Synthesis of 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine derivatives as CDK inhibitors and cytotoxic agents.
We here report the synthesis and biological evaluation of new 3,5-bis(2-indolyl)pyridine and 3-[(2-indolyl)-5-phenyl]pyridine designed as potential CDK inhibitors. Indole, 5-hydroxyindole, and phenol derivatives were used to generate three substitutions of the pyridine. The resulting skeletons were successively exploited to introduce various dimethylaminoalkyl side chains by Williamson type reactions. The synthesis includes Stille or Suzuki type reactions, which were realized on the 3,5-dibromopyridine. The preparation and the use of stannylindoles in mono or bis cross-coupling reactions were also described and each step was optimized and detailed. Kinase assays were realized and shown that nude compounds 7, 18, and 25 inhibited CDK1 in the 0.3-0.7 micromolar range with a good selectivity over GSK-3. Cytotoxicity against CEM human leukemia cells was evaluated with IC(50) values in the 5-15 micromolar range. Precise structure-activity relationships were delineated. Molecular modeling and docking solutions were proposed to complete the studies and to explain the observed SAR in the CDK assays.
Jacquemard
Ulrich
U
Institut de Chimie Organique et Analytique, (1) Université d'Orléans, (2) CNRS UMR 6005, Rue de Chartres, BP 6759, 45067 Orléans Cedex 2, France.
Dias
Nathalie
N
Lansiaux
Amélie
A
Bailly
Christian
C
Logé
Cédric
C
Robert
Jean-Michel
JM
Lozach
Olivier
O
Meijer
Laurent
L
Mérour
Jean-Yves
JY
Routier
Sylvain
S
D000595:Amino Acid Sequence; D016203:CDC2 Protein Kinase / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004247:DNA / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship
D047428:Protein Kinase Inhibitors; D011725:Pyridines; D004247:DNA; D016203:CDC2 Protein Kinase