Synthesis of C,N'-linked bis-heterocycles using a deprotometalation-iodination-N-arylation sequence and evaluation of their antiproliferative activity in melanoma cells.
Benzothiophene, benzofuran, benzothiazole and benzoxazole were deprotometalated using the lithium-zinc combination prepared from ZnCl2·TMEDA (TMEDA=N,N,N',N'-tetramethylethylenediamine, 1equiv) and lithium 2,2,6,6-tetramethylpiperidide (LiTMP, 3equiv). Subsequent interception of the 2-metalated derivatives using iodine as electrophile led to the iodides in 81%, 82%, 67% and 42% yields, respectively. These yields are higher (10% more) than those obtained using ZnCl2·TMEDA (0.5equiv) and LiTMP (1.5equiv), except in the case of benzoxazole (10% less). The crude iodides were involved in the N-arylation of pyrrole, indole, carbazole, pyrazole, indazole, imidazole and benzimidazole in the presence of Cu (0.2equiv) and Cs2CO3 (2equiv), and using acetonitrile as solvent (no other ligand) to provide after 24h reflux the expected N-arylated azoles in yields ranging from 33% to 81%. Using benzotriazole also led to N-arylation products, but in lower 34%, 39%, 36% and 6% yields, respectively. A further study with this azole evidenced the impact of 2,2,6,6-tetramethylpiperidine on the N-arylation yields. Most of the C,N'-linked bis-heterocycles thus synthesized (in particular those containing benzimidazole) induced a high growth inhibition of A2058 melanoma cells after a 72h treatment at 10(-5)M.
Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes 1, Bâtiment 10A, Case 1003, Campus de Beaulieu, 35042 Rennes, France; Laboratoire de Synthèse Organique Appliquée, Faculté des Sciences, Université d'Oran, BP 1524 El M'Naouer, 31000 Oran, Algeria.
Madani
M
Hedidi
Laboratoire de Synthèse Organique Appliquée, Faculté des Sciences, Université d'Oran, BP 1524 El M'Naouer, 31000 Oran, Algeria. Electronic address: badri_sofi@yahoo.fr.
Ghenia
G
Bentabed-Ababsa
Laboratoire de Synthèse Organique Appliquée, Faculté des Sciences, Université d'Oran, BP 1524 El M'Naouer, 31000 Oran, Algeria.
Aïcha
A
Derdour
Centre de Diffractométrie X, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes 1, Bâtiment 10B, Campus de Beaulieu, 35042 Rennes Cedex, France.
Thierry
T
Roisnel
Centre de Diffractométrie X, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes 1, Bâtiment 10B, Campus de Beaulieu, 35042 Rennes Cedex, France.
Vincent
V
Dorcet
Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes 1, Bâtiment 10A, Case 1003, Campus de Beaulieu, 35042 Rennes, France.
Floris
F
Chevallier
Laboratoire Littoral Environnement et Sociétés, UMRi CNRS 7266, Université de La Rochelle, 17042 La Rochelle, France.
Laurent
L
Picot
Laboratoire Littoral Environnement et Sociétés, UMRi CNRS 7266, Université de La Rochelle, 17042 La Rochelle, France. Electronic address: valerie.thiery@univ-lr.fr.
Valérie
V
Thiéry
Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes, UMR 6226, CNRS-Université de Rennes 1, Bâtiment 10A, Case 1003, Campus de Beaulieu, 35042 Rennes, France. Electronic address: florence.mongin@univ-rennes1.fr.
Florence
F
Mongin
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007454:Iodides / Q000737:chemistry / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D007454:Iodides; D014230:Triazoles; C012771:benzotriazole
Antiproliferative activity; Deprotonative metalation; Five-membered aromatic heterocycles; Melanoma; N-arylation