含过氧桥化合物的合成方法及生物学效应研究
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摘要
恶性肿瘤严重威胁人民群众的身体健康，发病率和死亡率呈逐年增长的趋势，现有临床药物疗效有限、毒副作用大、有交叉耐药的现象发生，持续开发新的抗肿瘤药物刻不容缓。以青蒿素为代表的天然来源和半合成的过氧化物在体外和体内实验中表现出显著的抗肿瘤活性，构效关系表明过氧键在这类化合物发挥抗肿瘤活性中具有重要作用。但是，天然或半合成过氧化物来源有限、结构单一、药代动力学性质不理想、作用机制不明，限制了它们成为抗肿瘤药物的可能性，所以，开发全合成类过氧化物的合成方法、研究它们的抗肿瘤活性和作用机制，对于发现具有全新抗肿瘤机制、与现有抗肿瘤药物无交叉耐药的过氧化物类抗肿瘤药物意义重大。本文对1,2,4-trioxolanes、1,2,4-trioxanes和1,2,4,5-tetraoxanes三类内过氧化物的合成方法、抗肿瘤活性和作用机制进行了初步研究。
1,2,4,5-tetraoxanes具有显著的抗肿瘤、抗疟、抗菌等药理作用。但这类化合物的合成方法存在收率低、操作不方便、所用催化剂对空气和水分敏感、价格昂贵等缺点。本文报道以无水硫酸镁为脱水剂、磷钼酸为催化剂，通过1,1-dihydroperoxides与羰基化合物缩合制备1,2,4,5-tetraoxanes的方法。该方法操作简单、价格低廉、收率高，可用于克数量级制备1,2,4,5-tetraoxanes。
过氧氢基化合物1,1-dihydroperoxides和β-hydroxyhydroperoxides是制备1,2,4,5-tetraoxanes和1,2,4-trioxanes的重要中间体。本文发展了一种使用同一体系（环氧乙烷-四氯化锡-过氧化氢）制备上述两种过氧氢基化合物的方法。用过氧化氢处理环氧乙烷-四氯化锡络合物，将以先重排后加成的两步“一锅法”反应高产率地得到1位单取代的1,1-dihydroperoxides。这种由环氧乙烷制备1,1-dihydroperoxides的方法由本课题组首次报道。如用四氯化锡-过氧化氢体系处理环氧乙烷，得到的是β-hydroxyhydroperoxides，该方法操作简单、底物普适性好、收率较高。
过氧化物中的过氧键对化合物的抗肿瘤活性贡献很大，但仅过氧键无法发挥抗肿瘤活性。为探讨不同取代基对过氧化物活性的影响，本文设计并合成了几类结构简单的1,2,4-trioxolanes、1,2,4-trioxanes和1,2,4,5-tetraoxanes类化合物。体外初步筛选结果表明：含有过氧键的化合物并不都有抗肿瘤活性；伯胺基团对于1,2,4,5-tetraoxanes发挥抗肿瘤活性非常重要。
过氧键可被体内亚铁离子激活，生成活性自由基，发挥抗肿瘤活性。基于此机理，本文设计并合成了过氧化物-二茂铁轭合物，以利用二茂铁中的亚铁离子激活过氧键，协同二者的抗肿瘤活性。本文发现过氧化物1,2,4-trioxane和非过氧化物1,3-dioxolane通过胺甲基与二茂铁连接的轭合物具有显著的抗肿瘤活性，且该作用无法用去铁胺拮抗，表明这类轭合物的抗肿瘤活性与过氧键无关。
肿瘤细胞内具有较高的铁离子浓度，可以选择性激活过氧化物，另外，铁螯合剂也会对肿瘤细胞产生选择性杀伤作用。基于此机理，本文设计并合成了过氧化物-铁螯合剂轭合物，以协同二者的活性和选择性。体外实验结果表明，不同的铁螯合剂具有不同程度的抗肿瘤活性，儿茶酚类和8-羟基喹啉类轭合物全部具有中等至显著的抗肿瘤活性，而且这种作用可以被去铁胺拮抗，表明这类轭合物通过铁代谢途径发挥活性，且过氧键在其中发挥重要作用。
内过氧化物结构中含有空间集中、体积较大的亲水基团，可作为氢键受体，靶点的氢键供体与之结合将有利于内过氧化物与特定靶点的结合，发挥更强的抗肿瘤活性。基于此假设，我们合成了内过氧化物-受体酪氨酸蛋白激酶抑制剂轭合物和内过氧化物-组蛋白去乙酰化酶抑制剂轭合物。体外抗肿瘤实验表明，酯类的受体酪氨酸蛋白激酶抑制剂轭合物和全部组蛋白去乙酰化酶抑制剂轭合物具有显著的抗肿瘤活性。
上述具有显著抗肿瘤活性的过氧化物的构效关系和作用机制还需要进一步的研究。
The incidence and mortality caused by cancer tend to increase quickly in recentyears. Due to the disadvantages of limited efficacy, serious side effects, and emergenceof cross resistance of the existing chemotherapy drugs, there is an urgent need todevelop new antitumor drugs.
