title: Synthesis and biological evaluation of naphthoquinone-coumarin conjugates as topoisomerase II inhibitors.
abstract: Based on previous Topoisomerase II docking studies of naphthoquinone derivatives, a series of naphthoquinone-coumarin conjugates was synthesized through a multicomponent reaction from aromatic aldehydes, 4-hydroxycoumarin and 2-hydroxynaphthoquinone. The hybrid structures were evaluated against the α isoform of human topoisomerase II (hTopoIIα), Escherichia coli DNA Gyrase and E. coli Topoisomerase I. All tested compounds inhibited the hTopoIIα-mediated relaxation of negatively supercoiled circular DNA in the low micromolar range. This inhibition was specific since neither DNA Gyrase nor Topoisomerase I were affected. Cleavage assays pointed out that naphthoquinone-coumarins act by catalytically inhibiting hTopoIIα. ATPase assays and molecular docking studies further pointed out that the mode of action is related to the hTopoIIα ATP-binding site.
authors.affiliation: Instituto Universitario de Bio-Orgánica (CIBICAN), Departamento de Química Orgánica, Universidad de La Laguna, 38206, Spain.
authors.forename: Idaira
authors.initials: I
authors.lastname: Hueso-Falcón
authors.affiliation: Instituto Universitario de Bio-Orgánica (CIBICAN), Departamento de Química Orgánica, Universidad de La Laguna, 38206, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Amesty
authors.affiliation: Unidad de Investigación Hospital Universitario Nuestra Señora de La Candelaria, 38010 Tenerife, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Anaissi-Afonso
authors.affiliation: Unidad de Investigación Hospital Universitario Nuestra Señora de La Candelaria, 38010 Tenerife, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Lorenzo-Castrillejo
authors.affiliation: Unidad de Investigación Hospital Universitario Nuestra Señora de La Candelaria, 38010 Tenerife, Spain. Electronic address: fmachin@funcanis.org.
authors.forename: Félix
authors.initials: F
authors.lastname: Machín
authors.affiliation: Instituto Universitario de Bio-Orgánica (CIBICAN), Departamento de Química Orgánica, Universidad de La Laguna, 38206, Spain. Electronic address: aestebra@ull.es.
authors.forename: Ana
authors.initials: A
authors.lastname: Estévez-Braun
mesh_terms: D003374:Coumarins / Q000737:chemistry / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D003374:Coumarins; D009285:Naphthoquinones; D059005:Topoisomerase II Inhibitors; C030123:coumarin; D004250:DNA Topoisomerases, Type II
keywords: 2-Hydroxynaphthoquinone; 4-Hydroxycoumarin; ATPase; Docking; Privileged structures; Topoisomerase II