Novel Natural Product- and Privileged Scaffold-Based Tubulin Inhibitors Targeting the Colchicine Binding Site

Abstract

Tubulin inhibitors are effective anticancer agents, however, there are many limitations to the use of available tubulin inhibitors in the clinic, such as multidrug resistance, severe side-effects, and generally poor bioavailability. Thus, there is a constant need to search for novel tubulin inhibitors that can overcome these limitations. Natural product and privileged structures targeting tubulin have promoted the discovery and optimization of tubulin inhibitors. This review will focus on novel tubulin inhibitors derived from natural products and privileged structures targeting the colchicine binding site on tubulin.

Synthesis and bioevaluation of N,4-diaryl-1,3-thiazole-2-amines as tubulin inhibitors with potent antiproliferative activity

“…Tubulin-binding drugs disrupt microtubule/tubulin dynamics by binding to distinct sites such as taxol, vinca alkaloid and colchicine binding sites and arrest cells during mitosis, leading to cell death [3–5]. In contrast to macromolecular paclitaxel and vinblastine, most novel colchicine binding site inhibitors (CBSIs) have high potency, relatively simple and diverse chemical structures for optimization, and selective toxicity toward tumor vasculature [6]. Given the success of paclitaxel and vinblastine, research efforts have been focused on developing CBSIs for cancer treatment, and a number of effective CBSIs are currently being investigated in clinical studies [7].…”

“…The common structural features of CBSIs include the 3,4,5-Trimethoxyphenyl unit and the appropriate distance and certain dihedral angle between the aromatic rings. These were proposed as important structural features that are responsible for their antiproliferative and antitubulin activities [6]. …”

Colchicine-Binding Site Inhibitors from Chemistry to Clinic: A Review

“…Changing the structure of colchicine's, a ring results in loss of binding affinity. B and C ring structural modifications are however possible [21].…”

Synthesis, Biological Evaluation and Molecular Docking Studies of the 7-Acetamido Substituted 2-Aryl-5-bromo-3-trifluoroacetylindoles as Potential Inhibitors of Tubulin Polymerization

“…Nitrogen-containing heterocycles such as indoles with anticancer properties have potential to inhibit tubulin polymerization by binding to colchicine-binding site [3][4][5]. The methoxy-substituted 2-aryl-3- of 22 formylindoles (a) shown in Figure 1, for example, have been found to completely block the microtubule assembly at micromolar concentrations, which suggests a correlation between cytotoxicity and the microtubule system [3].…”