Artemisinin and semi-synthetic derivatives exhibit potent antitumor activity both invitro and in vivo. It has been proven that the peroxide bridge plays an important role forartemisinin to exert various biological activity. The use of aretemisinin derivatives incancer therapy are limited by their source, rigid structure, poor pharmacokineticproperties and unclear mechanism of action. Therefore, new methodology developmentfor synthetic peroxides may solve the above mentioned problems and provide newgeneration antitumor drugs. In this work, the synthetic methodology, antitumor activityand mechanism of action of endoperoxides1,2,4-trioxolanes,1,2,4-trioxanes and1,2,4,5-tetraoxanes were reported.
1,2,4,5-Tetraoxanes exhibit potent antitumor, antimalarial and antibacterialactivities. But synthesis of1,2,4,5-tetraoxanes was limited by lack of efficient methodsand catalysts. In this work, we developed a phosphomolybdic acid catalyzed method forthe preparation of1,2,4,5-tetraoxanes. Using anhydrous magnesium sulfate asdehydrating agent, phosphomolybdic acid efficiently catalyzed the condensation of1,1-dihydroperoxides and carbonyl compounds to afford1,2,4,5-tetraoxanes in highyield. We proved phosphomolybdic acid is a convenient, economical and efficientcatalyst for the preparation of1,2,4,5-tetraoxanes.
1,1-Dihydroperoxides and β-hydroxyhydroperoxides are important intermediatesfor biologically active1,2,4,5-tetraoxanes and1,2,4-trioxanes. The preparation of thesetwo hydroperoxides was limited by the lack of efficient method. In this work, we havedisclosed an oxirane-SnCl4-H2O2system which could convert oxiranes to eitherβ-hydroxyhydroperoxides or primary1,1-dihydroperoxides in moderate to good yields by adjusting the order of addition, reaction temperature and the amount of SnCl4. SnCl4acted as an efficient catalyst in the preparation of β-hydroxyhydroperoxides. In the caseof preparing primary1,1-dihydroperoxides, SnCl4first promoted rearrangement ofoxirane to aldehyde, then catalyzed the condensation reaction of aldehyde withhydrogen peroxide. This is the first report that primary1,1-dihydroperoxides could beefficiently prepared from corresponding oxirane via a two-step, one-pot tandemreaction.
Both peroxide group and related auxiliary moiety contribute to the compoundantitumor activity. About thirty1,2,4-trioxolanes,1,2,4-trioxanes and1,2,4,5-tetraoxanes were designed, synthesized and evaluated for their antiproliferationactivity toward cancer cells. The results showed that presence of a primary amino groupseems critical for endoperoxides to display antitumor activity in1,2,4,5-tetraoxanes.
It has been reported that activation of the peroxide bond, possiblely by the ferrousion, is essential for peroxidesto play biological effects. Base on this hypothesis,endoperoxide-ferrocene conjugates were designed and synthesized to synergize theirantitumor activity. Primary screening results showed that a1,2,4-trioxane conjugate anda non-peroxide conjugate exhibited excellent antitumor activity. The activity could notbeen impaired by deferoxamine, suggesting a pathway independent of iron metabolicpathway and peroxide group.
Ferrous ion concentration in cancer cell is much higher than that in normalcell,thus cancer cells are more suspective to iron chelators and peroxides which need theactivation by ferrous ion. Based on this observation, endoperoxide-iron chelatorconjugates were designed and synthesized to enhance the efficacy and tumor cellselectivity. Our results showed that all pyrocatechol-and8-hydroxyquinoline-conjugates exhibited moderate or potent antitumor activity. The activity of theseconjugates could be impaired by deferoxamine, which proved that iron metabolicpathway may be involved in the antitumor mechanism and peroxide group playedimportant role in the antitumor activity.
