ABSTRACT
A series of novel isocombretaquinazolines (isoCoQ) 4 were quickly prepared by coupling N-toluenesulfonylhydrazones with 4-chloroquinazolines under palladium catalysis. These compounds, which can be regarded as isocombretastatinâ A-4 (isoCA-4) analogues that lack the 3,4,5-trimethoxyphenyl ring, displayed nanomolar-level cytotoxicity against various human cancer cell lines and were observed to effectively inhibit tubulin polymerization. The isoCoQ compounds 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)phenol (4 b), 4-[1-(3-fluoro-4-methoxyphenyl)vinyl]-2-methylquinazoline (4 c), and 2-methoxy-5-(1-(2-methylquinazolin-4-yl)vinyl)aniline (4 d), which respectively bear the greatest resemblance to isoCA-4, isoFCA-4, and isoNH2 CA-4, are able to arrest HCT116 cancer cells in the G2 /M cell-cycle phase at very low concentrations. Preliminary in vitro antivascular assay results show that 4 d is able to disrupt a network of capillary-like structures formed by human umbilical vein endothelial cells on Matrigel. All these results clearly demonstrate that replacement of the 3,4,5-trimethoxyphenyl ring of isoCA-4 with a quinazoline nucleus is a feasible approach toward new and highly promising derivatives with the potential for further development as antitubulin agents.
Subject(s)
Bibenzyls/chemistry , Quinazolines/chemistry , Tubulin Modulators/chemistry , Tubulin/metabolism , Apoptosis/drug effects , Binding Sites , Cell Proliferation/drug effects , Crystallography, X-Ray , G2 Phase Cell Cycle Checkpoints/drug effects , HCT116 Cells , Human Umbilical Vein Endothelial Cells , Humans , M Phase Cell Cycle Checkpoints/drug effects , Molecular Conformation , Molecular Docking Simulation , Protein Structure, Tertiary , Quinazolines/chemical synthesis , Quinazolines/toxicity , Structure-Activity Relationship , Tubulin/chemistry , Tubulin Modulators/metabolism , Tubulin Modulators/toxicityABSTRACT
A series of N-methyl-diarylamines 2 was designed and synthesized as a novel class of CA-4 and isoCA-4 analogues. Compounds 2b and 2m showed excellent antiproliferative activity with mean GI50 values at a nanomolar level in a diverse set of human cancer cells. These compounds also inhibited tubulin assembly at a micromolar range, arrested the cellular cycle in the G2/M phase and induced apoptosis at very low concentrations. Preliminary in vitro results revealed that 2b and 2m displayed substantial efficacy as potent antivascular agents. Docking studies indicates that these lead compounds showed a binding mode similar to those observed with isoCA-4 at the colchicine binding site of tubulin.
Subject(s)
Antineoplastic Agents/pharmacology , Aza Compounds/pharmacology , Bibenzyls/pharmacology , Drug Discovery , Human Umbilical Vein Endothelial Cells/drug effects , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Aza Compounds/chemical synthesis , Aza Compounds/chemistry , Bibenzyls/chemical synthesis , Bibenzyls/chemistry , Binding Sites/drug effects , Cell Cycle/drug effects , Cell Line , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , K562 Cells , Models, Molecular , Molecular Structure , Phenol , Sheep , Structure-Activity Relationship , Tubulin/metabolismABSTRACT
A series of novel benzoxepins 6 was designed and prepared as rigid-isoCA-4 analogs according to a convergent strategy using the coupling of N-tosylhydrazones with aryl iodides under palladium catalysis. The most potent compound 6b, having the greatest resemblance to CA-4 and isoCA-4 displayed antiproliferative activity at nanomolar concentrations against various cancer cell lines and inhibited tubulin assembly at a micromolar range. In addition, benzoxepin 6b led to the arrest of HCT116, K562, H1299 and MDA-MB231 cancer cell lines in the G2/M phase of the cell cycle, and strongly induced apoptosis at low concentrations. Docking studies demonstrated that benzoxepin 6b adopt an orientation similar to that of isoCA-4 at the colchicine binding site on ß-tubulin.
Subject(s)
Antineoplastic Agents, Phytogenic/pharmacology , Benzoxepins/pharmacology , Drug Design , Stilbenes/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Apoptosis/drug effects , Benzoxepins/chemical synthesis , Benzoxepins/chemistry , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , HCT116 Cells , Humans , Models, Molecular , Molecular Structure , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationships associated with a series of 1,1-diarylethylene tubulin polymerization inhibitors 3 and 4 are described. The key step for their preparation involves a palladium-catalyzed coupling of N-arylsulfonylhydrazones with aryl halides, thus providing flexible and convergent access to tri- and tetrasubstituted 1,1-diarylolefins 3 and 4 related to isocombretastatin A-4 (isoCA-4). These compounds have been evaluated for tubulin polymerization inhibitory activity as well as for cytotoxic activity. The most potent compounds are 1,1-diaryl-2-methoxyethylenes 4b, 4d and 4e having a trisubstituted double bond. They exhibited good antiproliferative activity against various human cancer cell lines (GI(50) = 8-80 nM). Compounds 4b and 4e strongly inhibited tubulin polymerization with IC(50) values of 2 and 3 µM, respectively, and induced cell cycle arrest in the G(2)/M phase in the K562 cell line. Docking studies in the colchicine binding site of tubulin allowed identification of residues most likely to interact with these inhibitors and explain their potent anti-tubulin activity.
Subject(s)
Alkenes/chemistry , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/pharmacology , Stilbenes/pharmacology , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacology , Tubulin/metabolism , Antineoplastic Agents, Phytogenic/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Molecular Structure , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity Relationship , Tubulin Modulators/chemical synthesisABSTRACT
A novel series of dihydronaphtalene, tetrahydronaphtalene and naphtalene derivatives as restricted analogues of isoCA-4 were designed, synthesized and evaluated for their anticancer properties. High cell growth inhibition against four tumour cell lines was observed at a nanomolar level with dihydronaphtalenes 1d, e and 1h, tetrahydronaphtalene 2c and naphtalene 3c. Structure-activity relationships are also considered. These compounds exhibited a significant inhibitory activity toward tubulin polymerization (IC(50) = 2-3 µM), comparable to that of isoCA-4. The effect of the lead compounds 1e and 2c on the cancer cells tested was associated with cell cycle arrest in the G(2)/M phase. Docking studies reveal that these compounds showed a binding mode similar to those observed with their non-constraint isoCA-4 and isoerianin congeners.
