Synthesis And Biological Activity Of4β-amines-demethylepipodophyllotoxins

Podophyllotoxin (PPT), extracted from the roots and rhizomes of Podophyllum species such as Podophyllum hexandrum and Podophyllum peltatum, has cathartic, antirheumatic and antiviral properties, and antimitotic activity. Etoposide (VP-16) and teniposide (VM-26) are semisynthetic glucosidic cyclic acetals of PPT currently used in the chemotherapy for various types of cancer, including small-cell lung cancer, testicular carcinoma, lymphoma, and Kaposi’s sarcoma. Although they are widely used in the clinic, several problems hinder their clinical efficacy such as drug-resistance and poor water-solubility. So there remains a need for new PPT analogs with anticancer activity, and with improved water-solubility. Then, extensive synthetic efforts have been deployed by a number of researchers in an attempt to address these limitations, and these efforts have led to the structure-activity relationships (SAR) unambiguously demonstrate that C4is the major molecular area tolerable to significant structural diversification, this thesis synthesize a series of4β-amino-4’-O-demethyl-4-deoxypodophyllotoxin derivatives, and their cytotoxicities against several human cancer cell lines, including HepG2, A549, HeLa and HCT-8cells, evaluated. These compounds exhibited higher levels of cytotoxicity than the anticancer drug etoposide. The IC50value of compound4β-N-(4-nitrophenyl piperazinyl)-4’-O-dernethyl-4-deoxypodophyllotoxin(11), which is the most promising in this group compounds, is1.43,0.16,0.07and2.12μM for HepG2, A549, HeLa and HCT-8cells, respectively. When HeLa cell treated with0.5μM compound11for24h, by morphological methods found the nucleus have obvious shrinkage, there are a lot of nucleosome, and cause cell apoptosis. Meanwhile, compound11promote apoptosis protein p53and caspase-3’s over expression, this phenomenon show that the compounds11inhibiting tumor cell proliferation may through trigger turner cell apoptosis pathways. In addition, treatment with11led to a dose-dependent accumulation of cells in the G2/M phase with a concomitant decrease in the population of G1phase cells. Furthermore, a population of sub-G1phase cells, which are characteristic apoptotic cells, was observed after24h of treatment with11. So that11was interfering with cell proliferation by arresting the cell cycle and that this compound induced G2/M arrest accompanied by apoptosis in HeLa cells. Meanwhile,11interacted with CT DNA in PBS, and caused the conformation of CT DNA changed from the B-form to a more compact C-form, which showed potent inhibitory activities towards DNA topo-Ⅱ. These results suggest that4β-N-(4-nitrophenyl piperazinyl)-4’-O-demethyl-4-deoxypodophyllotoxin has potential for further development as anticancer agent.