INTRODUCTIONPodophyllotoxin (PPT) is a naturally occurring antimitotic agent and an interesting lead in the development of anticancer agents. Its optimization led to the development of etoposide and teniposide used in combination chemotherapy with other anticancer drugs; unlike PPT these drugs act by inhibiting topoisomerases. Clinical success and toxicity issues at later stages of etoposide usage inclined researchers to develop structurally modified PPT derivatives. Some of the compounds obtained are under clinical investigations and are anticipated to reach the market.AREAS COVEREDThe present review summarizes the attempts made by researchers across the globe to find out newer anticancer agents based on the PPT structure. It brings out the outline of the inventions filed in the form of patents during the years 2012 - 2014.EXPERT OPINIONAfter the successful development of etoposide and teniposide there has been considerable interest in the PPT skeleton to develop newer chemotherapeutic agents. In this regard, several PPT derivatives such as TOP53, GL331, NK611, F11782, and so on, have been developed and are undergoing clinical trials. However, its low natural abundance is a major problem in carrying out research on PPT skeleton. This issue is expected to be addressed with the development of newer synthetic strategies to access structurally modified PPTs.

19 Apr 2011·BiochemistryQ3 · BIOLOGY

Interactions between the Etoposide Derivative F14512 and Human Type II Topoisomerases: Implications for the C4 Spermine Moiety in Promoting Enzyme-Mediated DNA Cleavage

Q3 · BIOLOGY

Article

Author: Bailly, Christian ; Pitts, Steven L. ; Osheroff, Neil ; Graves, David E. ; Jablonsky, Michael J. ; Gentry, Amanda C.

F14512 is a novel etoposide derivative that contains a spermine in place of the C4 glycosidic moiety. The drug was designed to exploit the polyamine transport system that is upregulated in some cancers. However, a preliminary study suggests that it is also a more efficacious topoisomerase II poison than etoposide [Barret et al. (2008) Cancer Res. 68, 9845-9853]. Therefore, we undertook a more complete study of the actions of F14512 against human type II topoisomerases. As determined by saturation transfer difference (1)H NMR spectroscopy, contacts between F14512 and human topoisomerase IIα in the binary enzyme-drug complex are similar to those of etoposide. Although the spermine of F14512 does not interact with the enzyme, it converts the drug to a DNA binder [Barret et al. (2008)]. Consequently, the influence of the C4 spermine on drug activity was assessed. F14512 is a highly active topoisomerase II poison and stimulates DNA cleavage mediated by human topoisomerase IIα or topoisomerase IIβ. The drug is more potent and efficacious than etoposide or TOP-53, an etoposide derivative that contains a C4 aminoalkyl group that strengthens drug-enzyme binding. Unlike the other drugs, F14512 maintains robust activity in the absence of ATP. The enhanced activity of F14512 correlates with a tighter binding and an increased stability of the ternary topoisomerase II-drug-DNA complex. The spermine-drug core linkage is critical for these attributes. These findings demonstrate the utility of a C4 DNA binding group and provide a rational basis for the development of novel and more active etoposide-based topoisomerase II poisons.

01 May 2005·Current Pharmaceutical DesignQ4 · MEDICINE

Podophyllotoxin Derivatives: Current Synthetic Approaches for New Anticancer Agents

Q4 · MEDICINE

Review

Author: You, Youngjae

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.

100 Deals associated with TOP-53

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Indication	Highest Phase	Country/Location	Organization	Date
Neoplasms	Phase 1	-	Taiho Pharmaceutical Co., Ltd.	-
Neoplasms	Phase 1	JP	-	-

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