Combretastatin A-4 sulfur-containing heterocyclic derivatives: Synthesis, antiproliferative activities and molecular docking studies.

Combretastatin A-4 inspired heterocyclic derivatives were synthesized and evaluated for their biological activities on tubulin polymerization and cell proliferation. Among the 19 described sulfur-containing compounds, derivatives (Z)-4h and (Z)-4j exhibited interesting in cellulo tubulin polymerization inhibition and antiproliferative activities with IC50 values for six different cell lines between 8 and 27 nM. Furthermore, in silico docking studies within the colchicine/CA-4 binding site of tubulin were carried out to understand the interactions of our products with the protein target. The effects on the cell cycle of follicular lymphoma cells were also investigated at 1-10 nM concentrations showing that apoptotic processes occurred.

Synthesis and biological evaluation of thiophene and benzo[b]thiophene analogs of combretastatin A-4 and isocombretastatin A-4: A comparison between the linkage positions of the 3,4,5-trimethoxystyrene unit.

Combretastatin A-4 and isocombretastatin A-4 derivatives having thiophenes or benzo[b]thiophenes instead of the B ring were prepared and evaluated for their in cellulo tubulin polymerization inhibition (TPI) and antiproliferative activities. The presence of the benzo[b]thiophene ring proved to have a crucial effect as most of the thiophene derivatives, except those having one methoxy group, were inactive to inhibit tubulin polymerization into microtubules. The influence of the attachment position was also studied: benzo[b]thiophenes having iso or cis 3,4,5-trimethoxystyrenes at position 2 were 12-30-fold more active than the 3-regioisomers for the TPI activity. Some of the novel designed compounds exhibited interesting anti-proliferative effects on two different cell lines.