Design, Synthesis, and Evaluation of the Novel Benzimidazole Derivatives Inspired YC‐1 as HIF‐1α Inhibitor That Possess Anti‐Colon Cancer Potential
TL;DR
In vivo studies have shown that compound 9o can inhibit tumor growth and reduce the levels of HIF‐1α and glycolysis rate‐limiting enzyme HK2 in HCT‐116 tumor‐bearing mice, and the acute toxicity results also demonstrated the safety of compound 9o in vivo.
Abstract
Hypoxia‐inducible factor‐1 α (HIF‐1α) is a key transcription factor for tumor cells to sense and adapt to the hypoxic microenvironment, regulate tumor progression such as tumor glycolysis, and is an important target for the development of anti‐tumor drugs. YC‐1 (1‐benzyl‐3‐(5’‐hydroxymethyl‐2’‐furyl)indazole), as a classic inhibitor of HIF‐1α, has received extensive attention in multiple anti‐tumor studies. Some derivatives that replace YC‐1 indazole with the benzimidazole skeleton have shown certain HIF‐1α inhibitory and anti‐tumor potential. In this study, a series of substituted benzimidazole derivatives were designed and synthesized, and their HIF‐1α inhibitory and anti‐tumor effects were screened and investigated. In vitro anti‐proliferation and dual‐luciferase reports showed that compound 9o had superior in vitro anti‐tumor (IC50 = 33.85 μM) and HIF‐1α transcriptional inhibitory activity (79.59% inhibition rate) compared with the positive control YC‐1. Meanwhile, compound 9o can also significantly inhibit the colony formation and survival rate of HCT‐116 cells. In addition, Western blotting, real‐time PCR and and lactic acid content experiments verified its inhibitory effect on HIF‐1α and downstream glycolysis. In addition, compound 9o was found to reduce platelet aggregation more than YC‐1, and the molecular docking results suggested that compound 9o weakened its interaction with soluble guanylate cyclase (sGC), which is beneficial for avoiding the bleeding risk during tumor treatment. In vivo studies have shown that compound 9o can inhibit tumor growth and reduce the levels of HIF‐1α and glycolysis rate‐limiting enzyme HK2 in HCT‐116 tumor‐bearing mice. The acute toxicity results also demonstrated the safety of compound 9o in vivo. Finally, we also explored its pharmacokinetic properties in rats, suggesting its potential for subsequent intravenous administration. These findings provide a basis for the further discovery of anti‐tumor candidate compounds based on HIF‐1α inhibitors.