Synthesis and biological evaluation of 4 arylcoumarin analogues as tubulin-targeting antitumor agents.
The synthesis of twenty-six 4-arylcoumarin analogues of combretastatin A-4 (CA-4) led to the identification of two new compounds (25 and 26) with strong cytotoxic activity. Both compounds had a high cytotoxic effect on a CA-4-resistant colon adenocarcinoma cell line (HT29D4). The compounds affected cell cycle progression characterized by a mitotic block. The activity of these compounds against microtubules both in vitro and in cells was examined and both compounds were found to potently inhibit in vitro microtubule formation via a sub-stoichiometric mode like CA-4. By immunofluorescence, it was observed that both compounds induced strong microtubule network disruption. Our results provide a strong experimental basis to develop new potent anti-tubulin molecules targeting CA-4-resistant cancer cells.
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; Department of Pharmacology & Pharmacognosy, College of Health Sciences, University of Nairobi, PO Box 19676-00202, Nairobi, Kenya.
Peggoty
P
Mutai
Aix-Marseille Université, INSERM UMR_S 911 CRO2, Faculté de Pharmacie, 27 bd Jean-Moulin, 13385 Marseille, France.
Gilles
G
Breuzard
Aix-Marseille Université, INSERM UMR_S 911 CRO2, Faculté de Pharmacie, 27 bd Jean-Moulin, 13385 Marseille, France.
Alessandra
A
Pagano
Aix-Marseille Université, INSERM UMR_S 911 CRO2, Faculté de Pharmacie, 27 bd Jean-Moulin, 13385 Marseille, France.
Diane
D
Allegro
Aix-Marseille Université, INSERM UMR_S 911 CRO2, Faculté de Pharmacie, 27 bd Jean-Moulin, 13385 Marseille, France. Electronic address: vincent.peyrot@univ-amu.fr.
Vincent
V
Peyrot
Department of Chemistry, University of Cape Town, Rondebosch 7701, South Africa; South African Medical Research Council Drug Discovery and Development Research Unit, University of Cape Town, Rondebosch 7701, South Africa; Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Rondebosch 7701, South Africa. Electronic address: Kelly.Chibale@uct.ac.za.
Kelly
K
Chibale
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005434:Flow Cytometry; D006801:Humans; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D014404:Tubulin / Q000187:drug effects*
D000970:Antineoplastic Agents; D003374:Coumarins; D014404:Tubulin