Endoperoxides could act as hydrogen bond receptor. The hydrogen bond donor inthe active site of target may bond to it and the interaction between them was enhanced.Based on the hypothesis, endoperoxide-enzyme inhibitor conjugates were designed andsynthesized. Primary results for these compounds toward cancer cells showed that theester derivative of endoperoxide-receptor tyrosine protein kinase inhibitor conjugates and all endoperoxide-histone deacetylase inhibitor conjugates exhibit potent antitumoractivity.
The structural activity relationship and mechanism of these potent antitumorperoxides need further study.
1,2,4,5-tetraoxanes具有显著的抗肿瘤、抗疟、抗菌等药理作用。但这类化合物的合成方法存在收率低、操作不方便、所用催化剂对空气和水分敏感、价格昂贵等缺点。本文报道以无水硫酸镁为脱水剂、磷钼酸为催化剂，通过1,1-dihydroperoxides与羰基化合物缩合制备1,2,4,5-tetraoxanes的方法。该方法操作简单、价格低廉、收率高，可用于克数量级制备1,2,4,5-tetraoxanes。
过氧氢基化合物1,1-dihydroperoxides和β-hydroxyhydroperoxides是制备1,2,4,5-tetraoxanes和1,2,4-trioxanes的重要中间体。本文发展了一种使用同一体系（环氧乙烷-四氯化锡-过氧化氢）制备上述两种过氧氢基化合物的方法。用过氧化氢处理环氧乙烷-四氯化锡络合物，将以先重排后加成的两步“一锅法”反应高产率地得到1位单取代的1,1-dihydroperoxides。这种由环氧乙烷制备1,1-dihydroperoxides的方法由本课题组首次报道。如用四氯化锡-过氧化氢体系处理环氧乙烷，得到的是β-hydroxyhydroperoxides，该方法操作简单、底物普适性好、收率较高。
过氧化物中的过氧键对化合物的抗肿瘤活性贡献很大，但仅过氧键无法发挥抗肿瘤活性。为探讨不同取代基对过氧化物活性的影响，本文设计并合成了几类结构简单的1,2,4-trioxolanes、1,2,4-trioxanes和1,2,4,5-tetraoxanes类化合物。体外初步筛选结果表明：含有过氧键的化合物并不都有抗肿瘤活性；伯胺基团对于1,2,4,5-tetraoxanes发挥抗肿瘤活性非常重要。
过氧键可被体内亚铁离子激活，生成活性自由基，发挥抗肿瘤活性。基于此机理，本文设计并合成了过氧化物-二茂铁轭合物，以利用二茂铁中的亚铁离子激活过氧键，协同二者的抗肿瘤活性。本文发现过氧化物1,2,4-trioxane和非过氧化物1,3-dioxolane通过胺甲基与二茂铁连接的轭合物具有显著的抗肿瘤活性，且该作用无法用去铁胺拮抗，表明这类轭合物的抗肿瘤活性与过氧键无关。
肿瘤细胞内具有较高的铁离子浓度，可以选择性激活过氧化物，另外，铁螯合剂也会对肿瘤细胞产生选择性杀伤作用。基于此机理，本文设计并合成了过氧化物-铁螯合剂轭合物，以协同二者的活性和选择性。体外实验结果表明，不同的铁螯合剂具有不同程度的抗肿瘤活性，儿茶酚类和8-羟基喹啉类轭合物全部具有中等至显著的抗肿瘤活性，而且这种作用可以被去铁胺拮抗，表明这类轭合物通过铁代谢途径发挥活性，且过氧键在其中发挥重要作用。
内过氧化物结构中含有空间集中、体积较大的亲水基团，可作为氢键受体，靶点的氢键供体与之结合将有利于内过氧化物与特定靶点的结合，发挥更强的抗肿瘤活性。基于此假设，我们合成了内过氧化物-受体酪氨酸蛋白激酶抑制剂轭合物和内过氧化物-组蛋白去乙酰化酶抑制剂轭合物。体外抗肿瘤实验表明，酯类的受体酪氨酸蛋白激酶抑制剂轭合物和全部组蛋白去乙酰化酶抑制剂轭合物具有显著的抗肿瘤活性。
上述具有显著抗肿瘤活性的过氧化物的构效关系和作用机制还需要进一步的研究。
The incidence and mortality caused by cancer tend to increase quickly in recentyears. Due to the disadvantages of limited efficacy, serious side effects, and emergenceof cross resistance of the existing chemotherapy drugs, there is an urgent need todevelop new antitumor drugs.
