Podophyllotoxin Derivatives: Current Synthetic Approaches for New Anticancer Agents

Abstract

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.

Natural compounds with P2X7 receptor-modulating properties

“…The semisynthetic, podophyllotoxin-derived TN, like the chemically related etoposide, acts as a topoisomerase inhibitor and thereby hinders the DNA replication during the S phase of the cell cycle to exert its strong anti-mitotic and anti-tumour activity [38,39]. Teniposide is currently being therapeutically used in various disseminated and solid tumour entities, including leukemia as well as breast, ovarian and brain tumours [39][40][41].…”

Plant Bioactive Metabolites and Drugs Produced by Endophytic Fungi of Spermatophyta

“…However, the higher reputation for podophyllotoxin ( Figure 7) and a few synthetic derivatives relies on their pharamacological applications, particularly as antitumor drugs [199,202]. These products have also been reported from an increasing number of endophytic fungi, such as Alternaria sp.…”

A lignan O-methyltransferase catalyzing the regioselective methylation of matairesinol in Carthamus tinctorius

“…A trimethoxylated aryltetralin lignan, podophyllotoxin (Figure 1), is an important antitumor agent that has been used as a raw material to prepare semi-synthetic antitumor medicines for cancer chemotherapy (Srivastava et al 2005;You 2005). A trimethoxylated dibenzylbutyrolactone lignan, arctigenin (4′-Omethylmatairesinol) is another antitumor lignan with selective toxicity against cancer cells under glucose starvation (Awale et al 2006;Kim et al 2010;Sun et al 2011).…”