Computational-Based Discovery of the Anti-Cancer Activities of Pyrrole-Based Compounds Targeting the Colchicine-Binding Site of Tubulin

Abstract

Despite the tubulin-binding agents (TBAs) that are widely used in the clinic for cancer therapy, tumor resistance to TBAs (both inherited and acquired) significantly impairs their effectiveness, thereby decreasing overall survival (OS) and progression-free survival (PFS) rates, especially for the patients with metastatic, recurrent, and unresectable forms of the disease. Therefore, the development of novel effective drugs interfering with the microtubules’ dynamic state remains a big challenge in current oncology. We report here about the novel ethyl 2-amino-1-(furan-2-carboxamido)-5-(2-aryl/tert-butyl-2-oxoethylidene)-4-oxo-4,5-dihydro-1H-pyrrole-3-carboxylates (EAPCs) exhibiting potent anti-cancer activities against the breast and lung cancer cell lines in vitro. This was due to their ability to inhibit tubulin polymerization and induce cell cycle arrest in M-phase. As an outcome, the EAPC-treated cancer cells exhibited a significant increase in apoptosis, which was evidenced by the expression of cleaved forms of PARP, caspase-3, and increased numbers of Annexin-V-positive cells. By using the in silico molecular modeling methods (e.g., induced-fit docking, binding metadynamics, and unbiased molecular dynamics), we found that EAPC-67 and -70 preferentially bind to the colchicine-binding site of tubulin. Lastly, we have shown that the EAPCs indicated above and colchicine utilizes a similar molecular mechanism to inhibit tubulin polymerization via targeting the T7 loop in the β-chain of tubulin, thereby preventing the conformational changes in the tubulin dimers required for their polymerization. Collectively, we identified the novel and potent TBAs that bind to the colchicine-binding site and disrupt the microtubule network. As a result of these events, the compounds induced a robust cell cycle arrest in M-phase and exhibited potent pro-apoptotic activities against the epithelial cancer cell lines in vitro.

In Vitro and in Vivo Studies of Folate-Functionalized PEGylated Chitosan/Superparamagnetic Iron Oxide Nanoparticle for the Fibrosarcoma-Targeted Delivery of Paclitaxel

“…Other studies have shown a strong link between the antitumor effect of PTX-loaded polymeric nanocarrier and immunological responses, such as splenocyte growth and cytokine production. These results were in line with those of those other studies [90][91][92][93][94][95][96][97][98][99].…”

“…Apoptosis was triggered in tumor cells by the protein PTX, which worked by inhibiting cell division [99] and stabilizing the microtubule assembly through noncovalent interactions with the cytoskeleton. Wang…”

Targeted delivery of paclitaxel drug using polymer-coated magnetic nanoparticles for fibrosarcoma therapy: in vitro and in vivo studies

“…Female BALB/c mice (6-8 weeks old, 20-25 g in weight) were obtained from the animal house of the Faculty of Veterinary Medicine Al-Qasim Green University. They were housed in a conventional animal facility under standard laboratory conditions 53 .…”

Synthesis, characterization, and inhibition effects of a novel eugenol derivative bearing pyrrole functionalities on the corrosion of mild steel in a HCl acid solution

“…19 Similarly, Abdelmaoujoud Taia and colleagues have synthesized new heterocycles, 1,2,3-triazoles, with anticorrosive activity, particularly for iron in acid solutions. 20 Moreover, heterocyclic pyrrole compounds, characterized by a ve-membered ring comprising four adjacent carbon atoms and one nitrogen atom, have recently been prepared by Sergei Boichuk et al 21 These products have found wide therapeutic applications 21,22 due to their diverse biological properties, 23 including antimicrobial 24 and anticancer activities. 25 Many pyrrole-based compounds are also widely used as anticorrosion agents to combat the degradation of various metallic materials, such as copper, iron, and aluminum, in corrosive environments.…”