Design and synthesis of a novel series of pyranonaphthoquinones as topoisomerase II catalytic inhibitors.
On the basis of previous pharmacophore modeling studies of naphthoquinones derivatives, we have designed and synthesized a new set of pyranonaphthoquinones. These compounds were obtained through a direct and highly efficient approach based on an intramolecular domino Knoevenagel hetero Diels-Alder reaction from lawsone (2-hydroxynaphthoquinone) and a variety of aldehydes containing an alkene. The synthesized pyranonaphthoquinones were evaluated against the alpha isoform of human topoisomerase II (hTopoIIalpha). Among the 11 derivatives studied, we found that six of them act as catalytic inhibitors of the enzyme in vitro. These six derivatives strongly preclude the enzyme from decatenating or relaxing suitable substrates. Finally, we correlate their active/inactive status with docking studies of these novel compounds into the ATPase domain of hTopoIIalpha.
Jiménez-Alonso
Sandra
S
Instituto Universitario de Bio-Orgánica "Antonio González", Universidad de La Laguna, Avda. Astrofísico Fco, Sánchez 2, 38206 La Laguna, Tenerife, Spain.
Orellana
Haydee Chávez
HC
Estévez-Braun
Ana
A
Ravelo
Angel G
AG
Pérez-Sacau
Elisa
E
Machín
Felix
F
D000447:Aldehydes / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D004250:DNA Topoisomerases, Type II / Q000737:chemistry / Q000378:metabolism; D004278:DNA, Superhelical / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011485:Protein Binding; D011714:Pyrans / Q000737:chemistry*; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors
D000447:Aldehydes; D000951:Antigens, Neoplasm; D004278:DNA, Superhelical; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D009285:Naphthoquinones; D011714:Pyrans; D059005:Topoisomerase II Inhibitors; D004250:DNA Topoisomerases, Type II