| 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.
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