Studies On Synthesis And Antitumor Activities Of Podophyllotoxin Derivatives

Cancer has become the most leading cause of death to human beings and severely threatened health and life of mankind. The chemotherapeutic medicines under clinical usage have lots of drawbacks such as low curative effect, high toxicity, difficult absorption, high price and multidrug resistance (MDR). It takes enormous efforts and spending every year to research and develop new medicines for preventing and treating cancer all over the world.Combined therapy is still the principal treatment to malignancy at present and chemotherapy is one of the main curing method to cancer. The problem of increasingly severe MDR of tumor is the main reason to abortive chemotherapy. MDR directly relates with patients’response to chemotherapy and their prognosis. NCI (National cancer institute) estimated that the more than90%death of tumor patients are concerned with MDR. Therefore, finding novel antitumor agents for overcoming MDR has currently become the focus of oncology.Podophyllotoxin and its derivatives possess antitumour activity and some of them, such as Etoposide (VP-16) and Teniposide (VM-26), have been used as anticancer drugs for clinical chemotherapy wildely. 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:(a) curative treatment of Yoshida AH13rat sarcomas at almost nontoxic doses;(b) oral applicability;(c) lack of neurotoxicity at curative doses;(d) efficacy toward MDR tumor cells;(e) easy to synthesis. Indibulin has been under clinical trials presently.A series of novel podophyllotoxin derivatives were designed using association strategy based on indibulin’s planar indole-3-glyoxylamide structure and synthesized from podophyllotoxin. The synthesized ten indole-3-glyoxyl podophyllotoxins were tested cytotoxicity in vitro by the standard MTT assay against KB and KBV200cell lines. The synthesized nine N-substituented, N’-(4β-4-desoxypodophyllotoxin) succinamides/ fumaleamides were tested cytotoxicity in vitro by the standard MTT assay against KB, KBV200, K562, K562/A02cell lines. Compounds (4.3.1a,4.3.1d,4.3.2b,4.4.1a,4.4.1d,4.4.2c) showed significant anticancer activities and overcomed MDR in vitro.All synthesized target compounds, which were not reported by previous literature were confirmed by1H-NMR, ESI-MS or HR-ES1-MS as well as melting point.