TY - JOUR
T1 - Design, synthesis and biological evaluation of quinoline-2-carbonitrile-based hydroxamic acids as dual tubulin polymerization and histone deacetylases inhibitors
AU - Hauguel, Camille
AU - Ducellier, Sarah
AU - Provot, Olivier
AU - Ibrahim, Nada
AU - Lamaa, Diana
AU - Balcerowiak, Coline
AU - Letribot, Boris
AU - Nascimento, Megane
AU - Blanchard, Vincent
AU - Askenatzis, Laurie
AU - Levaique, Helene
AU - Bignon, Jérôme
AU - Baschieri, Francesco
AU - Bauvais, Cyril
AU - Bollot, Guillaume
AU - Renko, Dolor
AU - Deroussent, Alain
AU - Prost, Bastien
AU - Laisne, Marie Catherine
AU - Michallet, Sophie
AU - Lafanechère, Laurence
AU - Papot, Sébastien
AU - Montagnac, Guillaume
AU - Tran, Christine
AU - Alami, Mouad
AU - Apcher, Sebastien
AU - Hamze, Abdallah
N1 - Publisher Copyright:
© 2022 Elsevier Masson SAS
PY - 2022/10/5
Y1 - 2022/10/5
N2 - A series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC50 value of 0.6 and 0.7 nM, respectively. Furthermore, these lead compounds showed good activities against CA-4-resistant colon-carcinoma and multidrug-resistant leukemia cells. In addition, compounds 12a and 12d induced HT29 cell cycle arrest in the G2/M phase and produced caspase-induced apoptosis of HT29 cells through mitochondrial dysfunction. Also, 12a and 12d inhibited HDAC8, 6, and 11 activities. Furthermore, lead compound 12a exhibited higher metabolic stability than isoCA-4 and was highly potent in suppressing tumor growth in the fibrosarcoma MCA205 tumor model. Collectively, these studies suggest that 12a represents a new dual inhibitor of TP and HDAC activities, which makes it a suitable candidate for further investigations in clinical development.
AB - A series of quinoline and quinazoline analogs were designed and synthesized as new tubulin polymerization (TP) and histone deacetylases (HDAC) inhibitors. Compounds 12a and 12d showed the best cytotoxicity activities against a panel of human cancer cell lines with an averaged IC50 value of 0.6 and 0.7 nM, respectively. Furthermore, these lead compounds showed good activities against CA-4-resistant colon-carcinoma and multidrug-resistant leukemia cells. In addition, compounds 12a and 12d induced HT29 cell cycle arrest in the G2/M phase and produced caspase-induced apoptosis of HT29 cells through mitochondrial dysfunction. Also, 12a and 12d inhibited HDAC8, 6, and 11 activities. Furthermore, lead compound 12a exhibited higher metabolic stability than isoCA-4 and was highly potent in suppressing tumor growth in the fibrosarcoma MCA205 tumor model. Collectively, these studies suggest that 12a represents a new dual inhibitor of TP and HDAC activities, which makes it a suitable candidate for further investigations in clinical development.
KW - Cancer
KW - Cytotoxicity
KW - HDACi
KW - Multitargeted compounds
KW - Tubulin
UR - http://www.scopus.com/inward/record.url?scp=85133171947&partnerID=8YFLogxK
U2 - 10.1016/j.ejmech.2022.114573
DO - 10.1016/j.ejmech.2022.114573
M3 - Article
C2 - 35797900
AN - SCOPUS:85133171947
SN - 0223-5234
VL - 240
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
M1 - 114573
ER -