Design and Synthesis of Tubulin and Histone Deacetylase Inhibitor Based on iso-Combretastatin A-4

Abstract

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.

Epigenetic polypharmacology: A new frontier for epi‐drug discovery

“…Among these compounds, 81 (Figure 9) showed the best antiproliferative results (IC 50 = 0.4-2 nM) in different tumor cell lines (K562, PC3, U87, CA-4, HT-29, BXPC3), inducing a strong inhibition of both HDAC8 (IC 50 = 340 nM) and tubulin polymerization (IC 50 = 1.6 μM) as well as cancer cells cycle arrest at the G 2 /M phase by disruption of the microtubule organization. 334 As previously reported, recent evidence highlighted the synergism deriving from the combination of HDAC6-selective and HSP90 inhibitors. The 4-isopropylresorcinol scaffold is known to fit into the hydrophobic and hydrophilic region of HSP90 playing a key role as binder at the ATP binding site.…”

“…Recently, the combination of vorinostat 3 plus vincristine has been shown to induce synergistic effects in both in vitro and in vivo models, suggesting that vorinostat 3 could alter microtubule dynamics through HDAC inhibition . Thus, another series of dual HDAC/tubulin polymerization inhibitors has been successfully developed by Lamaa et al by merging the structure of belinostat 5 with the 1,1‐diarylethylene scaffold of iso ‐combretastatin A‐4 80 (IC 50 for ITP = 2.0 μM) (Figure ). Among these compounds, 81 (Figure ) showed the best antiproliferative results (IC 50 = 0.4‐2 nM) in different tumor cell lines (K562, PC3, U87, CA‐4, HT‐29, BXPC3), inducing a strong inhibition of both HDAC8 (IC 50 = 340 nM) and tubulin polymerization (IC 50 = 1.6 μM) as well as cancer cells cycle arrest at the G 2 /M phase by disruption of the microtubule organization …”

Bifunctional HDAC Therapeutics: One Drug to Rule Them All?

“…It is structurally related to colchicine (employed in hybrids 9 and 10 ) and has been utilised in combination with chemotherapy and antiangiogenic drugs for enhanced and sustained therapeutic effects [ 116 , 117 ]. A CA-4 analogue termed iso combretastatin A-4 ( iso CA-4) was developed by the Alami group and equipped with broad spectrum HDAC inhibitors vorinostat and belinostat to afford a series of dual-targeting agents [ 118 ]. In vitro assays revealed compounds 15 and 16 as the most potent dual inhibitors, both of which contain the olefinic linker derived from belinostat.…”

How do we improve histone deacetylase inhibitor drug discovery?

“…Therefore, the research of multi-target inhibitors is also an important direction for the development of next-generation HDACis. Additionally, there have recently been many efforts into the integration of HDAC inhibitor warheads with other targeting functionalities into one compound as dual inhibitory agents, and these have been very successful [23][24][25][26].…”