Synthesis and biological evaluation of novel phenylcarbazoles as potential anticancer agents.
We here report the synthesis and biological evaluation of new phenylcarbazole derivatives designed as potential anticancer agents. Indole and hydroxyindole were used to generate three scaffolds that were successively exploited to introduce various substituents on the maleimide moiety. The synthesis includes a final intramolecular key Heck-type reaction, which was carried out with a triflate derivative or with a bromophenyl derivative. Each step was optimized and the complete chemical strategy is detailed. Several compounds showed a marked cytotoxicity against CEM human leukemia cells with IC(50) values in the 10-100 nM range. Precise structure-activity relationships were delineated. Cell cycle analysis, topoisomerase I inhibition, and interaction with DNA were evaluated, and inhibition of CDK activity was also investigated. Although binding of the drugs to DNA likely contributes to the cytotoxic action, the exact molecular targets of these molecules remain undiscovered. The efficient chemical routes reported here for the design of highly cytotoxic compounds provide novel opportunities to identify antitumor agents in the phenylcarbazole series.
Routier
Sylvain
S
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d'Orléans, 45067 Orléans Cedex 2, France. sylvain.routier@univ-orleans.fr
Mérour
Jean-Yves
JY
Dias
Nathalie
N
Lansiaux
Amélie
A
Bailly
Christian
C
Lozach
Olivier
O
Meijer
Laurent
L
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors; D002227:Carbazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D051360:Cyclin-Dependent Kinase 5 / Q000037:antagonists & inhibitors; D004247:DNA / Q000737:chemistry; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008301:Maleimides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D059004:Topoisomerase I Inhibitors
D000970:Antineoplastic Agents; D002227:Carbazoles; D007211:Indoles; D008301:Maleimides; D059004:Topoisomerase I Inhibitors; D004247:DNA; D051360:Cyclin-Dependent Kinase 5; D016203:CDC2 Protein Kinase; D038362:Glycogen Synthase Kinase 3