jm6b00847_si_001.pdf (7.19 MB)
Synthesis and Biological Evaluation of N‑[2-(4-Hydroxyphenylamino)-pyridin-3-yl]-4-methoxy-benzenesulfonamide (ABT-751) Tricyclic Analogues as Antimitotic and Antivascular Agents with Potent in Vivo Antitumor Activity
journal contribution
posted on 2016-08-18, 00:00 authored by Zacharie Segaoula, Julien Leclercq, Valérie Verones, Nathalie Flouquet, Marie Lecoeur, Lionel Ach, Nicolas Renault, Amélie Barczyk, Patricia Melnyk, Pascal Berthelot, Xavier Thuru, Nicolas LebegueBenzopyridothiadiazepine (2a) and benzopyridooxathiazepine
(2b) were modified to produce tricyclic quinazolinone 15–18 or benzothiadiazine 26–27 derivatives. These compounds were evaluated
in cytotoxicity and tubulin inhibition assays and led to potent inhibitors
of tubulin polymerization. N-[2(4-Methoxyphenyl)ethyl]-1,2-dihydro-pyrimidino[2,1-b]quinazolin-6-one (16a) exhibited the best in vitro cytotoxic activity (GI50 10–66.9
nM) against the NCI 60 human tumor cell line and significant potency
against tubulin assembly (IC50 0.812 μM). In mechanism
studies, 16a was shown to block cell cycle in G2/M phase
and to disrupt microtubule formation and displayed good antivascular
properties as inhibition of cell migration, invasion, and endothelial
tube formation. Compound 16a was evaluated in C57BL/6
mouse melanoma B16F10 xenograft model to validate its antitumor activity,
in comparison with reference ABT-751 (1). Compound 16a displayed strong in vivo antitumor and
antivascular activities at a dose of 5 mg/kg without obvious toxicity,
whereas 1 needed a 10-fold higher concentration to reach
similar effects.