PARP-1抑制劑的設計、合成與生物活性評價
發(fā)布時間：2018-07-15 10:20
【摘要】：癌癥作為嚴重危害人類健康與生命的全球公共衛(wèi)生問題,已經引起世界范圍的廣泛關注。我國作為一個發(fā)展中的大國,隨著人口老齡化等諸多因素的影響,癌癥發(fā)病率與死亡率均呈持續(xù)上升趨勢。乳腺癌和卵巢癌是婦科常見的惡性腫瘤,其中乳腺癌在女性惡性腫瘤中發(fā)病率最高,特別是侵襲性強、生存期短的三陰性乳腺癌目前仍無有效治療手段;卵巢癌死亡率居婦科惡性腫瘤首位,復發(fā)和耐藥一直是治療中所面臨的難題。流行病學調查發(fā)現,約10~40%的三陰性乳腺癌及8~18%的卵巢癌患者中檢測出了BRCA1/2基因突變,BRCA1/2基因水平的改變一方面增加了罹患乳腺癌和卵巢癌的風險,同時又為此類癌癥的預防及治療提供了契機。近年來,PARP-1抑制劑單獨或與其他藥物聯(lián)合應用于BRCA1/2缺陷的乳腺癌和卵巢癌成為癌癥治療領域研究的熱點,給三陰性乳腺癌和復發(fā)性卵巢癌的治療帶來了希望。聚腺苷二磷酸核糖聚合酶(Poly(ADP-ribose)polymerases,PARPs)是真核生物細胞中存在的一種核酶,主要參與DNA修復過程并維持基因組的穩(wěn)定性。PARP家族的18個成員中,PARP-1在細胞內含量最高,研究也最為深入,主要以NAD+為底物催化ADP-核糖單元轉移至核受體蛋白,從而形成聚ADP-核糖聚合物進而引導修復酶對DNA缺口進行修復,在堿基切除修復通路中發(fā)揮關鍵作用。在當今藥物研發(fā)優(yōu)質靶標極其缺乏的現狀下,PARP-1給我們提供了為數不多經過臨床驗證的抗癌靶點。但其發(fā)展歷程因受作用機制認識的局限和藥物結構的制約等因素而頗為曲折。最初的研究方向是通過與放療或化療藥物聯(lián)合應用以增強藥物療效和降低用藥劑量,但是這種機制一直受毒性所限,三十余年的研究仍未取得成功。合成致死理論的提出和應用給此類藥物的發(fā)展帶來了轉機,PARP-1抑制劑可通過切斷同源重組修復缺陷腫瘤細胞的堿基切除修復通路從而發(fā)揮靶向作用,因此可單獨應用于此類腫瘤,如BRCA1/2缺陷的乳腺癌和卵巢癌等。2014年12月,Olaparib首先被批準用于治療BRCA1/2缺陷的鉑敏感復發(fā)性卵巢癌,其單獨或聯(lián)合應用于同源重組修復缺陷的其他適應癥如乳腺癌、胰腺癌和前列腺癌等的臨床研究也正在進行中。作為21世紀抗腫瘤領域取得的重大突破,合成致死理論促成了Olaparib的成功上市,并開始真正激發(fā)PARP-1抑制劑的應用潛能,在其他類型缺陷的腫瘤中也展現出巨大的潛力。在合成致死理論之外,PARP-1抑制劑的研究還存在著諸多挑戰(zhàn)與機遇,包括最近發(fā)現其與C-Met抑制劑、AKT抑制劑和PD-1抑制劑聯(lián)用有助于克服腫瘤耐藥問題,甚至在實體瘤之外的血液瘤中也已表現出療效。這些研究大大拓展了PARP-1抑制劑的潛在應用領域和發(fā)展空間,具有重大意義。現有PARP-1抑制劑大多以酶天然底物NAD+的煙酰胺部分為結構基礎進行設計,其結構差異較大。我們基于靶標和底物的結合特征進行分析,發(fā)現PARP-1抑制劑的共同結構特點是具有關鍵酰胺基團和剛性平面結構,這些關鍵特征是活性PARP-1抑制劑與蛋白結合的基礎。此外,活性位點內部還存在一個大的疏水口袋,可允許PARP-1抑制劑側鏈引入不同的基團以增加抑制活性、改善水溶性及其他理化性質,此結構特點給了PARP-1抑制劑非常大的改造空間。本文以進展最快、研究最多的Olaparib和Veliparib為模板,在保持酰胺構象和母核平面結構這些關鍵特征的基礎上,設計了四類不同母核的PARP-1抑制劑,分別為三唑并嘧啶類、噻吩并咪唑類、二氫喹唑啉酮類和單環(huán)三嗪酮類;考慮到活性位點內部的大疏水口袋可容納基團的多樣性,進一步在母核的基礎上連接脂肪族和芳香族側鏈、以及不同的長側鏈和短側鏈以考查其對活性的影響。同時本文采用分子對接技術,通過分析化合物與PARP-1之間的相互作用,驗證化合物設計的合理性、確保所設計目標化合物與PARP-1蛋白之間能夠較好結合。在目標化合物的合成中,本文通過合成路線的合理設計和反應條件的不斷探索,完成了三唑并嘧啶類、噻吩并咪唑類、二氫喹唑啉酮類三類化合物的合成工作,根據母核連接側鏈的不同,本文目標化合物的合成共涉及7條合成路線,主要包括縮合、環(huán)合、還原、氨解等反應步驟,并對合成路線中的關鍵步驟進行改進。第四類單環(huán)三嗪酮類化合物在合成過程中遇到一些困難,目前仍在打通合成路線中。本文共合成了56個目標化合物,其結構均經過MS,1H-NMR確證。對所合成化合物進行了酶水平和細胞水平的初步生物活性評價。1.PARP-1酶水平的抑制活性評價中,第一類和第三類化合物只初步測定了化合物在10μM下的抑制率,其中第一類三唑并嘧啶類初篩抑制率均低于10%,可能由于化合物的溶解性較差,考慮將部分化合物做成鹽酸鹽重新測定。第二類噻吩并咪唑類化合物初篩后選出抑制率大于50%的化合物進行IC50值的測定。令人遺憾的是哌嗪長側鏈化合物與相同側鏈的陽性藥相比活性差距較大,IC50值均在微摩爾級,有幸的是我們獲得了意外的發(fā)現,隨著取代基團體積逐漸減小,活性有所提高,并推測可能由于咪唑環(huán)的存在限制了側鏈的構象,大基團側鏈在噻吩并咪唑母核之上不能較好的與活性位點匹配。隨后合成的側鏈縮短化合物活性總體得到提高,驗證了上述推測,其中化合物27l的活性最好(IC50=43 n M)。2.活性最好的四個化合物(27g,27i,27j,27l)進行了細胞水平的活性評價,PARylation試驗結果顯示,四個化合物在Hela細胞上抑制活性弱于兩個陽性藥,其中活性最好的是27i(1.080μM);然而在BRCA-1/2缺陷的HCC1937細胞上,4個化合物的抗增殖活性均優(yōu)于兩個陽性藥。推測化合物透膜性等因素可能是其中原因之一,目前正在開展進一步驗證。本文通過合理藥物設計、目標化合物的合成與生物活性評價,發(fā)現了活性較好的噻吩并咪唑全新骨架的PARP-1抑制劑,其中四個化合物(27g,27i,27j,27l)單獨作用于BRCA1/2細胞系HCC1937和CAPAN-1的活性優(yōu)于陽性藥,且對于人正常細胞(人胚胎纖維細胞)的毒性低于陽性藥,值得進一步研究。初步的構效關系研究對開展PPAR抑制劑的進一步優(yōu)化設計具有一定的指導意義。本研究也提示,盡管如今的藥物設計方法提供了更加合理和多樣化的手段,但藥物結構對活性的影響尚難以通過現有的這些藥物設計手段進行精確預測,藥物設計的挑戰(zhàn)尚在,同時其不確定性也是藥物研究者的希望和動力所在。
