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Novel Furochromone Derivatives of Potential Anticancer Activity Targeting EGFR Tyrosine Kinase. Synthesis and Molecular Docking Study

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Abstract

In this study, a new class of furochromone derivatives bearing β-naphthol was synthesized via one-pot multicomponent reactions. First, condensation one mole of furochromone carbaldehyde (I) with two moles of β-naphthol afforded the corresponding Xanthene’ dye derivatives (II). A one-pot three-component reaction of (I), β-naphthol and urea or thiourea result in the formation of the corresponding oxazinones (IIIa, b). Moreover, reaction of (I) and β-naphthol with primary aromatic amines, heterocyclic amines or 2ry amines using triethyl amine as catalyst afforded the corresponding amino derivatives (IV–XIII). On the other hand, a one-pot three-component reaction of (I) and β-naphthol with active methylene compounds namely, malononitrile, propionitrile, diethylmalonate methyl propionate or diethyl succinate led to the formation of furochromone derivatives (VIV)–(XVIII). The antitumor activities of certain selected new compounds were screened, in vitro, against a panel of three (liver, HepG2; breast, MCF-7, HepG-2 and PC-3) human solid tumor cell lines as well as the normal cell line (human normal melanocyte, HFB4) in comparison to the known anticancer drug: 5-fluorouracil using MTT assay. Our results showed that the vast majority of the newly synthesized derivatives did not exert any activity against the growth of HFB4normal cell line. Compounds (IV), (XIIIa), and (XIIIb) revealed remarkable anticancer activity against MCF-7 cell line with IC50 5.4, 4.65, and 6.09 μg/mL respectively compared to 5-fluorouracil (IC50 = 4.7 μg/mL). Moreover, compounds (IIIb), (VII), (IX), and (XVI) showed potent activity against HepG-2 cancer cell line of IC50 ranging from 5.57 to 6.34 μg/mL. Compound (VII) revealed also anticancer activity against PC-3 cancer cell line with IC50 6.77 μg/mL vs. 5.05 for 5-fluorouracil. The inhibitory activity of the most active anti-proliferative compounds (IIIb), (IV), (VII), (IX), (XIIIa, b) and (XVI) against EGFR were studied. Compound (VII) showed the best inhibitory activity against EGFR with IC50 39.93 ng/ml in comparison to erlotinib (IC50 29.18 ng/mL). Molecular docking simulation was performed to position compounds (IIIb), (IV), (VII), (IX), (XIIIa, b), and (XVI) into the EGFR active site to determine the probable binding mode.

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ACKNOWLEDGMENTS

The authors are grateful to Dr. Esam Rashwan, Head of the confirmatory diagnostic unit VACSERA-EGYPT, for carrying out the enzyme assays.

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Authors and Affiliations

  1. Chemistry of Natural and Microbial Products Department, Pharmaceutical Industries Research Institute, National Research Center, Giza, Egypt

    N. M. Fawzy

  2. Chemistry of Natural Compounds Department, Pharmaceutical Industries Research Institute, National Research Centre, Giza, Egypt

    K. M. Ahmed & H. M. Abo-Salem

  3. Genetics Division, Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt

    M. S. Aly

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  1. N. M. Fawzy
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Correspondence to H. M. Abo-Salem.

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This article does not contain any studies involving human participants performed by any of the authors and does not contain any studies involving animals performed by any of the author.

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Fawzy, N.M., Ahmed, K.M., Abo-Salem, H.M. et al. Novel Furochromone Derivatives of Potential Anticancer Activity Targeting EGFR Tyrosine Kinase. Synthesis and Molecular Docking Study. Russ J Bioorg Chem 48, 749–767 (2022). https://doi.org/10.1134/S1068162022040082

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