Artemisinin and semi-synthetic derivatives exhibit potent antitumor activity both invitro and in vivo. It has been proven that the peroxide bridge plays an important role forartemisinin to exert various biological activity. The use of aretemisinin derivatives incancer therapy are limited by their source, rigid structure, poor pharmacokineticproperties and unclear mechanism of action. Therefore, new methodology developmentfor synthetic peroxides may solve the above mentioned problems and provide newgeneration antitumor drugs. In this work, the synthetic methodology, antitumor activityand mechanism of action of endoperoxides1,2,4-trioxolanes,1,2,4-trioxanes and1,2,4,5-tetraoxanes were reported.
1,2,4,5-Tetraoxanes exhibit potent antitumor, antimalarial and antibacterialactivities. But synthesis of1,2,4,5-tetraoxanes was limited by lack of efficient methodsand catalysts. In this work, we developed a phosphomolybdic acid catalyzed method forthe preparation of1,2,4,5-tetraoxanes. Using anhydrous magnesium sulfate asdehydrating agent, phosphomolybdic acid efficiently catalyzed the condensation of1,1-dihydroperoxides and carbonyl compounds to afford1,2,4,5-tetraoxanes in highyield. We proved phosphomolybdic acid is a convenient, economical and efficientcatalyst for the preparation of1,2,4,5-tetraoxanes.
1,1-Dihydroperoxides and β-hydroxyhydroperoxides are important intermediatesfor biologically active1,2,4,5-tetraoxanes and1,2,4-trioxanes. The preparation of thesetwo hydroperoxides was limited by the lack of efficient method. In this work, we havedisclosed an oxirane-SnCl4-H2O2system which could convert oxiranes to eitherβ-hydroxyhydroperoxides or primary1,1-dihydroperoxides in moderate to good yields by adjusting the order of addition, reaction temperature and the amount of SnCl4. SnCl4acted as an efficient catalyst in the preparation of β-hydroxyhydroperoxides. In the caseof preparing primary1,1-dihydroperoxides, SnCl4first promoted rearrangement ofoxirane to aldehyde, then catalyzed the condensation reaction of aldehyde withhydrogen peroxide. This is the first report that primary1,1-dihydroperoxides could beefficiently prepared from corresponding oxirane via a two-step, one-pot tandemreaction.
Both peroxide group and related auxiliary moiety contribute to the compoundantitumor activity. About thirty1,2,4-trioxolanes,1,2,4-trioxanes and1,2,4,5-tetraoxanes were designed, synthesized and evaluated for their antiproliferationactivity toward cancer cells. The results showed that presence of a primary amino groupseems critical for endoperoxides to display antitumor activity in1,2,4,5-tetraoxanes.
It has been reported that activation of the peroxide bond, possiblely by the ferrousion, is essential for peroxidesto play biological effects. Base on this hypothesis,endoperoxide-ferrocene conjugates were designed and synthesized to synergize theirantitumor activity. Primary screening results showed that a1,2,4-trioxane conjugate anda non-peroxide conjugate exhibited excellent antitumor activity. The activity could notbeen impaired by deferoxamine, suggesting a pathway independent of iron metabolicpathway and peroxide group.
Ferrous ion concentration in cancer cell is much higher than that in normalcell,thus cancer cells are more suspective to iron chelators and peroxides which need theactivation by ferrous ion. Based on this observation, endoperoxide-iron chelatorconjugates were designed and synthesized to enhance the efficacy and tumor cellselectivity. Our results showed that all pyrocatechol-and8-hydroxyquinoline-conjugates exhibited moderate or potent antitumor activity. The activity of theseconjugates could be impaired by deferoxamine, which proved that iron metabolicpathway may be involved in the antitumor mechanism and peroxide group playedimportant role in the antitumor activity.
Endoperoxides could act as hydrogen bond receptor. The hydrogen bond donor inthe active site of target may bond to it and the interaction between them was enhanced.Based on the hypothesis, endoperoxide-enzyme inhibitor conjugates were designed andsynthesized. Primary results for these compounds toward cancer cells showed that theester derivative of endoperoxide-receptor tyrosine protein kinase inhibitor conjugates and all endoperoxide-histone deacetylase inhibitor conjugates exhibit potent antitumoractivity.
The structural activity relationship and mechanism of these potent antitumorperoxides need further study.
引文
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