Drug-Clinical Agent Molecular Hybrid: Synthesis of Diaryl(trifluoromethyl)pyrazoles as Tubulin Targeting Anticancer Agents

Abstract

Twenty-three combretastatin A-4 (CA-4) analogues were synthesized by judiciously incorporating a functional N-heterocyclic motif present in Celecoxib (a marketed drug) while retaining essential pharmacophoric features of CA-4. Combretastatin-(trifluoromethyl)pyrazole hybrid analogues, i.e., 5-trimethoxyphenyl-3-(trifluoromethyl)pyrazoles with a variety of relevantly substituted aryls and heteroaryls at 1-position were considered as potential tubulin polymerization inhibitors. The cytotoxicity of the compounds was evaluated using MCF-7 cells. Analog 23 (C-23) was found to be the most active among the tested compounds. It showed pronounced cytotoxicity against HeLa, B16F10, and multidrug-resistant mammary tumor cells EMT6/AR1. Interestingly, C-23 displayed significantly lower toxicity toward noncancerous cells, MCF10A and L929, than their cancerous counterparts, MCF-7 and B16F10, respectively. C-23 depolymerized interphase microtubules, disrupted mitotic spindle formation, and arrested MCF-7 cells at mitosis, leading to cell death. C-23 inhibited the assembly of tubulin in vitro. C-23 bound to tubulin at the colchicine binding site and altered the secondary structures of tubulin. The data revealed the importance of (trimethoxyphenyl)(trifluoromethyl)pyrazole as a cis-restricted double bond-alternative bridging motif, and carboxymethyl-substituted phenyl as ring B for activities and interaction with tubulin. The results indicated that the combretastatin-(trifluoromethyl)pyrazole hybrid class of analogues has the potential for further development as anticancer agents.

Tubulin-Binding 3,5-Bis(styryl)pyrazoles as Lead Compounds for the Treatment of Castration-Resistant Prostate Cancer

“…To further validate the docking, we docked epothilone, a paclitaxel site binder, with tubulin. The RMSD of the docked conformation of epothilone to the epothilone conformation present in complex with tubulin (PDB ID 404I) was found to be 1 Å, confirming that the docking protocols were appropriate ( Figure 11) (Hura et al, 2018). Since competitive binding data with colchicine showed that 2l does not bind to the colchicine site (Supplemental Figure 14a), we further analysed the docking data only for paclitaxel site.…”

“…The structure of 2l was drawn in PubChem Sketcher (V2.4) and the PDB coordinates of 2l were generated in PRODRG server (Schuttelkopf et al, 2004). The Autodock Vina tool was used for docking of 2l on tubulin (Trott and Olson, 2010) as described previously (Rane et al, 2017, Hura et al, 2018. The crystal structure of tubulin (PDB ID 5LYJ) was used for docking 2l with tubulin.…”

“…The Consequently, in order to determine the putative binding site, we performed molecular docking with the tubulin crystal structure (PDB ID 5LYJ) as described previously (Rane et al, 2017, Hura et al, 2018. We found that most conformations of 2l were interacting with two distinct sites on tubulin; the paclitaxel binding site on -tubulin ( Figure 10) and the interface of the α-and β-tubulin heterodimer (Supplemental Figure 15), near the colchicine site.…”

Design, Synthesis and Biological Activities of New Pyrazole Derivatives Possessing Both Coxib and Combretastatins Pharmacophores

“…These findings make celecoxib an attractive leading compound for developing new anticancer agents. [13][14][15][16] Combretastatins, a family of stilbenoids from the South African willow tree Combretum caffrum (ECKL. & Supporting information for this article is available on the WWW under https://doi.org/10.1002/cbdv.201900108 ZEYH.)…”

Design, synthesis, and biological evaluation of 2,3‐diphenyl‐cycloalkyl pyrazole derivatives as potential tubulin polymerization inhibitors

“…In our previous work, a great amount of compounds containing pyrazole such as compounds 1 (Yang et al., ) and 2 (Qin et al., ; shown in Figure S1) was synthesized and showed potent antiproliferative activity. Besides, a series of CA‐4 analogues containing pyrazole with anti‐tubulin polymerization activity have been reported such as compounds 3 – 10 (Burja et al., ; Hura, Naaz, Prassanawar, Guchhait, & Panda, ; Lai et al., ; Wang et al., ; Xu et al., ; shown in Figure S1). The IC 50 values of different compounds were all displayed in Figure S1, indicating that compounds containing pyrazole showed strongly antiproliferative capability.…”