[Abstract]:As a global public health problem that seriously endangers human health and life, cancer has attracted worldwide attention. As a big developing country, cancer incidence and mortality are on the rise continuously with the influence of many factors such as population aging. Breast and ovarian cancer are common malignant tumors in gynecology. The incidence of breast cancer in female malignant tumors is the highest, especially the aggressive, and the three negative breast cancer with short survival time is still not effective. The mortality of ovarian cancer is the first in gynecologic malignant tumor, and the relapse and resistance have been the difficult problems in the treatment. The flow disease survey found that about 10~40% of three negative breast cancer and 8 The BRCA1/2 gene mutation was detected in ~18% patients with ovarian cancer. The changes in the BRCA1/2 gene level increased the risk of breast and ovarian cancer, and also provided an opportunity for the prevention and treatment of such cancers. In recent years, PARP-1 inhibitors have been used alone or in combination with other drugs in BRCA1/2 deficient breast and ovarian cancer. Poly (ADP-ribose) polymerases (PARPs), a ribozyme existing in eukaryotic cells, is a ribozyme in eukaryotic cells, which is mainly involved in the DNA repair process and maintains the stability of the genomic stability of the 18.PARP family. Among the members, the content of PARP-1 is the highest in the cell, and the research is also the most in depth. NAD+ is used as the substrate to catalyze the transfer of the ADP- ribose unit to the nuclear receptor protein, thus forming a poly (ADP- ribose) polymer to guide the repair enzyme to repair the DNA gap and to play a key role in the base removal repair pathway. In the absence of the current situation, PARP-1 provides us with a few clinically proven anticancer targets, but its development is rather tortuous due to the limitations of the mechanism of action and the constraints of the drug structure. The initial research direction is to enhance the efficacy and reduce the drug use by combining with radiotherapy or chemotherapy drugs. However, this mechanism has been limited to toxicity, and more than thirty years of research have not been successful. The introduction and application of synthetic lethal theory have brought about the development of this kind of drug. The PARP-1 inhibitor can be used alone by cutting the base excision repair pathway of the defective tumor cells by cutting off the homologous recombination and thus can be used alone. In December, Olaparib was first approved for the treatment of BRCA1/2 deficient platinum sensitive recurrent ovarian cancer in this kind of tumor, such as BRCA1/2 deficient breast and ovarian cancer. Clinical studies on other indications, such as breast cancer, pancreatic cancer and prostate cancer, are also in progress. For the major breakthrough in the field of anti-cancer in twenty-first Century, the