Synthesis and study of antiproliferative, antitopoisomerase II, DNA-intercalating and DNA-damaging activities of arylnaphthalimides.
A series of arylnaphthalimides were designed and synthesized to overcome the dose-limiting cytotoxicity of N-acetylated metabolites arising from amonafide, the prototypical antitumour naphthalimide whose biomedical properties have been related to its ability to intercalate the DNA and poison the enzyme Topoisomerase II. Thus, these arylnaphthalimides were first evaluated for their antiproliferative activity against two tumour cell lines and for their antitopoisomerase II in vitro activities, together with their ability to intercalate the DNA in vitro and also through docking modelization. Then, the well-known DNA damage response in Saccharomyces cerevisiae was employed to critically evaluate whether these novel compounds can damage the DNA in vivo. By performing all these assays we conclude that the 5-arylsubstituted naphthalimides not only keep but also improve amonafide's biological activities.
Instituto Universitario de Bio-Orgánica 'Antonio González', Centro de Investigaciones Biomédicas de Canarias (CIBICAN), Departamento de Química Orgánica, Universidad de La Laguna, Avda. Astrofísico Fco. Sánchez 2, 38206 La Laguna, Tenerife, Spain; Instituto Canario de Investigación del Cáncer (ICIC), Spain(†).
Patricia
P
Quintana-Espinoza
Jonay
J
García-Luis
Angel
A
Amesty
Patricia
P
Martín-Rodríguez
Isabel
I
Lorenzo-Castrillejo
Angel G
AG
Ravelo
Leandro
L
Fernández-Pérez
Félix
F
Machín
Ana
A
Estévez-Braun
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000737:chemistry* / Q000378:metabolism; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D007364:Intercalating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D053644:Naphthalimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D017434:Protein Structure, Tertiary; D012441:Saccharomyces cerevisiae / Q000235:genetics
D000970:Antineoplastic Agents; D007364:Intercalating Agents; D053644:Naphthalimides; D004247:DNA; D004250:DNA Topoisomerases, Type II
Antiproliferative activity; Arylnaphthalimides; DNA damage; Saccharomyces cerevisiae; Topoisomerase II