Oxazole-Bridged Combretastatin A-4 Derivatives with Tethered Hydroxamic Acids: Structure–Activity Relations of New Inhibitors of HDAC and/or Tubulin Function

Abstract

New inhibitors of tubulin polymerization and/or histone deacetylase (HDAC) activity were synthesized by attaching alkyl tethered hydroxamic acid appendages of varying length to oxazole-bridged combretastatin A-4 analogous caps. While their antiproliferative and microtubule disrupting effect was most pronounced for derivatives with short spacers, HDAC inhibition was strongest for those with longer spacers. These findings were further supported by computational methods such as structure-based docking experiments exploring the target interactions of the derivatives with varying linkers. For instance, compounds featuring short four-atom spacers between cap and hydroxamic acid inhibited the growth of various cancer cell lines and human endothelial hybrid cells with IC50 values in the low nanomolar range. In line with their ability to inhibit the microtubule assembly, four- and five-atom spacered hydroxamic acids caused an accumulation of 518A2 melanoma cells in G2/M phase, whereas a compound featuring a six-atom spacer and performing best in HDAC inhibition, induced a G1 arrest in these cells. All these beneficial anticancer activities together with their selectivity for cancer cells over non-malignant cells, point out the great potential of these novel pleiotropic HDAC and tubulin inhibitors as drug candidates for cancer therapy.

Discovery of novel quinoline-based analogues of combretastatin A-4 as tubulin polymerisation inhibitors with apoptosis inducing activity and potent anticancer effect

“…Unfortunately, the cis configuration of CA-4 has a propensity for undergoing transformation to the inactive trans configuration upon storage and during in vivo metabolism. To overcome this, many structural modifications of CA-4 have been undertaken where the cis double bond is replaced with heterocycles, either monocyclic, such as oxadiazole, isoxazole and imidazole, resulting in compounds, such as 1, 2 and 3 respectively (Figure 1) [27][28][29][30][31][32][33] or fused heterocyclic, such as pyrazolopyridines 34 , triazolopyridines 35 and triazolothiadiazine derivatives 36 . These compounds, like CA-4 showed pronounced activity against a panel of cancer cell lines.…”

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

“…HDAC inhibitors show synergistic effects in combination with tubulin-binding anti-cancer drugs. This group describe a series of tubulin-targeting oxazole-bridged derivatives with hydroxamate appendages (highlighted in blue, 44, Figure 7) [104]. These compounds were potent antiproliferative compounds against Ea.Hy926 cells (endothelial hybrid cells) with IC 5o values ranging from 1.2 to 410 nM, with selectivity over non-malignant human dermal fibroblasts (HDFa cells; IC 50 23.9 to >100 µM).…”

“…Compound 44 is a promising drug candidate with antiproliferative, cell cycle arresting, microtubule-destabilizing effects in addition to HDAC inhibition. In vivo investigations are underway [104].…”

Hybrid cis-stilbene Molecules: Novel Anticancer Agents

“…Compounds 78 and 79 (Figure 25) (Table 1) exhibited strong antiproliferative activity arisen from the inhibitory effect on tubulin polymerization and the inhibition of HDAC8 activity [41]. In the valuable studies of Schmitt and co-workers [87], oxazole-bridged CA-4 was attached to alkyl tethered hydroxamic acids of varying length as HDAC inhibitors ( 80 ) (Figure 25). The antiproliferative effect and antitubulin activity were the most pronounced for derivatives with 4- and 5-atom spacers, whereas HDAC inhibition increased for those with longer spacers.…”