synthetic lethal theory contributed to the successful listing of Olaparib, and began to truly stimulate the potential of PARP-1 inhibitors, and showed great potential in other types of tumors. In addition to the synthetic lethal theory, there are many challenges and opportunities for the research of PARP-1 inhibitors. The combination of C-Met inhibitors, AKT inhibitors, and PD-1 inhibitors has recently been found to help overcome the problem of tumor resistance, even in haematoma other than solid tumors. These studies have greatly expanded the potential applications and development space of PARP-1 inhibitors. Most of the existing PARP-1 inhibitors are enzymes. The nicotinamide part of the natural substrate NAD+ is designed for the structure basis, and its structure is different. Based on the analysis of the binding characteristics of the target and substrate, we find that the common structural characteristics of the PARP-1 inhibitors are the key amide group and the rigid plane structure. These key features are the basis of the binding of active PARP-1 inhibitors and proteins. In addition, there is a large hydrophobic pocket inside the active site, which allows the PARP-1 inhibitor side chain to introduce different groups to increase the inhibitory activity, improve the water solubility and other physical and chemical properties. This structure has given the PARP-1 inhibitor a very large transformation space. This paper is the fastest progresses, the most studied Olaparib and Veliparib as the template, On the basis of maintaining the key characteristics of the conformation of amides and the planar structure of the parent nucleus, four kinds of PARP-1 inhibitors with different parent nuclei are designed, which are three azolimidines, thiophenazolidazole, two hydroquinazolones and mono ring three pylozones, which take into account the diversity of the large water pockets within the active site, and further in the mother. On the basis of the nuclear connection, the aliphatic and aromatic side chains, the different long side chains and the short side chains are used to examine the effect on the activity. At the same time, the molecular docking technique is used to verify the rationality of the compound design by analyzing the interaction between the compound and the PARP-1, so as to ensure that the designed target compounds and the PARP-1 protein can be compared. In the synthesis of target compounds, through the rational design of synthetic routes and the continuous exploration of reaction conditions, the synthesis of three zazolidines, thiophenacidazoles and two hydrogen quinazolones is completed. According to the difference of the side chain of the parent nucleus, the synthesis of the target compounds involves 7 synthetic routes. It mainly includes the reaction steps of condensation, cyclization, reduction and ammoniation, and improving the key steps in the synthesis route. The