Synthesis And Antitumor Activity Of Novel Podophyllotoxin Derivatives

Combined therapy is still the principal treatment to malignancy at present and chemotherapy is one of the main curing methods to cancer. During the course of cancer chemotherapy treatment, it has been found that prolonged treatment of carcinoma patients with certain anticancer medicines can result in an acquired resistance toward multiple drugs, which is known as multidrug resistance (MDR). The problem of increasingly severe multidrug resistance of tumor is the main reason to cause abortive chemotherapy. Finding novel synthetic antitumor agents for overcoming MDR has currently become the focus of oncology.Podophyllotoxin, an aryl tetralin lignan, has important antineoplastic and antiviral properties. Because of its toxic side effects, extensive structure modifications have been performed since the1950s.Podophyllotoxin derivatives possess antitumor activity, some of which, such as etoposide (VP-16) and teniposide (VM-26) have been widely used as anticancer drugs for clinical chemotherapy. However, their low water solubility, acquired drug-resistance, myelosuppression and severe gastrointestinal disturbances promoted people to search for new derivatives of podophyllotoxin. The replacement of the C-4sugar moiety of etoposide with a non-sugar substitution has proven to be significant in overcoming the drug resistance of etoposide. The C-4non-sugar substitution can be linked through O-, S-or N-linkage. In general, the O-linked derivatives (ethers, esters) and the S-linked derivatives (thioethers) are inactive or show lower activity in comparison to the N-linked congeners.4β-N-substituted podophyllotoxin derivatives exhibits superior anticancer activity compared to etoposide against some of the human cancer cell lines. To obtain better therapeutic agents, NK611, NPF, as well as GL331and TOP53are presently under clinical trial.Based on the structure-activity relationships of podophyllotoxins and in order to find compounds with superior bioactivity and overcoming multidrug resistance, a novel series of4β-N-substituted podophyllotoxin derivatives were synthesized and evaluated as potential antitumor agents. Ten novel podophyllotoxin derivatives were synthesized by linking 4β-amino-4-deoxypodophyllotoxin with alcohols and amines through maleic acid. Nine novel podophyllotoxin derivatives were synthesized by linking4β-amino-4-deoxypodophyllotoxin with alcohols and amines through succinic acid.1,3-dipolar cycloaddition of4β-azido-4-deoxypodophyllotoxin to alkynes resulted in the six novel1,2,3-triazol podophyllotoxin derivatives.We have synthesized29target compounds in all, in which28derivatives were not reported by previous literature, structurally confirmed by MS,’HNMR and evaluated for their antitumor activities in vitro by MTT assay and SRB assay. Some derivatives exhibit superior anticancer activity compared to etoposide in vitro. Some derivatives may overcome MDR compared to etoposide in vitro. We can assert that the promising results obtained for the new4β-N-substituted podophyllotoxin derivatives described in this study make them potential candidates to take up further synthesis and evaluation of such new derivatives.