多靶向抗肿瘤转移天然产物ECO-4601的全合成研究
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摘要
肿瘤转移是指恶性肿瘤细胞脱离原发肿瘤,通过各种方式转移到其他组织或器官继续生长,形成与原发肿瘤相同性质的继发性肿瘤的过程。肿瘤转移是恶性肿瘤的基本特征,是临床肿瘤患者(90%以上)死亡的最主要原因。如何防止肿瘤转移一直是肿瘤治疗的最大难关。目前采用的大多数抗肿瘤药物主要是抑制肿瘤细胞的增殖和杀伤肿瘤细胞,这对增殖期的肿瘤细胞特别有效,而对许多处于休眠或蛰伏期的肿瘤细胞无效。因此,研制针对转移过程和微小转移灶的抗肿瘤转移药物,是提高恶性肿瘤治愈率、降低治疗后复发率和死亡率、延长患者生命、提高患者的生活质量的一个最主要的途径。
一般认为,肿瘤侵袭与转移是一个复杂的过程,牵涉到细胞脱落、浸润、迁移运行、着床、新生血管生成等。从理论上讲,只要能够阻止上述一个或多个过程,就能抑制肿瘤转移。但是临床应用中作用靶点单一的抗肿瘤转移药物很难达到临床应用要求。因此,理想的抗肿瘤侵袭与转移药物应是多靶向的,最好能作用于肿瘤侵袭与转移过程的多个环节,同时对增殖期的肿瘤细胞也有效。多靶向、多作用机制应成为抗肿瘤侵袭与转移药物的研究新策略。
ECO-4601(10-法尼基-4,6,8-三羟基-5,10-二氢二苯并[b,e][1,4]二氮杂卓-11-酮)是从真放线菌株(046-ECO11)的二次代谢产物中分离得到的,其母核为独特的二苯二氮杂卓酮结构,在天然产物中非常罕见。ECO-4601具有广谱抗肿瘤作用,对60余种肿瘤细胞系表现出高抑制活性(GI50在微摩尔级)。ECO-4601可以选择性作用于外周苯二氮卓受体,干扰肿瘤Ras信号,诱导肿瘤细胞凋亡,抑制肿瘤细胞增殖；ECO-4601对基质金属蛋白酶MMP-2和MMP-9具有强抑制活性；ECO-4601还能明显抑制肿瘤的侵袭与转移,抑制肿瘤新生血管生成等。因此,ECO-4601具有多靶向抗肿瘤和抗肿瘤转移能力,目前已进入Ⅲ期临床研究。
目前,ECO-4601只能从真放线菌的二次代谢产物中分离得到,尚未有ECO-4601的全合成研究报道,有关ECO-4601的构效关系也不明确。本研究的目的,就是通过建立ECO-4601的全合成方法,探讨提供ECO-4601的有效化学途径,并为进一步合成ECO-4601衍生物,研究其抗肿瘤与抗肿瘤转移活性,明确该类化合物的构效关系、寻找选高效低毒的抗肿瘤转移ECO-4601衍生物奠定基础。
通过逆合成分析,我们以2,4-二氯硝基苯为原料,经甲氧基取代、还原、氨基保护、硝化、氨基脱保护、重氮化溴代反应等,制备得到1,5-二甲氧基-3-硝基-2溴苯；以间甲氧基苯甲酸为原料,经硝化及硝基还原反应,合成了2-氨基-3-甲氧基苯甲酸。通过探讨1,5-二甲氧基-3-硝基-2溴苯和2-氨基-3-甲氧基苯甲酸的偶联反应,建立了以铜催化的Ullmann偶合反应合成二芳基取代胺的方法；通过对分子内环合反应以及酯的氨解反应条件等进行一系列探讨,确立了以酯的氨解反应,合成关键环状中间体取代二苯二氮杂卓酮的方法；最终引入法尼基,合成了天然产物ECO-4601的酚羟基甲基化衍生物Me-ECO-4601。生物活性实验表明,Me-ECO-4601的抗肿瘤血管生成和抗细胞迁移运动活性优于天然产物ECO-4601,而其细胞毒性较ECO-4601低,这表明通过对ECO-4601的结构修饰,有望发现高效低毒的抗肿瘤转移ECO-4601衍生物。
总之,通过对ECO-4601的全合成研究,我们建立了合成关键环状中间体取代二苯二氮杂卓酮的方法,合成了ECO-4601的甲基化衍生物Me-ECO-4601,研究了其抗肿瘤与抗肿瘤转移活性,为进一步合成ECO-4601衍生物、探讨该类化合物的构效关系奠定了基础。由于时间的关系,Me-ECO-4601的脱甲基化条件尚在探讨,另外有些步骤的反应收率有待提高。
Tumor metastasis is the process whereby uncontrolled tumor cell leaves the primary tumor, invades into neighboring tissues and then establishes a secondary tumor at a distant site. Metastasis is the fiducial markers of cancer, over 90% of the cancer patients will eventually lead to death by tumor metastasis. Therefore, how ho control tumor cell metastasis is the most difficulty task in the treatment of cancer. Conventional chemotherapeutic anticancer drugs usually directly act on the tumor cells by killing them or inhibiting their growth and proliferation, but are ineffective towards the metastastic tumor cells. The developments of novel anti-metastatic drugs that target the metastasis processes are very important for the treatment of cancer and reducement of the recurrence and death rate, prolonging the survival time and improving the life quality of the cancer patients.
