Design, synthesis and biological evaluation of benzoylacrylic acid shikonin ester derivatives as irreversible dual inhibitors of tubulin and EGFR

Discovery of Anilino-1,4-naphthoquinones as Potent EGFR Tyrosine Kinase Inhibitors: Synthesis, Biological Evaluation, and Comprehensive Molecular Modeling

“…Notably, both compounds are more potent than the previously reported shikonin derivative II ( Figure 1 , IC 50 = 22.7 nM). 25 Moreover, the most potent compound 3 showed more promising activity than several classes of small molecules reported as EGFR inhibitors, including 6,7-dimorpholinoalkoxy quinazoline derivative (IC 50 = 7.0 nM), 46 thiazole-based chalcone derivative (IC 50 = 33.66 nM), 47 1,2,4-triazole derivative (IC 50 = 1500 nM), 48 vinyl sulfone derivative (IC 50 = 7.85 nM), 49 aminopyrimidine derivative bearing a 4,5,6,7-tetrahydrothieno [3,2-c]pyridine (IC 50 = 6.4 nM), 50 sulfamoylphenyl-quinazoline derivative (IC 50 = 13.7 nM), 51 4,6-pyrimidinediamine derivative (IC 50 = 202 nM), 52 thiazolyl-pyrazoline derivative (IC 50 = 4340 nM), 53 6-(2-substituted acetamido)-4-anilinoquinazoline derivative (IC 50 = 32 nM), 54 and N4,N6-disubstituted pyrimidine-4,6-diamine derivative (IC 50 = 26 nM). 55 Notably, the inhibitory activity of compounds 3 , 8 , and 10 against L858R/T790M double mutant EGFR was very low (IC 50 > 100 nM, Figure S1 ), indicating that our synthesized naphthoquinones are specific toward the wild-type form of EGFR.…”

“…Examples of naphthoquinones acting as EGFR inhibitors are shown in Figure 1 . Furano-1,2-naphthoquinone I ( 24 ) and synthetic shikonin derivatives containing benzoylacrylic acid II ( 25 ) ( Figure 1 ) were reported to inhibit EGFR and induce cell cycle arrest in the G2/M phase, leading to cellular apoptosis. Some plant-derived 1,4-naphthoquinone derivatives with EGFR inhibitory effect were also reported.…”

Synthesis and Pharmacological In Vitro Investigations of Novel Shikonin Derivatives with a Special Focus on Cyclopropane Bearing Derivatives

“…Except for three recently published studies about benzoylacrylates [34], succinamides, and maleinamides [35,36], all carbonyl groups in the acyl chain of shikonin or alkannin esters were part of acetoxy groups mainly derived from β-hydroxy acylates. However, the substances of Sun et al [34] are of unknown chirality, among them the p- The second goal was to produce a broad spectrum of structural features within the acyl residue of shikonin to find potential novel drug leads. For better comparison and a more complete picture, we also included some already known derivatives.…”

“…As there have been no reports about any shikonin alkynylacyl esters yet, we synthesized tetrolate 10, 2-butynoate 11, and 3-phenylpropiolate 12 to investigate the influence of a triple bond. Except for three recently published studies about benzoylacrylates [34], succinamides, and maleinamides [35,36], all carbonyl groups in the acyl chain of shikonin or alkannin esters were part of acetoxy groups mainly derived from β-hydroxy acylates. However, the substances of Sun et al [34] are of unknown chirality, among them the pmethylbenzoylacrylate 13.…”

Discovery of Potent EGFR Inhibitors With 6-Arylureido-4-anilinoquinazoline Derivatives

“…The EGFR has been confirmed to be closely related to tumor growth, progression, metastasis, and the poor prognosis of cancer patients, prompting extensive studies on the EGFR signaling pathway ( Bishayee, 2000 ; Bridges, 2001 ; Ogiso et al, 2002 ; Hirsch et al, 2003 ; Bazley and Gullick, 2005 ; Allam et al, 2020 ; Han et al, 2020 ). Increasing evidence has shown that EGFR inhibitors have great potential in the treatment of tumors, especially non-small-cell lung cancer, hepatocellular carcinoma, and pancreatic cancer, which has inspired a research boom based on the design and synthesis of EGFR inhibitors ( Umekita et al, 2000 ; Elgazwy et al, 2013 ; Mghwary et al, 2019 ; Sever et al, 2019 ; Sun et al, 2019 ; Zhu et al, 2019 ; Zhang et al, 2020 ).…”