fourth kind of mono ring three mazine compounds have encountered some difficulties in the synthesis process, and are still in the synthesis route. This paper has synthesized 56 target compounds, their structure is confirmed by MS, 1H-NMR. In the evaluation of the inhibitory activity of the initial Bioactivity Evaluation of the enzyme level and cell level, the first and third compounds only preliminarily determined the inhibitory rate of the compound under 10 mu M, of which the first type of three azolimidines was lower than 10%, which may be due to the poor solubility of the compounds. The second class of thiophene and imidazole compounds were selected for the determination of the IC50 value of the compounds with inhibitory rate greater than 50%. It is regrettable that the activity gap between the piperazine long side chain compounds and the same side chain positive drugs is larger, and the IC50 values are at the mole level, and fortunately we have obtained the results. As the volume of the substituent group gradually decreased, the activity increased, and it was presumed that the conformation of the side chain was limited by the presence of the imidazole ring, and the large group side chain was not well matched with the active site on the thiophene and imidazole parent nucleus. It is speculated that the best four compounds (27g, 27i, 27j, 27L) of the best activity of compound 27L (27g, 27i, 27j, 27L) were evaluated at the cell level. The results of PARylation test showed that the inhibitory activity of four compounds on Hela cells was less than two positive drugs, of which the best activity was 27i (1.080 mu). The antiproliferative activity of the 4 compounds on CC1937 cells is better than that of two positive ones. It is presumed that the membrane permeability of the compound may be one of the reasons, and is now being further verified. In this paper, the synthesis and Bioactivity Evaluation of the target compounds and the evaluation of the biological activity of the target compounds have been developed by the rational drug design, and the P of the highly active thiophene and imidazole skeleton has been developed. ARP-1 inhibitors, of which four compounds (27g, 27i, 27j, 27L) are superior to the positive drugs in BRCA1/2 cell lines HCC1937 and CAPAN-1, and the toxicity of the normal cells (human embryonic fibroblasts) is lower than that of the positive drug. It is worth further study. The preliminary structure-activity relationship study on the further optimization of the PPAR inhibitors is designed. This study also suggests that, although the current drug design approach provides a more reasonable and diversified approach, the impact of drug structure on activity is still difficult to accurately predict through existing methods of drug design, the challenge of drug design is still at the same time, and its uncertainty is also the hope of drug researchers. The motivation lies.
