Podophyllotoxin derivatives: current synthetic approaches for new anticancer agents.
Podophyllotoxin is an antimitotic natural product. Its inhibitory activity on cell growth led to the development of the clinically valuable anticancer agents, etoposide, teniposide and the water-soluble prodrug, etoposide phosphate. The cytotoxic mechanism of these drugs is the inhibition of topoisomerase II, unlike the lead compound which inhibits mitosis. Through extensive structure-activity relationship studies, several potential drug candidates were synthesized such as GL-331, TOP 53, NK611, and azatoxin. Recently, more complex and diverse analogues have been synthesized either to get more potent compounds or to overcome drug resistance. At the same time, a number of prodrug approaches have been tried to enhance the tumor selectivity or to increase the aqueous solubility. The prodrugs can release cytotoxic etoposide through the actions of hydrolysis, enzymes or catalytic antibodies. More sophisticated prodrug strategies have been applied in etoposide and these produced some interesting results. In this review, the current research trends in the design of new derivatives will be covered with a brief introduction of podophyllotoxin and related analogues.
You
Youngjae
Y
Department of Chemistry, University at Buffalo, The State University of New York, Buffalo, NY 14260-3000, USA. yjyou@eng.buffalo.edu
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D011034:Podophyllotoxin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011355:Prodrugs; D011034:Podophyllotoxin