Design, synthesis, and biological evaluation of the first podophyllotoxin analogues as potential vascular-disrupting agents.

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Labruere R, Gautier B, Testud M, Seguin J, Lenoir C, Desbene-Finck S, Helissey P, Garbay C, Chabot GG, Vidal M, Giorgi-Renault S

Design, synthesis, and biological evaluation of the first podophyllotoxin analogues as potential vascular-disrupting agents.

ChemMedChem. 2010 Dec 3;5(12):2016-25. doi: 10.1002/cmdc.201000305.

PubMed ID

20979080 [ View in PubMed

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Abstract

We designed and synthesized two novel series of azapodophyllotoxin analogues as potential antivascular agents. A linker was inserted between the trimethoxyphenyl ring E and the tetracyclic ABCD moiety of the 4-aza-1,2-didehydropodophyllotoxins. In the first series, the linker enables free rotation between the two moieties; in the second series, conformational restriction of the E nucleus was considered. We have identified several new compounds with inhibitory activity toward tubulin polymerization similar to that of CA-4 and colchicine, while displaying low cytotoxic activity against normal and/or cancer cells. An aminologue and a methylenic analogue were shown to disrupt endothelial cell cords on Matrigel at subtoxic concentrations, and an original assay of drug washout allowed us to demonstrate the rapid reversibility of this effect. These two new analogues are promising leads for the development of vascular-disrupting agents in the podophyllotoxin series.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Podofilox	Tubulin alpha-4A chain	Protein	Humans	Yes	Inhibitor	Details