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

Abstract

A new series of quinoline derivatives of combretastatin A-4 have been designed, synthesised and demonstrated as tubulin polymerisation inhibitors. These novel compounds showed significant antiproliferative activities, among them, 12c exhibited the most potent inhibitory activity against different cancer cell lines (MCF-7, HL-60, HCT-116 and HeLa) with IC 50 ranging from 0.010 to 0.042 mM, and with selectivity profile against MCF-10A non-cancer cells. Further mechanistic studies suggest that 12c can inhibit tubulin polymerisation and cell migration, leading to G 2 /M phase arrest. Besides, 12c induces apoptosis via a mitochondrial-dependant apoptosis pathway and caused reactive oxygen stress generation in MCF-7 cells. These results provide guidance for further rational development of potent tubulin polymerisation inhibitors for the treatment of cancer. HIGHLIGHTS A novel series of quinoline derivatives of combretastatin A-4 have been designed and synthesised. Compound 12c showed significant antiproliferative activities against different cancer cell lines. Compound 12c effectively inhibited tubulin polymerisation and competed with [ 3 H] colchicine in binding to tubulin. Compound 12c arrested the cell cycle at G 2 /M phase, effectively inducing apoptosis and inhibition of cell migration.

Synthesis and Cytotoxic Activity of Combretastatin A-4 and 2,3-Diphenyl-2H-indazole Hybrids

“…In addition, it was also shown that compound 5 triggers the apoptosis of HeLa cells ( Figure S31 in supplementary information ). Our data agrees with the mechanism of action of different microtubule depolymerizing agents such as nocodazole [ 33 ], colchicine [ 34 ], and CA-4 and its derivatives [ 31 , 35 ] that induce the program cell death.…”

Recent Advances of Tubulin Inhibitors Targeting the Colchicine Binding Site for Cancer Therapy

“…One of the synthesized compounds, St.47 ( Figure 9 ), was considered a tubulin polymerization inhibitor by the performed mechanistic studies, and regarding cell cycle analysis it was made in accumulation and arrest in G2/M phase. In addition, this compound was the most active compound against MCF-7, HL-60, HCT-116, and HeLa cancer cell lines with IC 50 values < 42 nM [ 113 ]. In a series of quinoline-pyrazole and quinoline-pyridone derivatives, St.48 and St.49 ( Figure 9 ) showed the most potent tubulin polymerization inhibitory activities with IC 50 values of 9.11 and 10.5 nM, respectively.…”

Advances in antitumor research of CA-4 analogs carrying quinoline scaffold

“…The results of the study showed 49% reduction in tumor volume in mice treated with compound 59 compared to the control group, with no significant effect on body weight, suggesting a lesser side effect and a worthwhile candidate to investigate for the treatment of cancer. Ibrahim et al (2020) started from the analysis of the structure of CA-4 and proposed the same idea as major chemists to use Another study was carried out by Ibrahim et al (2021), who further optimized CA-4 from its structure by inserting rigid oxazolones and imidazolines between the A and B ring to maintain cis-activity, and then maintained 3,4,5trimethoxyphenyl by altering the electron group substitution effect. The designed compounds were subjected to antiproliferative activity assays against four MCF-7, HL-60, HCT-116, HeLa) using CA-4 as a control, where compound 66 (Figure 11) stood out with the optimal effect (IC 50 = 0.019-0.042 μM), and more excitingly the compound was selective for cancer cells by verifying that MCF-10A (IC 50 > 50 μM), compared to an IC 50 value of 6.1 μM for CA-4.…”

“…Another study was carried out by Ibrahim et al (2021) , who further optimized CA-4 from its structure by inserting rigid oxazolones and imidazolines between the A and B ring to maintain cis -activity, and then maintained 3,4,5-trimethoxyphenyl by altering the electron group substitution effect. The designed compounds were subjected to antiproliferative activity assays against four MCF-7, HL-60, HCT-116, HeLa) using CA-4 as a control, where compound 66 ( Figure 11 ) stood out with the optimal effect (IC 50 = 0.019–0.042 μM), and more excitingly the compound was selective for cancer cells by verifying that MCF-10A (IC 50 > 50 μM), compared to an IC 50 value of 6.1 μM for CA-4.…”