Synthesis and biological activities of new furo[3,4-b]carbazoles: potential topoisomerase II inhibitors.
New 1,5-dihydro-4-(substituted phenyl)-3H-furo[3,4-b]carbazol-3-ones were synthesised via a key step Diels-Alder reaction under microwave irradiation. 3-Formylindole was successfully used in a 6-step synthesis to obtain those complex heterocycles. The Diels-Alder reaction generating the carbazole ring was optimised under thermal conditions or microwave irradiation. After cleavage of functional groups, DNA binding, topoisomerase inhibition and cytotoxic properties of the new-formed furocarbazoles were investigated. These carbazoles do not present a strong interaction with the DNA, and do not modify the relaxation of the DNA in the presence of topoisomerase I or II except for one promising compound. This compound is a potent topoisomerase II inhibitor, and its cellular activity is not moderated compared to etoposide. The synthesis of these molecules allowed the generalisation of the method using indole and 5-OBn indole and several benzaldehydes. The synthesis of these molecules produced chemical structures endowed with promising cytotoxic and topoisomerase II inhibition activities.
Hajbi
Youssef
Y
Institut de Chimie Organique et Analytique, Université d'Orléans, CNRS UMR 6005, B.P. 6759, 45067 Orléans Cedex 2, France.
Neagoie
Cléopatra
C
Biannic
Bérenger
B
Chilloux
Aurélie
A
Vedrenne
Emeline
E
Baldeyrou
Brigitte
B
Bailly
Christian
C
Mérour
Jean-Yves
JY
Rosca
Sorin
S
Routier
Sylvain
S
Lansiaux
Amélie
A
D002227:Carbazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D004250:DNA Topoisomerases, Type II / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D059003:Topoisomerase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
D002227:Carbazoles; D059003:Topoisomerase Inhibitors; D004250:DNA Topoisomerases, Type II