It is well established that metastasis is complex and multistep processes, which are influenced by a number of events including the detaching from the primary lesions, the degrading the extracellular matrix (ECM), invading the surrounding stroma, transfering, adapting to the newly colonized organ and angiogenesis. Interfering with any metastatic stages can in theory prevents the metastasis of tumor cells. However, single targeted anti-merastasis drugs prove to be not very effective in clinical treatment of cancer. Ideally, an effective anti-metastasis drug should have synergistic effects by targeting more than one of the metastasis processes, and at the same time has the ability to inhibit the tumor cell proliferation. Therefore, multi-targeted anti-metastasis and anti-invasion drugs will be considered as a new strategy for cancer therapy.
ECO-4601 (4,6,8-trihydroxy-10-(3,7,11-trimethyldodeca-2,6,10-trienyl)-5,10-di-hydrodibenzo[b,e][1,4]diazepin-11-one), is a novel farnesylated dibenzodiazepinone (MW 462.58), produced by a Micromonospora strain (046-ECO11). ECO-4601 owns a benzodiazepine moiety that is rare in natural products. ECO-4601 has a broad cytotoxic activity (lowμM) against over 60 kinds of tumor cell lines in vitro and has high antitumor efficacy in vivo. It selectively acts on the peripheral benzodiazepine receptors (PBR) that is related to the initiation and regulation of apoptosis of tumor cells. It can also strong inhibits the Ras-MAPK pathway, producing an effect on the inhibition of tumor cell proliferation and migration. Furthemore, ECO-4601 can inhibit the activities of MMP-2 and MMP-9, reduces the tumor cell motility and migration at nanomolar concentrations, and has potent anti-angiogenic effects. Therefore, ECO-4601 is a multi-targeted and cancer and anti-metastasis agent. It is now under clinical phase III evaluation.
At the present time, ECO-4601 is only obtained from microbial metabolism. No method has been reported for its synthesis and the structure and antitumor activity relationships are not clear. The purpose of this study is to develop a method for the total synthesis of ECO-4601 and set up a synthetic way for the production of ECO-4601. It will provide a new method for the synthesis of ECO-4601 analogues for the further study the structure and activity relationships and for the discovery more potent and less toxic anti-metastasis agents.
Based on the retrosynthesis analysis, we choose 2,4-dichloronitrobenzene as the starting material and prepared 2-bromo-1,5-dimethoxy-3-nitrobenzene via methoxy substitution, reduction of nitro group, protecting the amino group, nitration, deprotecing, and diazonium bromination; From 3-methoxybenzoic acid, 2-amino-3-methoxybenzoic acid was prepared via nitration follwed by reduction. Various conditions for the coupling of 2-bromo-1,5-dimethoxy-3-nitrobenzene and 2-amino-3-methoxybenzoic acid were studied, and the cooper catalyzed Ullmann reaction was successfully applied on the preparation of the substituted diarylamine. Following the reduction of the nitro group, the intramolecular amide formation conditions were studied. By methyl esterfication and acid catalyzed intramolecular amniolysis, the important dibenzodiazepinone moiety was constructed. Finally, by introducing a farnesyl group, the O-methylated analogue of ECO-4601 (Me-ECO-4601) was prepared. Bioassay studies showed that Me-4601 exhibited higher anti-angiogenic activity and displayed an improvement in the inhibition of cell migration than ECO-4601, and had lower cytotoxicity. This study indicates it is possible to find more potent and less toxic anti-metastasis ECO-4601 analogue by structural modification of ECO-4601.
