Conformational mimetics of the α-methyl chalcone TUB091 binding tubulin: Design, synthesis and antiproliferative activity

Abstract

Based on the conformation of the α-methyl chalcone TUB091 in its complex with tubulin, a series of conformational mimetics have been designed and synthesized where the methyl group of the chalcone has been fused to phenyl ring B resulting in 1,2,3,4-tetrahydronaphthalen-2-yl aryl ketones. Among the synthesized compounds, the 5-amino-6-methoxy derivative, with a similar substitution pattern to that of TUB091, showed antiproliferative activity around 20 nM against tumor and endothelial cells. Tubulin binding experiments confirmed its binding to tubulin at the colchicine site with a Kb of 2.4 × 10 M resulting in the inhibition of the in vitro assembly of purified tubulin. Moreover, based on the recently reported complex of combretastatin A4 (CA4) with tubulin, a comparative analysis of the binding mode of CA4 and the α-methyl chalcone to tubulin has been performed.

Design and Synthesis of New 6-Nitro and 6-Amino-3,3a,4,5-Tetrahydro-2H-Benzo[g]indazole Derivatives: Antiproliferative and Antibacterial Activity

“…Finally, the nitro derivatives 11 – 14a,b were reduced to their amino analogs by treatment with Fe in an EtOH:H 2 O mixture at reflux in the presence of HCl (Scheme 2), following the procedure previously used for the reduction of the 5-nitrotetrahydronaphthalenes [22], providing compounds 15a – 18a and 15b – 18b in moderate to good yields (25–75%). These compounds 15a – 18a and 15a – 18b showed similar spectroscopic data and therefore, we discuss here compound 15a as the representative of this series.…”

“…We have recently reported on tetrahydronaphtalene derivatives as conformational restricted mimetics of chalcone derivatives that also bind the colchicine binding site in tubulin [22]. As in the previous examples, an amino group was incorporated at position 5 on ring B and this was shown to be crucial for the antiproliferative activity and the tubulin binding capacity.…”

Molecular targets and anticancer activity of quinoline–chalcone hybrids: literature review

“…1,2 The cancer rates increase annually, and it is expected that cancer rates will increase by about 60% over the next 20 years. According to chalcone-based compounds have been reported in the last decade as tubulin inhibitors, [49][50][51][52][53][54][55][56][57][58] in addition to several other possible molecular targets that chalcones directly interact with 59 (see ESI †).…”

Synthesis and biological evaluation of quinoxaline derivatives as tubulin polymerization inhibitors that elevate intracellular ROS and triggers apoptosis via mitochondrial pathway

“…However, the clinical efficacy of the drugs is often limited by occurrence and evolution of resistance mechanisms that is further compounded by a narrow therapeutic index (Du et al., ; Gigant et al., ; Kavallaris, ; Perez, ; Wang, Chen, Miller, & Li, ; Wang et al., ). Recently, some colchicine binding tubulin inhibitors exhibit significant ability to overcome multidrug resistance (Bacher et al., ; Banerjee et al., ; Bueno et al., ; Cui et al., ; Dohle et al., ; Gangjee et al., ; Lauria et al., ; Li et al., ; Ohsumi et al., ; Pang et al., ; Suman et al., ). Even some drug candidates have already entered the clinical trial stage (Figure ).…”