Design,Synthesis Of Brartemicin Derivatives And Evaluation Of Their Anti-invasive Activity

Tumor invasion and metastasis are the typical features of malignant tumors. Translocation of tumor cells across extracellular matrix barriers is named as invasion. Invasive tumor cells can migrate either as single cells or collectively in the form of files, clusters, or sheets. Tumor metastasis is the process that tumor cells invade beyond the constraints of the normal tissue from which they originate, disseminate to a distant site via the circulatory system, and establish a secondary tumor. Tumor invasion and metastasis are interrelated pathological processes, tumor invasion is the premiss of metastasis, the metastasis process must include the invasion, but the invasion is not necessarily led to metastasis. Tumor invasion is a critical step to accomplish the metastasis. Metastasis is the major cause for the death of most of the cancer patients, and it remains a key hurdle in cancer treatment.Tumor invasion and metastasis constitute is a major problem in the treatment of carcinoma patients. About30%of patients with newly diagnosed solid tumors already have clinically detectable metastases. Metastasizing is a complex, multi-step biochemical process. It involves the detachment of cancer cells from primary tumor, migration, adhesion, and invasion of cancer cells into the blood or lymphatic vessels, extravasation out of the vessel, and finally, interactions with the target tissue, and growth out to micrometastasis and macrometastasis/secondary tumors. Degradation of basement membranes and stromal ECM is crucial for invasion and metastasis of malignant cells.As metastasis is the main cause of death in cancer patients, there is a great demand for therapeutics interfering with metastasis. So far, most chemotherapy treatments are anti-proliferatives, which seek to retard growth of the primary tumor or to reduce the existing tumor burden. In fact, most of the anticancer drugs act directly to inhibit or kill cancer cells. However, many tumor cells are unaffected by this type of chemotherapy, because some tumor cells are able to stay dormant for months, or even years, and to grow later into new tumors, and the migrating cells are known to show a decreased proliferation rate and are thus less sensitive to standard chemotherapy. Therefore, the developments of anti-invasive and anti-metastatic drugs that can interfere with the biological processes of tumor cell invasion and metastasis are the new strategies for the cancer therapy.Natural products are important sources in drug discoveries and developments. Brartemicin, a trehalose-containing metabolite, is recently isolated from the culture broth of the actinomycete of the genus Nonomuraea. It can inhibit the invasion of murine colon carcinoma26-L5cells with an IC50value of0.39μM, and has no cytotoxicity even at the concentration of16μM. Brartemicin is composed of a trehalose scaffold and two identical2,4-dihydroxy-6-methylbenzoate units, which are connected by two ester bonds. As a high potent and selective anti-invasive agent, the mechanism and structure-activity relationships of brartemicin are still not elucidated. In a preliminary study, Prof. Zhaopeng Liu’s group designed and synthesized the6,6’-diester-trehalose and6.6’-diamide-trehalose analogs, and found three trehalose analogs that exhibited more potent inhibitory activity than brartemicin in the anti-invasive assay against murine colon26-L5carcinoma cells.Privileged structures are molecular scaffolds with versatile binding properties, such that a single scaffold is able to provide potent and selective ligands for a range of different biological targets through modification of functional groups. In addition, privileged structures typically exhibit good drug-like properties, which in turn lead to more drug-like compound libraries and leads. The privileged structure based drug-like molecule design has emerged as a fruitful strategy in drug discovery. Urea functional group is such a privileged structure. It contains both hydrogen bond acceptors and donors, and is favorable for the improvement of water solubility of a molecule. Therefore, urea functional group is often found in many anticancer drugs and anticancer agents. According to the privileged structure principle, we designed and synthesized six urea trehalose analogs. In addition, in order to study the role of the trehalose hydroxyl group on anti-invasive activity, we selectively converted4-and4’-hydroxyl into methoxy groups, and prepared its six corresponding urea analogs.In this dissertation, two synthetic routes are designed for the synthesis of the two6,6’-urea series of trehalose analogs. Totally,26novel compounds were prepared that include12target compounds. Their structures were comfirmed by1H-NMR, I3C-NMR, and ESI-MS. Preliminary anti-tumor invasion bioassay indicated that compound LYJ-20has good anti-invasive activity. Futher anti-tumor invasion bioassay and anti-invasive mechanism studies are still undergoing.