In summary, in the studies of total synthesis of ECO-4601, we have established a novel method for the preparation the important dibenzodiazepinone intermediate and prepared the methylated analogues of ECO-4601 and studied its antitumor anti-metastasis activities. Our researches may provide useful information for further synthesis of ECO-4601 analogues, to study their structure-activity relationships, and to find more potent and less toxic anti-metastasis drugs. Due to the time limit, the demethylation conditions are still undergoing, and the yields for some steps in the total synthesis ECO-4601 need further improvements.
一般认为,肿瘤侵袭与转移是一个复杂的过程,牵涉到细胞脱落、浸润、迁移运行、着床、新生血管生成等。从理论上讲,只要能够阻止上述一个或多个过程,就能抑制肿瘤转移。但是临床应用中作用靶点单一的抗肿瘤转移药物很难达到临床应用要求。因此,理想的抗肿瘤侵袭与转移药物应是多靶向的,最好能作用于肿瘤侵袭与转移过程的多个环节,同时对增殖期的肿瘤细胞也有效。多靶向、多作用机制应成为抗肿瘤侵袭与转移药物的研究新策略。
ECO-4601(10-法尼基-4,6,8-三羟基-5,10-二氢二苯并[b,e][1,4]二氮杂卓-11-酮)是从真放线菌株(046-ECO11)的二次代谢产物中分离得到的,其母核为独特的二苯二氮杂卓酮结构,在天然产物中非常罕见。ECO-4601具有广谱抗肿瘤作用,对60余种肿瘤细胞系表现出高抑制活性(GI50在微摩尔级)。ECO-4601可以选择性作用于外周苯二氮卓受体,干扰肿瘤Ras信号,诱导肿瘤细胞凋亡,抑制肿瘤细胞增殖；ECO-4601对基质金属蛋白酶MMP-2和MMP-9具有强抑制活性；ECO-4601还能明显抑制肿瘤的侵袭与转移,抑制肿瘤新生血管生成等。因此,ECO-4601具有多靶向抗肿瘤和抗肿瘤转移能力,目前已进入Ⅲ期临床研究。
目前,ECO-4601只能从真放线菌的二次代谢产物中分离得到,尚未有ECO-4601的全合成研究报道,有关ECO-4601的构效关系也不明确。本研究的目的,就是通过建立ECO-4601的全合成方法,探讨提供ECO-4601的有效化学途径,并为进一步合成ECO-4601衍生物,研究其抗肿瘤与抗肿瘤转移活性,明确该类化合物的构效关系、寻找选高效低毒的抗肿瘤转移ECO-4601衍生物奠定基础。
通过逆合成分析,我们以2,4-二氯硝基苯为原料,经甲氧基取代、还原、氨基保护、硝化、氨基脱保护、重氮化溴代反应等,制备得到1,5-二甲氧基-3-硝基-2溴苯；以间甲氧基苯甲酸为原料,经硝化及硝基还原反应,合成了2-氨基-3-甲氧基苯甲酸。通过探讨1,5-二甲氧基-3-硝基-2溴苯和2-氨基-3-甲氧基苯甲酸的偶联反应,建立了以铜催化的Ullmann偶合反应合成二芳基取代胺的方法；通过对分子内环合反应以及酯的氨解反应条件等进行一系列探讨,确立了以酯的氨解反应,合成关键环状中间体取代二苯二氮杂卓酮的方法；最终引入法尼基,合成了天然产物ECO-4601的酚羟基甲基化衍生物Me-ECO-4601。生物活性实验表明,Me-ECO-4601的抗肿瘤血管生成和抗细胞迁移运动活性优于天然产物ECO-4601,而其细胞毒性较ECO-4601低,这表明通过对ECO-4601的结构修饰,有望发现高效低毒的抗肿瘤转移ECO-4601衍生物。
总之,通过对ECO-4601的全合成研究,我们建立了合成关键环状中间体取代二苯二氮杂卓酮的方法,合成了ECO-4601的甲基化衍生物Me-ECO-4601,研究了其抗肿瘤与抗肿瘤转移活性,为进一步合成ECO-4601衍生物、探讨该类化合物的构效关系奠定了基础。由于时间的关系,Me-ECO-4601的脱甲基化条件尚在探讨,另外有些步骤的反应收率有待提高。
Tumor metastasis is the process whereby uncontrolled tumor cell leaves the primary tumor, invades into neighboring tissues and then establishes a secondary tumor at a distant site. Metastasis is the fiducial markers of cancer, over 90% of the cancer patients will eventually lead to death by tumor metastasis. Therefore, how ho control tumor cell metastasis is the most difficulty task in the treatment of cancer. Conventional chemotherapeutic anticancer drugs usually directly act on the tumor cells by killing them or inhibiting their growth and proliferation, but are ineffective towards the metastastic tumor cells. The developments of novel anti-metastatic drugs that target the metastasis processes are very important for the treatment of cancer and reducement of the recurrence and death rate, prolonging the survival time and improving the life quality of the cancer patients.
