Synthesis And Antitumor Activity Of Novel Podophyllotoxin Derivatives

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. To obtain better therapeutic agents, NK611, NPF, GL331and TOP53are presently under clinical trial while VP-16and VM-26are now in clinic use. Meanwhile, a novel tubulin inhibitor named D-24851(Indibulin) 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.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 using association strategy and evaluated as potential antitumor agents. Twenty-five novel podophyllotoxin derivatives were synthesized by coupling4β-amino-4-deoxypodophyllotoxin and indole parent nucleus with oxalyl group, and1,3-dipolar cycloaddition of4β-azido-4-deoxypodophyllotoxin to alkynes resulted in the eleven novel1,2,3-triazol podophyllotoxin derivatives. Some derivatives exhibit superior anticancer activity compared to etoposide in vitro, some derivatives can overcome MDR compared to etoposide in vitro. We can assert that the promising4β-N-substituted podophyllotoxin derivatives obtained especially4-triazloes-substituded ones which has many advantages such as novel structure and minor molecular weight may have extensive perspective for in-depth searching.