【學位授予單位】：中國人民解放軍軍事醫(yī)學科學院
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R91;R914.5
本文編號：2123749
[Abstract]:As a global public health problem that seriously endangers human health and life, cancer has attracted worldwide attention. As a big developing country, cancer incidence and mortality are on the rise continuously with the influence of many factors such as population aging. Breast and ovarian cancer are common malignant tumors in gynecology. The incidence of breast cancer in female malignant tumors is the highest, especially the aggressive, and the three negative breast cancer with short survival time is still not effective. The mortality of ovarian cancer is the first in gynecologic malignant tumor, and the relapse and resistance have been the difficult problems in the treatment. The flow disease survey found that about 10~40% of three negative breast cancer and 8 The BRCA1/2 gene mutation was detected in ~18% patients with ovarian cancer. The changes in the BRCA1/2 gene level increased the risk of breast and ovarian cancer, and also provided an opportunity for the prevention and treatment of such cancers. In recent years, PARP-1 inhibitors have been used alone or in combination with other drugs in BRCA1/2 deficient breast and ovarian cancer. Poly (ADP-ribose) polymerases (PARPs), a ribozyme existing in eukaryotic cells, is a ribozyme in eukaryotic cells, which is mainly involved in the DNA repair process and maintains the stability of the genomic stability of the 18.PARP family. Among the members, the content of PARP-1 is the highest in the cell, and the research is also the most in depth. NAD+ is used as the substrate to catalyze the transfer of the ADP- ribose unit to the nuclear receptor protein, thus forming a poly (ADP- ribose) polymer to guide the repair enzyme to repair the DNA gap and to play a key role in the base removal repair pathway. In the absence of the current situation, PARP-1 provides us with a few clinically proven anticancer targets, but its development is rather tortuous due to the limitations of the mechanism of action and the constraints of the drug structure. The initial research direction is to enhance the efficacy and reduce the drug use by combining with radiotherapy or chemotherapy drugs. However, this mechanism has been limited to toxicity, and more than thirty years of research have not been successful. The introduction and application of synthetic lethal theory have brought about the development of this kind of drug. The PARP-1 inhibitor can be used alone by cutting the base excision repair pathway of the defective tumor cells by cutting off the homologous recombination and thus can be used alone. In December, Olaparib was first approved for the treatment of BRCA1/2 deficient platinum sensitive recurrent ovarian cancer in this kind of tumor, such as BRCA1/2 deficient breast and ovarian cancer. Clinical studies on other indications, such as breast cancer, pancreatic cancer and prostate cancer, are also in progress. For the major breakthrough in the field of anti-cancer in twenty-first Century, the synthetic lethal theory contributed to the successful listing of Olaparib, and began to truly stimulate the potential of PARP-1 inhibitors, and showed great potential in other types of tumors. In addition to the synthetic lethal theory, there are many challenges and opportunities for the research of PARP-1 inhibitors. The combination of C-Met inhibitors, AKT inhibitors, and PD-1 inhibitors has recently been found to help overcome the problem of tumor resistance, even in haematoma other than solid tumors. These studies have greatly expanded the potential applications and development space of PARP-1 inhibitors. Most of the existing PARP-1 inhibitors are enzymes. The nicotinamide part of the natural substrate NAD+ is designed for the structure basis, and