Discovery of Potent Cytotoxic Ortho-Aryl Chalcones as New Scaffold Targeting Tubulin and Mitosis with Affinity-Based Fluorescence

Abstract

A series of new ortho-aryl chalcones have been designed and synthesized. Many of these compounds were found to exhibit significant antiproliferation activity toward a panel of cancer cell lines. Selected compounds show potent cytotoxicity against several drug resistant cell lines including paclitaxel (Taxol) resistant human ovarian carcinoma cells, vincristine resistant human ileocecum carcinoma cells, and doxorubicin resistant human breast carcinoma cells. Further investigation revealed that active analogues could inhibit the microtubule polymerization by binding to colchicine site and thus induce multipolar mitosis, G2/M phase arrest, and apoptosis of cancer cells. Furthermore, affinity-based fluorescence enhancement was observed during the binding of active compounds with tubulin, which greatly facilitated the determination of tubulin binding site of the compounds. Finally, selected compound 26 was found to exhibit obvious in vivo antitumor activity in A549 tumor xenografts model. Our systematic studies implied a new scaffold targeting tubulin and mitosis for novel antitumor drug discovery.

Unambiguous Identification of β‐Tubulin as the Direct Cellular Target Responsible for the Cytotoxicity of Chalcone by Photoaffinity Labeling

“…This potential binding site is consistent with several other literature reports. For instance, docking studies suggested that cytotoxic chalcones fit well in the colchicine binding site, and colchicine was shown to compete with cytotoxic chalcones for tubulin binding . Such a potential binding site is also consistent with the fact that C95 labeled α‐tubulin as well, which indicated that C95 may bind around the interface of the α‐tubulin and β‐tubulin heterodimer.…”

“…Moreover, there has been little evidence to support any direct interactions of cytotoxic chalcones with these putative targets in intact cells. Taking tubulin as an example, although chalcone‐based compounds have been documented to inhibit tubulin polymerization ex vitro, their direct interaction in cells remains to be validated. Similarly, whereas cells upon cytotoxic chalcone exposure would lose microtubule structure, such an effect can be mediated by multiple mechanisms .…”

Blocking Blood Flow to Solid Tumors by Destabilizing Tubulin: An Approach to Targeting Tumor Growth

“…Interestingly, compound 36 and similar analogues were found to exhibit affinity-induced fluorescence during tubulin-binding. 78 Also within chalcones, the B-ring can accommodate indol rings, as exemplified by 37 (IPP51) 79 that inhibited tumor growth in a human bladder xenograft model. Other examples where the bridge connecting rings A and B contains a pyridine have been described by Zheng et al 80 2.4.2.…”

Synthesis, biological evaluation and mechanism study of chalcone analogues as novel anti-cancer agents

“…13 Chalcones, the precursors of flavonoids and isoflavonoids, are abundant in edible plants, and have also been shown to display a diverse array of pharmacological activities. 16 With millepachine, a chalcone analogue isolated from the Millettia pachycarpa as the model, Chen synthesized and evaluated twenty one dirivatives for their antiproliferative activity and the optimal compound was considered as promising anticancer agent. For example, Ducki incorporated the aryl substitution pattern of CA4 into chalcones and found that some of these compounds exhibited good antimitotic properties.…”