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. 2024 Aug 31;17(9):1154.
doi: 10.3390/ph17091154.

Synthesis of New Thiazole-Privileged Chalcones as Tubulin Polymerization Inhibitors with Potential Anticancer Activities

Hamada Hashem  1 , Abdelfattah Hassan  2   3 , Walid M Abdelmagid  4 , Ahmed G K Habib  5 , Mohamed A A Abdel-Aal  6 , Ali M Elshamsy  7 , Amr El Zawily  8   9 , Ibrahim Taha Radwan  10 , Stefan Bräse  11 , Ahmed S Abdel-Samea  12 , Safwat M Rabea  13   14
Affiliations

Synthesis of New Thiazole-Privileged Chalcones as Tubulin Polymerization Inhibitors with Potential Anticancer Activities

Hamada Hashem et al. Pharmaceuticals (Basel). .

Abstract

A series of novel thiazole-based chalcones were evaluated for their anticancer activity as potential tubulin polymerization inhibitors. In vitro anticancer screening for the thiazole derivatives 2a-2p exhibited broad-spectrum antitumor activity against various cancer cell lines particularly Ovar-3 and MDA-MB-468 cells with a GI50 range from 1.55 to 2.95 μΜ, respectively. Compound 2e demonstrated significant inhibition of tubulin polymerization, with an IC50 value of 7.78 μM compared to Combretastatin-A4 (CA-4), with an IC50 value of 4.93 μM. Molecular docking studies of compounds 2e, 2g, and 2h into tubulin further supported these findings, revealing that they bind effectively to the colchicine binding site, mirroring key interactions exhibited by CA-4. Computational predictions suggested favorable oral bioavailability and drug-likeness for these compounds, highlighting their potential for further development as chemotherapeutic agents.

Keywords: anticancer; colchicine binding site; thiazole chalcones; tubulin inhibitors.

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Conflict of interest statement

The authors declare that this study received No funding from Apogee Pharmaceuticals Inc. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

Figures

Figure 1
Figure 1
Some reported heterocyclic-chalcones and thiazole derivatives targeting colchicine binding site on tubulin.
Figure 2
Figure 2
Design of novel thiazole-chalcones targeting colchicine binding site.
Scheme 1
Scheme 1
Synthesis of thiazole-based chalcones 2a–2p. Reagents and conditions: (i) ethanol, 20 °C, 6 h.; (ii) appropriate aromatic aldehyde, 60% NaOH, ethanol, 0 °C, 18 h.
Figure 3
Figure 3
The inhibitory activity of thiazole derivatives 2e, 2g, 2h, 2j, 2q, and CA-4 on tubulin polymerization.
Figure 4
Figure 4
The superimposition of the redocked (orange) and co-crystallized (green) poses of colchicine (RMSD = 1.0090 Å).
Figure 5
Figure 5
Interactions of CA-4 with colchicine binding site: (A) the 2D binding interactions; (B) the 3D binding interactions.
Figure 6
Figure 6
Interactions of 2e with colchicine binding site: (A) the 2D binding interactions; (B) the 3D binding interactions.
Figure 7
Figure 7
Interactions of 2g with colchicine binding site: (A) the 2D binding interactions; (B) the 3D binding interactions.
Figure 8
Figure 8
Interactions of 2h with colchicine binding site: (A) the 2D binding interactions; (B) the 3D binding interactions.
Figure 9
Figure 9
BOILED Egg plot of target compounds 2a–2p and CA-4.
Figure 10
Figure 10
Rader model for target compounds 2a–2p and Combretastatin A4.
Figure 11
Figure 11
Structure–activity relationship of thiazole–chalcone derivatives.
See this image and copyright information in PMC

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