ABSTRACT
Potent anticancer 4-arylchromene agents 6, as restricted isoCA-4 analogues, were prepared with excellent yields by a rapid and versatile synthetic pathway. First, in the presence of PTSA in EtOH, a variety of arylalkynols 9 were transformed into substituted 4-chromanones 10 in a one pot procedure which include regioselective arylalkynols hydration, alcohol etherification, MOM-cleavage, and cyclization. Further palladium coupling reactions, using aryl halides and N-tosylhydrazones 11 gave access to a small library of functionalized 4-arylchromenes 6 with good yields. From this series of 4-arylchromenes, we have identified compound 6s which inhibit tubulin assembly at a micromolar level and demonstrate a remarkable nanomolar level of cytotoxicity against four human cancer cell lines. Docking studies showed that isoCA-4 and its restricted chromene analogue 6s adopt a similar positioning in the colchicine binding-site of tubulin.
Subject(s)
Alcohols/chemistry , Antineoplastic Agents, Phytogenic/pharmacology , Benzopyrans/pharmacology , Stilbenes/pharmacology , Antineoplastic Agents, Phytogenic/chemical synthesis , Antineoplastic Agents, Phytogenic/chemistry , Benzopyrans/chemical synthesis , Benzopyrans/chemistry , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , K562 Cells , Models, Molecular , Molecular Structure , Stilbenes/chemical synthesis , Stilbenes/chemistry , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Iridium dimer complexes were found to catalyze the [3 + 2] cycloaddition reaction of azides with bromoalkynes, yielding 1,5-disubstituted 4-bromo-1,2,3-triazoles in reasonable to excellent yields under mild conditions. The reaction offers a direct route to new 1,4,5-trisubstituted triazoles.
Subject(s)
Alkynes/chemistry , Azides/chemistry , Hydrocarbons, Brominated/chemistry , Hydrocarbons, Brominated/chemical synthesis , Iridium/chemistry , Triazoles/chemical synthesis , Catalysis , Cyclization , Cycloaddition Reaction , Molecular Structure , Temperature , Triazoles/chemistryABSTRACT
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
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.
Subject(s)
Benzene/chemistry , Bibenzyls/chemistry , Chlorophenols/chemistry , Molecular Conformation , Naphthalenes/chemistry , Naphthalenes/pharmacology , Peptides, Cyclic/chemistry , Protein Multimerization/drug effects , Tubulin Modulators/pharmacology , Tubulin/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Humans , Models, Molecular , Naphthalenes/chemical synthesis , Naphthalenes/toxicity , Phenol , Protein Structure, Quaternary , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/toxicityABSTRACT
A novel class of isocombretastatin A-4 (isoCA-4) analogues with modifications at the 3'-position of the B-ring by replacement with C-linked substituents was studied. Exploration of the structure-activity relationships of theses analogues led to the identification of several compounds that exhibit excellent antiproliferative activities in the nanomolar concentration range against H1299, MDA-MB231, HCT116, and K562 cancer cell lines; they also inhibit tubulin polymerization with potency similar to that of isoCA-4. 1,1-Diarylethylenes 8 and 17, respectively with (E)-propen-3-ol and propyn-3-ol substituents at the 3'-position of the B-ring, proved to be the most active in this series. Both compounds led to the arrest of various cancer cell lines at the G(2) /M phase of the cell cycle and strongly induced apoptosis. Docking of compounds 8 and 17 in the colchicine binding site indicated that their C3' substituents guide the positioning of the B-ring in a manner different from that observed for isoCA-4.
Subject(s)
Anisoles/chemistry , Antineoplastic Agents/chemistry , Styrenes/chemistry , Anisoles/chemical synthesis , Anisoles/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Cell Survival/drug effects , Computer Simulation , Humans , Neoplasms , Protein Structure, Tertiary , Structure-Activity Relationship , Styrenes/chemical synthesis , Styrenes/pharmacology , Tubulin/chemistry , Tubulin/metabolism , Tubulin Modulators/chemical synthesis , Tubulin Modulators/chemistry , Tubulin Modulators/pharmacologyABSTRACT
A series of triarylolefins bearing the combretastatin A-4 and the isocombretastatin A-4 cores were synthesized and evaluated. The cooperative ortho-effect of a labile bromine atom in the regioselective hydrostannation of unsymmetrical diarylalkynes leading to stereodefined triarylolefins is presented.
