Abstract
Benzopyridothiadiazepine (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.
MeSH terms
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Angiogenesis Inhibitors / chemical synthesis
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Angiogenesis Inhibitors / chemistry
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Angiogenesis Inhibitors / pharmacology
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Angiogenesis Inhibitors / therapeutic use
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Animals
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Antimitotic Agents / chemical synthesis
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Antimitotic Agents / chemistry*
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Antimitotic Agents / pharmacology
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Antimitotic Agents / therapeutic use*
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Benzenesulfonamides
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Benzothiadiazines / chemical synthesis
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Benzothiadiazines / chemistry
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Benzothiadiazines / pharmacology
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Benzothiadiazines / therapeutic use
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Cell Line, Tumor
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Humans
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Male
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Melanoma / blood supply
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Melanoma / drug therapy*
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Melanoma / metabolism
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Mice
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Mice, Inbred C57BL
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Quinazolinones / chemical synthesis
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Quinazolinones / chemistry
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Quinazolinones / pharmacology
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Quinazolinones / therapeutic use
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis
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Sulfonamides / chemistry*
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Sulfonamides / pharmacology
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Sulfonamides / therapeutic use*
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Tubulin / metabolism
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Tubulin Modulators / chemical synthesis
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Tubulin Modulators / chemistry
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Tubulin Modulators / pharmacology
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Tubulin Modulators / therapeutic use
Substances
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ABT751
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Angiogenesis Inhibitors
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Antimitotic Agents
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Benzothiadiazines
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Quinazolinones
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Sulfonamides
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Tubulin
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Tubulin Modulators