1,1-Diheterocyclic Ethylenes Derived from Quinaldine and Carbazole as New Tubulin-Polymerization Inhibitors: Synthesis, Metabolism, and Biological Evaluation

Abstract

We report the synthesis and metabolic and biological evaluation of a series of 17 novel heterocyclic derivatives of isocombretastatin-A4 (iso-CA-4) and their structure−activity relationships. Among these derivatives, the most active compound, 4f, inhibited the growth of a panel of seven cancer cell lines with an IC 50 in the low nanomolar range. In addition, 4f showed interesting activity against CA-4-resistant colon-carcinoma cells and multidrug-resistant leukemia cells. It also induced G 2 /M cell-cycle arrest. Structural data indicated binding of 4f to the colchicine site of tubulin, likely preventing the curved-tostraight tubulin structural changes that occur during microtubule assembly. Also, 4f disrupted the blood-vessel-like assembly formed by human umbilical-vein endothelial cells in vitro, suggesting its function as a vascular-disrupting agent. An in vitro metabolism study of 4f showed its high human-microsomal stability in comparison with that of iso-CA-4. The physicochemical properties of 4f may be conducive to CNS permeability, suggesting that this compound may be a possible candidate for the treatment of glioblastoma.

Microtubule Destabilizing Sulfonamides as an Alternative to Taxane-Based Chemotherapy

“…Detecting changes in drug potency when inhibiting MDR-mediated efflux reflect that these transporters reduce the intracellular drug concentration. HT-29 has been reported to express moderate levels of MDR1, accounting for a resistant phenotype [53]. A comparison of the antiproliferative IC50 values of each MDS in the presence or absence of verapamil provides an estimate of the susceptibility of each compound to efflux pumps.…”

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

“…Compound 49 was more active than isoCA-4 against A549, U87-MG and HUVEC cells and it was 67-fold more potent than CA-4 in lung adenocarcinoma epithelial cells (A549). When tested in a range of MDR cells lines, 49 was up to 27 times better than isoCA-4 and CA-4, including against HT-29 cells (IC 50 of 3 nM compared to 265 µM and >8000 µM for isoCA-4 and CA-4 respectively) [110]. It has a high logP value of 5.26 and therefore potentially could partition through the blood-brain barrier.…”

Synthesis and Anticancer Properties of Oxazepines Related to Azaisoerianin and IsoCoQuines

“…[36] Molecular modeling Atomic coordinates for tubulin α,β-dimer were retrieved from the Protein Data Bank (accession code 6H9B). [21] Missing hydrogen atoms were added using the Dock Prep module from the UCSF Chimera v1.13 software package, [37] and atoms from the ligand cocrystallized in the colchicine binding at the interface between chains C and D were deleted. Coordinates for a low-energy starting conformer of compound 1g were obtained using the conformers function from MarvinSketch v19.12 software package [38] with default parameters.…”

“…In this medicinal chemistry program, we have next synthesized other highly bioactive analogues through chemical modifications on the Bring of isoCA-4, and identified new stable and promising antiproliferative agents such as isoNH2CA-4 and isoFCA-4, [15] or constrained isoCA-4 derivatives of type naphthyls, [16] chromenes, [17] and benzoxepins. [18] Recently, we successfully replaced for the first time, the classical 3,4,5-trimethoxyphenyl A-ring of isoCA-4 derivatives by a quinazoline or a quinoline nucleus leading to isoCombretaQuinazolines (isoCoQs), [19] isoCombretaQuinolines (isoCoQuines) [20] and other bioactive analogues [21,22] having comparable or better antiproliferative activities than those of isoCA-4 and CA-4. Based on these results, Chen [23 ] has combined into a single chemical structure azaisoerianin and isoCoQuines to give 4-anilinoquinolines as potent tubulin polymerization inhibitors which displayed nanomolar levels of cytotoxicity.…”