It is well established that metastasis is complex and multistep processes, which are influenced by a number of events including the detaching from the primary lesions, the degrading the extracellular matrix (ECM), invading the surrounding stroma, transfering, adapting to the newly colonized organ and angiogenesis. Interfering with any metastatic stages can in theory prevents the metastasis of tumor cells. However, single targeted anti-merastasis drugs prove to be not very effective in clinical treatment of cancer. Ideally, an effective anti-metastasis drug should have synergistic effects by targeting more than one of the metastasis processes, and at the same time has the ability to inhibit the tumor cell proliferation. Therefore, multi-targeted anti-metastasis and anti-invasion drugs will be considered as a new strategy for cancer therapy.
ECO-4601 (4,6,8-trihydroxy-10-(3,7,11-trimethyldodeca-2,6,10-trienyl)-5,10-di-hydrodibenzo[b,e][1,4]diazepin-11-one), is a novel farnesylated dibenzodiazepinone (MW 462.58), produced by a Micromonospora strain (046-ECO11). ECO-4601 owns a benzodiazepine moiety that is rare in natural products. ECO-4601 has a broad cytotoxic activity (lowμM) against over 60 kinds of tumor cell lines in vitro and has high antitumor efficacy in vivo. It selectively acts on the peripheral benzodiazepine receptors (PBR) that is related to the initiation and regulation of apoptosis of tumor cells. It can also strong inhibits the Ras-MAPK pathway, producing an effect on the inhibition of tumor cell proliferation and migration. Furthemore, ECO-4601 can inhibit the activities of MMP-2 and MMP-9, reduces the tumor cell motility and migration at nanomolar concentrations, and has potent anti-angiogenic effects. Therefore, ECO-4601 is a multi-targeted and cancer and anti-metastasis agent. It is now under clinical phase III evaluation.
At the present time, ECO-4601 is only obtained from microbial metabolism. No method has been reported for its synthesis and the structure and antitumor activity relationships are not clear. The purpose of this study is to develop a method for the total synthesis of ECO-4601 and set up a synthetic way for the production of ECO-4601. It will provide a new method for the synthesis of ECO-4601 analogues for the further study the structure and activity relationships and for the discovery more potent and less toxic anti-metastasis agents.
Based on the retrosynthesis analysis, we choose 2,4-dichloronitrobenzene as the starting material and prepared 2-bromo-1,5-dimethoxy-3-nitrobenzene via methoxy substitution, reduction of nitro group, protecting the amino group, nitration, deprotecing, and diazonium bromination; From 3-methoxybenzoic acid, 2-amino-3-methoxybenzoic acid was prepared via nitration follwed by reduction. Various conditions for the coupling of 2-bromo-1,5-dimethoxy-3-nitrobenzene and 2-amino-3-methoxybenzoic acid were studied, and the cooper catalyzed Ullmann reaction was successfully applied on the preparation of the substituted diarylamine. Following the reduction of the nitro group, the intramolecular amide formation conditions were studied. By methyl esterfication and acid catalyzed intramolecular amniolysis, the important dibenzodiazepinone moiety was constructed. Finally, by introducing a farnesyl group, the O-methylated analogue of ECO-4601 (Me-ECO-4601) was prepared. Bioassay studies showed that Me-4601 exhibited higher anti-angiogenic activity and displayed an improvement in the inhibition of cell migration than ECO-4601, and had lower cytotoxicity. This study indicates it is possible to find more potent and less toxic anti-metastasis ECO-4601 analogue by structural modification of ECO-4601.
In summary, in the studies of total synthesis of ECO-4601, we have established a novel method for the preparation the important dibenzodiazepinone intermediate and prepared the methylated analogues of ECO-4601 and studied its antitumor anti-metastasis activities. Our researches may provide useful information for further synthesis of ECO-4601 analogues, to study their structure-activity relationships, and to find more potent and less toxic anti-metastasis drugs. Due to the time limit, the demethylation conditions are still undergoing, and the yields for some steps in the total synthesis ECO-4601 need further improvements.
引文
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