An Indole–Chalcone Inhibits Multidrug-Resistant Cancer Cell Growth by Targeting Microtubules

Abstract

Multidrug resistance and toxic side effects are the major challenges in cancer treatment with microtubule-targeting agents (MTAs), and thus, there is an urgent clinical need for new therapies. Chalcone, a common simple scaffold found in many natural products, is widely used as a privileged structure in medicinal chemistry. We have previously validated tubulin as the anticancer target for chalcone derivatives. In this study, an α-methyl-substituted indole-chalcone (FC77) was synthesized and found to exhibit an excellent cytotoxicity against the NCI-60 cell lines (average concentration causing 50% growth inhibition = 6 nM). More importantly, several multidrug-resistant cancer cell lines showed no resistance to FC77, and the compound demonstrated good selective toxicity against cancer cells versus normal CD34 blood progenitor cells. A further mechanistic study demonstrated that FC77 could arrest cells that relate to the binding to tubulin and inhibit the microtubule dynamics. The National Cancer Institute COMPARE analysis and molecular modeling indicated that FC77 had a mechanism of action similar to that of colchicine. Overall, our data demonstrate that this indole-chalcone represents a novel MTA template for further development of potential drug candidates for the treatment of multidrug-resistant cancers.

Antiproliferative Effect of Acridine Chalcone Is Mediated by Induction of Oxidative Stress

“…Furthermore, antiproliferative/antitumor activities of chalcones have also been intensively studied [9][10][11][12][13][14]. The available studies revealed multitargeted activity of chalcones including various kinases [15], microtubules [16], multidrug-resistance proteins [17], or different signalling pathways associated with…”

Role of Indole Scaffolds as Pharmacophores in the Development of Anti-Lung Cancer Agents

“…Cong et al reported an indole-chalcone derivative (FC77, Scheme 6) that can arrest cancer cell growth by binding to tubulin, exhibiting a similar mechanism of action as colchicine. FC77 exhibited a potent growth inhibitor of a majority of NCI-60 human cancer cell lines with GI50 ~ 6 μM [79]. The ability of FC77 to retain its cytotoxicity against multi-drug resistant cancer cell lines (with nanomolar GI values) and low cytotoxicity levels towards normal mobilized peripheral blood cells revealed that FC77 may be a potential therapeutic agent in treating multi-drug resistant cancers such as NSCLC.…”

“…The ability of FC77 to retain its cytotoxicity against multi-drug resistant cancer cell lines (with nanomolar GI values) and low cytotoxicity levels towards normal mobilized peripheral blood cells revealed that FC77 may be a potential therapeutic agent in treating multi-drug resistant cancers such as NSCLC. Moreover, the direct interaction of FC77 with tubulin and inhibition of microtubule dynamics with IC50 values of 3 nM compared to popular drugs such as paclitaxel and vincristine with IC50 values of 14 nM and 37 nM, respectively, makes it an attractive microtubule-targeting agent for the treatment of multidrug-resistant cancers [79]. The synthesis of FC77 was accomplished in a single step, as shown in Scheme 6 [79].…”

“…Moreover, the direct interaction of FC77 with tubulin and inhibition of microtubule dynamics with IC50 values of 3 nM compared to popular drugs such as paclitaxel and vincristine with IC50 values of 14 nM and 37 nM, respectively, makes it an attractive microtubule-targeting agent for the treatment of multidrug-resistant cancers [79]. The synthesis of FC77 was accomplished in a single step, as shown in Scheme 6 [79]. The condensation reaction between the acetophenone derivative (40) with the indole-3-carboxaldehyde (41) in the presence of piperidine afforded the target compound (FC77).…”

“…Their experiments revealed that NMK-BH3 was more sensitive to human lung adenocarcinoma A549 cells with IC 50 of~2 µM, while highly resistant to normal human lung fibroblasts (WI38) with IC 50 of 48.5 µM (24 fold). The synthesis of FC77 was accomplished in a single step, as shown in Scheme 6 [79]. The condensation reaction between the acetophenone derivative (40) with the indole-3-carboxaldehyde (41) in the presence of piperidine afforded the target compound (FC77).…”