its structure is different. Based on the analysis of the binding characteristics of the target and substrate, we find that the common structural characteristics of the PARP-1 inhibitors are the key amide group and the rigid plane structure. These key features are the basis of the binding of active PARP-1 inhibitors and proteins. In addition, there is a large hydrophobic pocket inside the active site, which allows the PARP-1 inhibitor side chain to introduce different groups to increase the inhibitory activity, improve the water solubility and other physical and chemical properties. This structure has given the PARP-1 inhibitor a very large transformation space. This paper is the fastest progresses, the most studied Olaparib and Veliparib as the template, On the basis of maintaining the key characteristics of the conformation of amides and the planar structure of the parent nucleus, four kinds of PARP-1 inhibitors with different parent nuclei are designed, which are three azolimidines, thiophenazolidazole, two hydroquinazolones and mono ring three pylozones, which take into account the diversity of the large water pockets within the active site, and further in the mother. On the basis of the nuclear connection, the aliphatic and aromatic side chains, the different long side chains and the short side chains are used to examine the effect on the activity. At the same time, the molecular docking technique is used to verify the rationality of the compound design by analyzing the interaction between the compound and the PARP-1, so as to ensure that the designed target compounds and the PARP-1 protein can be compared. In the synthesis of target compounds, through the rational design of synthetic routes and the continuous exploration of reaction conditions, the synthesis of three zazolidines, thiophenacidazoles and two hydrogen quinazolones is completed. According to the difference of the side chain of the parent nucleus, the synthesis of the target compounds involves 7 synthetic routes. It mainly includes the reaction steps of condensation, cyclization, reduction and ammoniation, and improving the key steps in the synthesis route. The fourth kind of mono ring three mazine compounds have encountered some difficulties in the synthesis process, and are still in the synthesis route. This paper has synthesized 56 target compounds, their structure is confirmed by MS, 1H-NMR. In the evaluation of the inhibitory activity of the initial Bioactivity Evaluation of the enzyme level and cell level, the first and third compounds only preliminarily determined the inhibitory rate of the compound under 10 mu M, of which the first type of three azolimidines was lower than 10%, which may be due to the poor solubility of the compounds. The second class of thiophene and imidazole compounds were selected for the determination of the IC50 value of the compounds with inhibitory rate greater than 50%. It is regrettable that the activity gap between the piperazine long side chain compounds and the same side chain positive drugs is larger, and the IC50 values are at the mole level, and fortunately we have obtained the results. As the volume of the substituent group gradually decreased, the activity increased, and it was presumed that the conformation of the side chain was limited by the presence of the imidazole ring, and the large group side chain was not well matched with the active site on the thiophene and imidazole parent nucleus. It is speculated that the best four compounds (27g, 27i, 27j, 27L) of the best activity of compound 27L (27g, 27i, 27j, 27L) were evaluated at the cell level. The results of PARylation test showed that the inhibitory activity of four compounds on Hela cells was less than two positive drugs, of which the best activity was 27i (1.080 mu). The antiproliferative activity of the 4 