Exploring Diverse-Ring Analogues on Combretastatin A4 (CA-4) Olefin as Microtubule-Targeting Agents

Abstract

Combretastatin-4 (CA-4) as a tubulin polymerization inhibitor draws extensive attentions. However, due to its weak stability of cis-olefin and poor metabolic stability, structure modifications on cis-configuration are being performed. In this work, we constructed a series of novel CA-4 analogues with linkers on olefin containing diphenylethanone, cis-locked dihydrofuran, α-substituted diphenylethanone, cyclobutane and cyclohexane on its cis-olefin. Cytotoxic activity of all analogues was measured by an SRB assay. Among them, compound 6b, a by-product in the preparation of diphenylethanone analogues, was found to be the most potent cytotoxic agents against HepG2 cells with IC50 values of less than 0.5 μM. The two isomers of 6b induced cellular apoptosis tested by Annexin V-FITC and propidium iodide (PI) double staining, arrested cells in the G2/M phase by PI staining analysis, and disrupted microtubule network by immunohistochemistry study in HepG2 cells. Moreover, 6b-(E) displayed a dose-dependent inhibition effect for tubulin assembly in in vitro tubulin polymerization assay. In addition, molecular docking studies showed that two isomers of 6b could bind efficiently at colchicine binding site of tubulin similar to CA-4.

Combretastatins: An Overview of Structure, Probable Mechanisms of Action and Potential Applications

“…Molecules 2020 , 25, 2560 7 of 32 3,4,5-trimethoxy groups at ring-A, 4′-methoxy group at ring-B and cis-configuration of the olefin are the crucial elements for excellent tubulin assembly inhibition [21,24,26].…”

Design, synthesis and structure–activity relationship studies on erianin analogues as pyruvate carboxylase inhibitors in hepatocellular carcinoma cells

“…Compounds 1–4 were synthesized according to reported literature procedures (Schemes 1 and 2). 20,21 For the synthesis of 5 , 22 14 23 and 15 (Scheme 3), the corresponding aryl bromides, were treated with n -butyl lithium, the obtained aryl lithium were then captured with Weinreb amides to produce intermediates S3-1 to S3-3 . The products 5 , 14 and 15 can be smoothly obtained via the catalytic hydrogenation of S3-1 to S3-3 .…”

“…The synthesis and characterization of compounds 1–7 , 10 , 14 , 21 , 39 and 40 had already been reported in previous studies. 21–27 The compounds 8 , 9 , 11–13 , 15–20 , 22–34 , 36–38 and 41–47 were synthesized according to the route in Schemes 3–8. The structures of all compounds were confirmed from the analytical data obtained from 1 H NMR and 13 C NMR spectroscopies, and mass spectrometry.…”

Development of Combretastatin A-4 Analogues as Potential Anticancer Agents with Improved Aqueous Solubility

“…One of the structures with outstanding activity is combretastatin A-4 ( Figure 1 , CA-4), which strongly inhibits tubulin assembly by interacting at the colchicine-binding site [ 4 ]. However, CA-4 is a poorly water-soluble and unstable compound [ 5 , 6 ]. Low solubility of a compound will have some negative effects in terms of drug development, such as low bioavailability and a short half-life in vivo [ 7 ], and the in vivo anti-tumour effect of the compound may be different from that in vitro [ 8 ].…”

“…Still, the goal of doubling the median survival rate has not been achieved [ 16 ]. In addition, the early research reports on CA-4 pointed out that the Z -restricted configuration can quickly convert into 100-fold less active trans isomerization under the conditions of absorbing heat, light and protonic media (configuration instability) [ 6 ]. Up to now, cis -stable CA-4 analogues that have not been tested in clinical trials, and compounds such as CA-4P and AVE8062 that have entered clinical trials contain isomeric olefinic bonds, which may become one of the factors hindering the sustained clinical success of these compounds.…”