The Design and Synthesis of a New Series of 1,2,3-Triazole-Cored Structures Tethering Aryl Urea and Their Highly Selective Cytotoxicity toward HepG2

Abstract

Target cancer drug therapy is an alternative treatment for advanced hepatocellular carcinoma (HCC) patients. However, the treatment using approved targeted drugs has encountered a number of limitations, including the poor pharmacological properties of drugs, therapy efficiency, adverse effects, and drug resistance. As a consequence, the discovery and development of anti-HCC drug structures are therefore still in high demand. Herein, we designed and synthesized a new series of 1,2,3-triazole-cored structures incorporating aryl urea as anti-HepG2 agents. Forty-nine analogs were prepared via nucleophilic addition and copper-catalyzed azide-alkyne cycloaddition (CuAAC) with excellent yields. Significantly, almost all triazole-cored analogs exhibited less cytotoxicity toward normal cells, human embryonal lung fibroblast cell MRC-5, compared to Sorafenib and Doxorubicin. Among them, 2m’ and 2e exhibited the highest selectivity indexes (SI = 14.7 and 12.2), which were ca. 4.4- and 3.7-fold superior to that of Sorafenib (SI = 3.30) and ca. 3.8- and 3.2-fold superior to that of Doxorubicin (SI = 3.83), respectively. Additionally, excellent inhibitory activity against hepatocellular carcinoma HepG2, comparable to Sorafenib, was still maintained. A cell-cycle analysis and apoptosis induction study suggested that 2m’ and 2e likely share a similar mechanism of action to Sorafenib. Furthermore, compounds 2m’ and 2e exhibit appropriate drug-likeness, analyzed by SwissADME. With their excellent anti-HepG2 activity, improved selectivity indexes, and appropriate druggability, the triazole-cored analogs 2m’ and 2e are suggested to be promising candidates for development as targeted cancer agents and drugs used in combination therapy for the treatment of HCC.

Rationale design, synthesis, cytotoxicity evaluation, andin silicomechanistic studies of novel 1,2,3-triazoles with potential anticancer activity

“…Silica gel Merck 60 F254 commercial plates were used for analytical TLC together with a UV light to follow the course of the reaction. The structure of all the compounds was confirmed by IR, 1 H NMR (500 MHz) and 13 C NMR spectroscopy (125 MHz). Chemicals shifts (d) are reported in parts per million (ppm) downfield from TMS, J values calculated in Hertz, and the splitting patterns are abbreviated as follows: s, singlet; d, doublet; t, triplet; q, quartet; and m, multiplet.…”

“…The 1 H NMR spectra of these acid derivatives also confirmed the proposed structures given that they show one D 2 O exchangeable singlet signal at the d value of B12.60 due to the OH, which is unapplicable for the other probable cyclic pyrrole-2,4-dione products. In the 13 C NMR spectrum of 22, the methyl carbons of both the triazole and hydrazinyl linkers resonated at 10.9 and 10.1 ppm, respectively. In addition, the carbonyl carbon of the thiazolino-4-one ring was observed, as predicted, at 178.0 ppm.…”

“…8,9 Recently, tivozanib (5) has been identified as the latest FDA-approved VEGFR-2 inhibitor for the treatment of patients with advanced renal cancer. 9 1,2,3-Triazole is a privileged building block in the discovery of new anticancer agents, [10][11][12][13] and some of its derivatives such as cefatrizine (6) and carboxyamidotriazole (7) have already been applied in clinics or under clinical trials for fighting cancer. [14][15][16][17] Additionally, 1,2,3-triazole-incorporating molecules have gained significant interest in recent years given that they can be easily synthesized either via copper-catalyzed azide-alkyne cycloaddition reaction or the reaction of azides with activated methylene compounds.…”

Recent updates in click and computational chemistry for drug discovery and development

“…Copper-catalyzed 1,3-dipolar cycloaddition (CuAAC) to form 1,2,3-triazoles is the most popular reaction in click chemistry. Recently, 1,2,3-triazole backbones with hydrogen bonds, moderate dipole moments and enhanced water solubility had been widely used to generate drug candidates of anti-tumor ( Brown et al, 2022 ; Elganzory et al, 2022 ; Mohammed et al, 2022 ; Oekchuae et al, 2022 ; Oliveira et al, 2022 ; Mironov et al, 2023 ), anti-seizure ( Bhattacherjee et al, 2022 ), anti-diabetic ( Dhameja et al, 2022 ), anti-parasitic ( Aljohani et al, 2022 ), anti-bacterial ( Daher et al, 2022 ; Mokariya et al, 2022 ; Nsira et al, 2022 ) and anti-viral ( Kutkat et al, 2022 ; Tatarinov et al, 2022 ) via CuAAC click chemistry ( Figure 1A ).…”

Design and synthesis of cabotegravir derivatives bearing 1,2,3-triazole and evaluation of anti-liver cancer activity

“…They found that compound 4 had an IC 50 value of 5.57 μM for HepG2 cells, which was comparable to the positive drug sofosbuvir ( Figure 2 ). It could induce apoptosis in HepG2 cells and showed good affinity, making it a potential anti-liver cancer lead compound ( Chen et al, 2022a ; Oekchuae et al, 2022 ).…”