compounds on CC1937 cells is better than that of two positive ones. It is presumed that the membrane permeability of the compound may be one of the reasons, and is now being further verified. In this paper, the synthesis and Bioactivity Evaluation of the target compounds and the evaluation of the biological activity of the target compounds have been developed by the rational drug design, and the P of the highly active thiophene and imidazole skeleton has been developed. ARP-1 inhibitors, of which four compounds (27g, 27i, 27j, 27L) are superior to the positive drugs in BRCA1/2 cell lines HCC1937 and CAPAN-1, and the toxicity of the normal cells (human embryonic fibroblasts) is lower than that of the positive drug. It is worth further study. The preliminary structure-activity relationship study on the further optimization of the PPAR inhibitors is designed. This study also suggests that, although the current drug design approach provides a more reasonable and diversified approach, the impact of drug structure on activity is still difficult to accurately predict through existing methods of drug design, the challenge of drug design is still at the same time, and its uncertainty is also the hope of drug researchers. The motivation lies.
【學位授予單位】：中國人民解放軍軍事醫(yī)學科學院
【學位級別】：博士
【學位授予年份】：2016
【分類號】：R91;R914.5
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6 許開武;宋新明;;PARP1及其抑制劑在腫瘤中的研究進展[J];消化腫瘤雜志(電子版);2013年01期
7 李凡;廖志鋼;;PARP的結構、功能及其與DNA損傷的關系[J];河南科技大學學報(醫(yī)學版);2005年04期
8 何勤;柯根杰;;PARP及相關分子在糖尿病性視網膜病變中的表達研究[J];實用防盲技術;2010年04期
9 毛力真;PARP與缺血性神經元損傷后DNA的修復[J];中國臨床神經科學;1999年04期
10 王鐵君;韓成敏;李星花;尹金植;陳玉丙;王紅勇;李英普;;小鼠PARP-1基因RNAi表達質粒的構建與篩選[J];中國生物制品學雜志;2009年02期
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1 張銘湘;;PARP-1心血管疾病治療新靶標[A];中華醫(yī)學會第十三次全國心血管病學術會議專題報告專輯[C];2011年
2 朱枝祥;金晶;陳曉光;;多聚二磷酸腺苷核糖聚合酶(PARP—1)抑制劑篩選方法的建立及化合物篩選[A];全國第十二屆生化與分子藥理學學術會議論文集[C];2011年
3 田琳;宋珊珊;高艾;牛丕業(yè);左昕;郭偉;;5Aza-dc調控石英惡性轉化人支氣管上皮細胞PARP-1基因表達及對細胞生長的抑制作用[A];全國生化/工業(yè)與衛(wèi)生毒理學學術會議論文集[C];2010年
4 王旭艷;朱啟華;朱虹;何俏軍;徐云根;;PARP-1抑制劑的設計,合成及生物活性研究[A];2012長三角藥物化學研討會論文集[C];2012年
5 Chunmei Gong;Gonghua Tao;Linqing Yang;Jianjun Liu;Qingcheng Liu;Wenjie Li;Zhixiong Zhuang;;Methylation of PARP-1 promoter involved in the regulation of nano-SiO_2-induced decrease of PARP-1 mRNA expression[A];2012深圳市預防醫(yī)學會學術研討會論文匯編[C];2012年
6 江燕;洪順家;;PARP在小鼠不同發(fā)育階段卵泡中的表達及PJ34對小鼠超排卵的影響[A];中華醫(yī)學會第三次全國絕經學術會議暨絕經相關問題學習班論文匯編[C];2011年
7 朱枝祥;金晶;陳曉光;;多聚(ADP-核糖)聚合酶-2(PARP2)抑制劑高通量篩選模型的建立[A];2013年全國老年性癡呆與相關疾病學術會議論文匯編[C];2013年
8 丁國憲;宗峰;程蘊琳;;PARP活性抑制對T淋巴細胞壽命影響的實驗研究[A];第七屆全國老年醫(yī)學學術會議暨海內外華人老年醫(yī)學學術會議論文匯編[C];2004年
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1 馬殿棟;PARP-1依賴parthanatos在脫氧鬼臼毒素誘導神經膠質瘤細胞死亡中的作用及機制研究[D];吉林大學;2015年
2 王凌霄;PARP-1抑制劑的設計、合成與生物活性評價[D];中國人民解放軍軍事醫(yī)學科學院;2016年
3 王宵旰;PARP1 Val762Ala多態(tài)性降低酶活性[D];中國協(xié)和醫(yī)科大學;2007年
4 王鐵君;Chk-1和PARP-1 SiRNA輻射增敏的實驗研究[D];吉林大學;2009年
5 李永進;PKC-MAPK信號通路及PARP在長期接觸低劑量氯化甲基汞所致腦發(fā)育損傷中的作用[D];吉林大學;2006年
6 李麗;PARP-1調控LPS誘導的巨噬細胞HMGB1釋放的機制及意義研究[D];華中科技大學;2012年
7 曹奕強;PARP-1在人腦膠質瘤中的表達及其抑制劑BMN-673對膠質瘤細胞治療的增敏作用[D];中南大學;2014年
8 王靜;PARP-1基因沉默對機械牽張誘導的人支氣管上皮細胞炎性細胞因子表達的研究[D];山東大學;2014年
9 柯悠;Caspase-1介導的PARP1激活在腎小管間質纖維化中的作用及機制[D];華中科技大學;2014年
10 羅希;1型多聚ADP核糖合成酶調節(jié)心血管系統(tǒng)相關基因轉錄的機制研究[D];華中科技大學;2012年
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1 張家平;孕鼠肢體缺血預處理對窘迫胎鼠復氧后海馬神經元PARP-1及AIF表達的影響[D];福建醫(yī)科大學;2015年
2 周瑩瑩;PARP-1/AIF介導的Parthanatos通路在戊二酸尿癥大鼠紋狀體損傷中的機制研究[D];鄭州大學;2015年
3 樊彩芳;PARP-1/AIF通路介導戊二酸尿癥Ⅰ型大鼠大腦皮質損傷的機制研究[D];鄭州大學;2015年
4 張光昊;抑制PARP-1改善衰老導致的內皮細胞功能紊亂[D];山東大學;2015年
5 呂樹卿;HGF/PARP-1信號通路調控卵巢癌細胞侵襲轉移的機制研究[D];山東大學;2015年
6 李燕;PARP-1對卵巢癌血管生成、增殖的影響及其機制探討[D];山東大學;2014年
7 劉琳琳;PARP-1活性參與NF-κB的基因轉錄調控的機制研究[D];東北師范大學;2011年
8 楊雪麗;PARP抑制劑的篩選與活性評價[D];江南大學;2014年
9 姜雪;PARP-1參與基因轉錄后mRNA穩(wěn)定性調控的機制研究[D];東北師范大學;2012年
10 張曉寧;HSP70入核與PARP-1結合在肝缺血再灌注損傷中的保護作用[D];南華大學;2014年
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