Mitotic arrest induced by a novel family of DNA topoisomerase II inhibitors.
A small structure-focused library of propargylic enol ethers was prepared by means of a modular and efficient chemodifferentiating organocatalyzed multicomponent reaction. The most active compound (GI(50) 0.25 microM) against solid tumor cells was selected as lead. Cell cycle analysis and immunoblotting demonstrated arrest at the metaphase, pointing out human topoisomerase II as plausible molecular target. In vitro assays were carried out, showing that the lead behaves as a catalytic inhibitor of the enzyme.
León
Leticia G
LG
BioLab, Instituto Universitario de Bio-Organica Antonio Gonzalez, Universidad de La Laguna, C/Astrofisico Francisco Sanchez 2, 38206 La Laguna, Spain.
Ríos-Luci
Carla
C
Tejedor
David
D
Pérez-Roth
Eduardo
E
Montero
Juan C
JC
Pandiella
Atanasio
A
García-Tellado
Fernando
F
Padrón
José M
JM
D000480:Alkynes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000138:chemical synthesis*; D002384:Catalysis; D002453:Cell Cycle / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004987:Ethers / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D008677:Metaphase / Q000187:drug effects; D008938:Mitosis / Q000187:drug effects*; D020005:Propanols / Q000494:pharmacology*; D054852:Small Molecule Libraries / Q000138:chemical synthesis; D059005:Topoisomerase II Inhibitors
D000480:Alkynes; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D004987:Ethers; D020005:Propanols; D054852:Small Molecule Libraries; D059005:Topoisomerase II Inhibitors; C531209:propargyl ether; C028255:propargyl alcohol