isocombretastatin-a-4 and fosbretabulin

In this work, a series of cyclic bridged analogs of isocombretastatin A-4 (isoCA-4) with phenyl or pyridine linkers were designed and synthesized. The synthesis of the desired analogs was performed by the formation of nitro-vinyl intermediates, followed by a Cadogan cyclization. Structure activity relationship (SAR) study demonstrates the critical role of the combination of quinaldine as ring A, pyridine as the linker, and indole as ring B in the same molecule, for the cytotoxic activity. Among all tested compounds, compound 42 showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 5.6 nM. Also, compound 42 showed high antiproliferative activity against the MDR1-overexpressing K562R cell line; thus, it was 1.5- and 12-fold more active than the reference compounds, isoCA-4 and CA-4, respectively. Moreover, 42 displayed a strong antiproliferative activity against the colon-carcinoma cells (HT-29), which are resistant to combretastatin A-4 and isoCA-4, and it was found to be 8000-fold more active than natural CA-4. Compound 42 also effectively inhibited tubulin polymerization both in vitro and in cells, and induced cell cycle arrest in G2/M phase. Next, we demonstrated that compound 42 dose-dependently caused caspase-induced apoptosis of K562 cells through mitochondrial dysfunction. Finally, we evaluated the effect of compound 42 in human no cancer cells compared to the reference compound. We demonstrated that 42 was 73 times less cytotoxic than isoCA-4 in quiescent peripheral blood lymphocytes (PBLs). In summary, these results suggest that compound 42 represents a promising tubulin inhibitor worthy of further investigation.

Topics: Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Cyclization; Drug Design; Humans; Molecular Docking Simulation; Neoplasms; Stilbenes; Tubulin; Tubulin Modulators

In this study, a variety of original ligands related to Combretastatin A-4 and isoCombretastatin A-4, able to inhibit the tubulin polymerization into microtubules, was designed, synthesized, and evaluated. Our lead compound 15d having a quinazoline as A-ring and a 2-substituted indole as B-ring separated by a N-methyl linker displayed a remarkable sub-nanomolar level of cytotoxicity (IC

Topics: Animals; Antineoplastic Agents; Binding Sites; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Drug Stability; Humans; Indoles; Microsomes, Liver; Molecular Docking Simulation; Rats; Stilbenes; Structure-Activity Relationship; Tubulin; Tubulin Modulators

Topics: Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; Fluorine; Humans; Models, Molecular; Molecular Structure; Polymerization; Stilbenes; Structure-Activity Relationship; Tubulin

Designing multitarget drugs have raised considerable interest due to their advantages in the treatment of complex diseases such as cancer. Their design constitutes a challenge in antitumor drug discovery. The present study reports a dual inhibition of tubulin polymerization and HDAC activity. On the basis of 1,1-diarylethylenes ( isoCA-4) and belinostat, a series of hybrid molecules was successfully designed and synthesized. In particular compounds, 5f and 5h were proven to be potent inhibitors of both tubulin polymerization and HDAC8 leading to excellent antiproliferative activity.

Topics: Antineoplastic Agents; Cell Proliferation; Chemistry Techniques, Synthetic; Drug Design; HCT116 Cells; Histone Deacetylase Inhibitors; Histone Deacetylases; Humans; K562 Cells; Protein Conformation; Stilbenes; Tubulin

Topics: Animals; Antineoplastic Agents; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Drug Design; Drug Screening Assays, Antitumor; G2 Phase; Humans; Male; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mice, Nude; Neoplasms; Rats, Sprague-Dawley; Selenium; Stilbenes

Topics: Antineoplastic Agents; Cell Proliferation; Cycloaddition Reaction; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Furans; HeLa Cells; Humans; Isoxazoles; Models, Molecular; Molecular Structure; Polymerization; Stilbenes; Structure-Activity Relationship; Tubulin; Tumor Cells, Cultured

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.

Topics: Alcohols; Antineoplastic Agents, Phytogenic; Benzopyrans; Cell Proliferation; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Humans; K562 Cells; Models, Molecular; Molecular Structure; Stilbenes; Structure-Activity Relationship; Tumor Cells, Cultured

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 β-tubulin.

Topics: Antineoplastic Agents, Phytogenic; Apoptosis; Benzoxepins; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Dose-Response Relationship, Drug; Drug Design; Drug Screening Assays, Antitumor; HCT116 Cells; Humans; Models, Molecular; Molecular Structure; Stilbenes; Structure-Activity Relationship

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.

Topics: Alkenes; Alkynes; Animals; Antineoplastic Agents; Bromine; Cell Line, Tumor; Cell Proliferation; Chlorophenols; Humans; Organotin Compounds; Peptides, Cyclic; Stereoisomerism; Stilbenes; Substrate Specificity