【摘要】：惡性腫瘤嚴(yán)重威脅人類(lèi)的生命健康,化療仍是治療腫瘤的主要手段之一。但臨床上抗腫瘤藥物存在毒性大、易產(chǎn)生耐藥性等缺點(diǎn),因此開(kāi)發(fā)高效、低毒的抗腫瘤藥物是新藥研發(fā)的熱點(diǎn)。其中,對(duì)天然產(chǎn)物進(jìn)行結(jié)構(gòu)改造和修飾,是尋找新型抗腫瘤藥物的有效途徑。 本論文以四環(huán)二萜類(lèi)化合物異斯特維醇(Isosteviol)為原料,通過(guò)酯化、Tollens反應(yīng)、Grob重排、1,3-偶極環(huán)加成、親核加成和縮合成環(huán)等反應(yīng),分別合成了五個(gè)系列共158個(gè)結(jié)構(gòu)新穎的新型異斯特維醇D-環(huán)修飾的雜環(huán)衍生物,其中133個(gè)為未見(jiàn)文獻(xiàn)報(bào)道的新化合物。所有目標(biāo)化合物均經(jīng)IR、1HNMR、13C NMR和HRMS等方法表征了其結(jié)構(gòu),其中18個(gè)新化合物經(jīng)X-射線(xiàn)單晶衍射分析確定了其絕對(duì)構(gòu)型；評(píng)價(jià)了異斯特維醇雜環(huán)衍生物的體外抗腫瘤活性。取得如下創(chuàng)新性研究成果： 1、從異斯特維醇1出發(fā),經(jīng)酯化、Tollens反應(yīng)和氧化反應(yīng)得到15-羥甲叉基異斯特維醇乙酯5,然后與肼縮合,選擇性合成了異斯特維醇D-環(huán)(15,16位)并吡唑衍生物6；進(jìn)而與不同取代的異硫氰酸苯酯反應(yīng),得到一系列取代苯氨基硫代甲�；〈倪吝蜓苌�7a-7u。 評(píng)價(jià)了該系列化合物對(duì)胃癌細(xì)胞SGC-7901、肺癌細(xì)胞A-549、宮頸癌細(xì)胞Hela和淋巴瘤細(xì)胞Raji的體外抗腫瘤活性。結(jié)果表明,所測(cè)化合物對(duì)Raji細(xì)胞的抑制活性最好；單取代比雙取代的衍生物表現(xiàn)出較好的抑制活性,且對(duì)位單取代衍生物活性最好；大部分化合物對(duì)Raji細(xì)胞的活性明顯高于陽(yáng)性對(duì)照物順鉑；對(duì)甲氧基苯基衍生物7p表現(xiàn)出最好的抗腫瘤活性,對(duì)SGC7901、A549、 Raji和Hela細(xì)胞的IC50值分別為9.65μM、17.73μM、6.51μM和13.91μM。 2、從15a-羥甲基-16β-羥基異斯特維醇3出發(fā),經(jīng)磺酸酯化和Grob重排得到異斯特維醇開(kāi)環(huán)衍生物9,再經(jīng)醛肟化和1,3-偶極環(huán)加成反應(yīng)得到異斯特維醇D-環(huán)并異嗯唑烷衍生物11,進(jìn)而與不同取代的異硫氰酸苯酯反應(yīng),得到一系列結(jié)構(gòu)新穎的取代苯氨基硫代甲酰基取代的異嗯唑烷衍生物12a-12u。 通過(guò)對(duì)上述4組腫瘤細(xì)胞的體外抗腫瘤活性測(cè)試,發(fā)現(xiàn)此類(lèi)化合物對(duì)Raji細(xì)胞的抑制活性?xún)?yōu)于SGC7901,A549和Hela細(xì)胞的抑制活性；二取代苯基衍生物表現(xiàn)出較好的抑制活性,其中2,6-二甲基取代的化合物12t活性最好,對(duì)SGC7901、A549和Raji細(xì)胞的IC50值分別為27.38μM、41.56μM和19.72μM。 3、由異斯特維醇開(kāi)環(huán)衍生物9衍生的各種取代苯腙13經(jīng)分子內(nèi)1,3-偶極環(huán)加成反應(yīng)得到一系N-取代苯基修飾的異斯特維醇D-環(huán)并吡唑啉衍生物14a-14ad。 評(píng)價(jià)了各化合物對(duì)4組腫瘤細(xì)胞的體外抗腫瘤活性。實(shí)驗(yàn)結(jié)果表明,這類(lèi)異斯特維醇吡唑啉衍生物對(duì)Raji細(xì)胞的抑制活性高于對(duì)A549、SGC7901和Hela等細(xì)胞的抑制活性；對(duì)于SGC7901細(xì)胞,苯環(huán)上含供電子取代基的衍生物比鹵素取代的衍生物活性高；部分化合物對(duì)Raji細(xì)胞和A549細(xì)胞的抑制活性?xún)?yōu)于順鉑；其中苯環(huán)對(duì)甲基取代的化合物141的活性最好,對(duì)SGC7901、A549、Raji和Hela細(xì)胞的IC50值分別為29.39μM、13.67μM、3.91μM和29.14μM。 4、由15-羥甲叉基異斯特維醇乙酯5與不同取代的苯肼經(jīng)環(huán)化縮合反應(yīng),區(qū)域選擇性地合成了一系列N-取代苯基衍生的異斯特維醇D-環(huán)并吡唑衍生物16a-16ad。 評(píng)價(jià)了該系列化合物對(duì)4組腫瘤細(xì)胞的體外抗腫瘤活性,實(shí)驗(yàn)結(jié)果表明,所測(cè)化合物對(duì)Raji細(xì)胞的抑制活性最好；單取代衍生物中,間位甲基衍生物活性最好；在對(duì)Raji細(xì)胞的活性測(cè)試中,所有化合物都表現(xiàn)出優(yōu)于順鉑的抑制活性；其中化合物2,4-二氯取代苯環(huán)衍生物16t的活性最好,對(duì)SGC790、A549、 Raji和Hela細(xì)胞的IC50值分別為2.71μM、3.18μM、1.09μM和13.52μM。 5、以異斯特維醇乙酯為原料,通過(guò)縮合、加成反應(yīng)得到縮氨基硫脲衍生物19a-19u,再經(jīng)氧化-環(huán)化得到一系列結(jié)構(gòu)新穎的噻二唑啉衍生物20a-20u。 評(píng)價(jià)了所合成的化合物對(duì)四組腫瘤細(xì)胞的抑制活性,結(jié)果表明大部分所測(cè)化合物的活性較差,而部分化合物對(duì)Raji細(xì)胞的活性較好；苯環(huán)不含取代基的衍生物20a比縮氨基硫脲衍生物19a表現(xiàn)出較好的活性,對(duì)A549和Raji細(xì)胞的IC5o值分別為17.07μM和29.79μM；在單取代衍生物中,鹵素衍生物活性較差,甲基、甲氧基和硝基衍生物中,只有對(duì)位取代衍生物表現(xiàn)出對(duì)Raji細(xì)胞較好的抑制活性,IC50值分別為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，

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