Studies On Synthesis And Antitumor Activity Of Substituted Indole-3-glyoxyl 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. 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. The replacement of the C-4 sugar moiety of etoposide with a non-sugar substitution has proven to be significant in overcoming the drug resistance of etoposide. The C-4 non-sugar substitution can be linked through O-, S- or N-linkage. 4β-N-substituted podophyllotoxin derivatives exhibits superior anticancer activity compared to etoposide against some of the human cancer cell lines. Indibulin is a novel synthetic small molecule anticancer agent with significant antitumor activity in vitro and in vivo. It destabilizes microtubules in tumor cells, as well as in cell-free system. This novel tubulin inhibitor was developed by ASTA Medica AG (DE). It has a number of superior properties: easy to synthesis; oral applicability; lack of neurotoxicity at curative doses; efficacy toward MDR tumor cells. Indibulin has been under clinical trials presently.Based on the structure-activity relationships of podophyllotoxins and in order to find compounds with superior bioactivity and overcoming multidrug resistance, a series of novel podophyllotoxin derivatives were designed using association strategy based on indibulin's planar indole-3-glyoxyl structure and synthesized from podophyllotoxin. We have synthesized twenty-two indole-3-glyoxyl podophyllotoxin derivatives in all. These derivatives 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 new podophyllotoxin derivatives described in this study make them potential candidates to take up further synthesis and evaluation of such new derivatives.