl-substituted compound 12t had the best activity, the IC50 values for SGC7901, A549 and Raji cells were 27.38. m u.M, 41.56. m M鍜，
本文编号：2476477
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