Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Dec;37(1):1884-1902.
doi: 10.1080/14756366.2022.2096019.

Design, synthesis and molecular docking of new fused 1 H-pyrroles, pyrrolo[3,2- d]pyrimidines and pyrrolo[3,2- e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

Amany Belal  1   2 , Nagwa M Abdel Gawad  3 , Ahmed B M Mehany  4 , Mohammed A S Abourehab  5   6 , Hazem Elkady  7 , Ahmed A Al-Karmalawy  8 , Ahmed S Ismael  1
Affiliations

Design, synthesis and molecular docking of new fused 1 H-pyrroles, pyrrolo[3,2- d]pyrimidines and pyrrolo[3,2- e][1, 4]diazepine derivatives as potent EGFR/CDK2 inhibitors

Amany Belal et al. J Enzyme Inhib Med Chem. 2022 Dec.

Abstract

A new series of 1H-pyrrole (6a-c, 8a-c), pyrrolo[3,2-d]pyrimidines (9a-c) and pyrrolo[3,2-e][1, 4]diazepines (11a-c) were designed and synthesised. These compounds were designed to have the essential pharmacophoric features of EGFR Inhibitors, they have shown anticancer activities against HCT116, MCF-7 and Hep3B cancer cells with IC50 values ranging from 0.009 to 2.195 µM. IC50 value of doxorubicin is 0.008 µM, compounds 9a and 9c showed IC50 values of 0.011 and 0.009 µM respectively against HCT-116 cells. Compound 8b exerted broad-spectrum activity against all tested cell lines with an IC50 value less than 0.05 µM. Compound 8b was evaluated against a panel of kinases. This compound potently inhibited CDK2/Cyclin A1, DYRK3 and GSK3 alpha kinases with 10-23% compared to imatinib (1-10%). It has also arrested the cell cycle of MCF-7 cells at the S phase. Its antiproliferative activity was further augmented by molecular docking into the active sites of EGFR and CDK2 cyclin A1.

Keywords: 1H-pyrrole; 4]diazepine; Anticancer; CDK2 inhibitor; EGFR inhibitor; pyrrolo[3,2-d]pyrimidine; pyrrolo[3,2-e][1.

PubMed Disclaimer

Conflict of interest statement

All authors of the above manuscript have not declared any conflict of interest.

Figures

Figure 1.
Figure 1.
FDA approved and reported kinases inhibitors with their essential pharmacophoric features.
Figure 2.
Figure 2.
ATP binding site of EGFR cavity composed of five main parts.
Figure 3.
Figure 3.
Design strategies of Scaffolds A, B and C.
Scheme 1.
Scheme 1.
Construction of compounds 5a–c. Reagents and conditions: (a) (CH3)2SO4, benzene, CH2(CN)2, reflux, 6 h; (b) ClCH2COCl, glacial acetic acid, CH2COONa, 30–40 °C, 2 h; (c) acetone, K2CO3, reflux, 24 h.
Scheme 2.
Scheme 2.
Synthesis of compounds 6a–c, 7a–c and 8a–c. Reagents and conditions: (a) 4-Nitrobenzaldehyde, absolute ethanol, glacial acetic acid; (b) ClCH2COCl, benzene; r.t.; 48 h; (c) piperidine, NaHCO3, absolute ethanol, reflux, 8 h.
Scheme 3.
Scheme 3.
Synthesis of compounds 9a–c, 10a–c and 11a–c. Reagents and conditions: (a) Excess CH3C(OC2H5)3, reflux, 12 h; (b) K2CO3, DMF, r.t., 48 h; (c) ClCH2COOC2H5, K2CO3, acetone, reflux, 6 h.
Figure 4.
Figure 4.
Cell cycle distribution of MCF-7 treated with compound 6a (µM, 72 h: x axis); % cell (y axis).
Figure 5.
Figure 5.
Cell cycle distribution of MCF-7 treated with compound 8b (µM, 72 h: x axis); % cell (y axis).
Figure 6.
Figure 6.
(A) superimposition of the docked ligand of erlotinib (turquoise) and the original ligand (green) with an RMSD value of 0.88 Å. (B) superimposition of the docked ligand of AZD5438 (pink) and the original ligand (green) with RMSD value of 0.54 Å.
Figure 7.
Figure 7.
Erlotinib docked into the active site of EGFR.
Figure 8.
Figure 8.
Compound 8b docked into the active site of EGFR.
Figure 9.
Figure 9.
Co-crystallised ligand (AZD5438) docked into the active site of CDK-2.
Figure 10.
Figure 10.
(A) Binding of compound 8b with CDK-2.
Figure 11.
Figure 11.
(A) Binding of compound 8b with DYRK3.
Figure 12.
Figure 12.
(A) Binding of compound 8b with GSK3 alpha.
Figure 13.
Figure 13.
The expected ADMET study.
See this image and copyright information in PMC

References

    1. El-Metwally SA, Abou-El-Regal MM, Eissa IH, et al. . Discovery of thieno [2, 3-d] pyrimidine-based derivatives as potent VEGFR-2 kinase inhibitors and anti-cancer agents. Bioorg Chem 2021;112:104947. - PubMed
    1. World Health Organization, Cancer . Available from: https://www.who.int/news-room/fact-sheets/detail/cancer [last accessed 1 March 2020].
    1. El-Zahabi MA, Sakr H, El-Adl K, et al. . Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer immunomodulatory agents. Bioorg Chem 2020;104:104218. - PubMed
    1. Chabner BA, Roberts TG.. Chemotherapy and the war on cancer. Nat Rev Cancer 2005;5:65–72. - PubMed
    1. G, Krauss, N, Schönbrunner, J, Cooper Biochemistry of signal transduction and regulation. Weinheim: Wiley Online Library; 2003.

MeSH terms