Design, synthesis and anticancer properties of IsoCombretaQuinolines as potent tubulin assembly inhibitors.
The synthesis and evaluation of a new series of IsoCombretaQuinolines (IsoCoQuines) 2 with a 2-substituted-quinoline in place of the 3,4,5-trimethoxyphenyl ring present in isoCA-4 and CA-4 are described. Most of these compounds displayed a potent cytotoxic activity (IC50< 10 nM) against a panel of five human cancer cell lines and inhibited tubulin assembly at a micromolar level. The most potent analogue 2b, having a 3-hydroxy-4-methoxyphenyl as B-ring, led to cell cycle arrest in G2/M phase. Docking studies indicate that 2b showed a binding mode comparable to those previously observed with quinazoline analogous (IsoCoQ) and with isoCA-4 at the colchicine binding site of tubulin.
BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France.
Ilhem
I
Khelifi
BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France.
Timothée
T
Naret
BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France.
Dolor
D
Renko
BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France.
Abdallah
A
Hamze
BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France.
Guillaume
G
Bernadat
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS Avenue de La Terrasse, F-91198 Gif sur Yvette, France.
Jérome
J
Bignon
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS Avenue de La Terrasse, F-91198 Gif sur Yvette, France.
Christine
C
Lenoir
Institut de Chimie des Substances Naturelles, UPR 2301, CNRS Avenue de La Terrasse, F-91198 Gif sur Yvette, France.
Joëlle
J
Dubois
BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France.
Jean-Daniel
JD
Brion
BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France. Electronic address: olivier.provot@u-psud.fr.
Olivier
O
Provot
BioCIS, Univ. Paris-Sud, CNRS, Université Paris-Saclay, 92290, Châtenay-Malabry, France. Electronic address: mouad.alami@u-psud.fr.
Mouad
M
Alami
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects; D062105:Molecular Docking Simulation; D055503:Protein Multimerization / Q000187:drug effects*; D020836:Protein Structure, Quaternary; D011799:Quinazolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014404:Tubulin / Q000737:chemistry* / Q000378:metabolism; D050257:Tubulin Modulators / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*
D000970:Antineoplastic Agents; D011799:Quinazolines; D014404:Tubulin; D050257:Tubulin Modulators
Binding; Cancer; Cytotoxicity; Quinoline; Tubulin; isoCA-4