Novel Anticancer Fused Pyrazole Derivatives as EGFR and VEGFR-2 Dual TK Inhibitors.

Nashwa M Saleh,Hala M Aly,Rana A Othman,Marwa G El-Gazzar

doi:10.3389/fchem.2019.00917

Nashwa M Saleh, Hala M Aly + Show 2 more

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https://doi.org/10.3389/fchem.2019.00917

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Abstract

EGFR and VEGFR-2 represent promising targets for cancer treatment as they are very important in tumor development as well as in angiogenesis and metastasis. In this work, 6-amino-4-(2-bromophenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile 1 and (E)-4-(2-Bromobenzylidene)-5-methyl-2,4-dihydro-3H-pyrazol-3-one 11 were selected as starting materials to synthesize different fused pyrazole derivatives; dihydropyrano[2,3-c]pyrazole 1, 2, 7–9, and 15, pyrazolo[4′,3′:5,6]pyrano[2,3-d]pyrimidine 3–6, pyrazolo[3,4-d]pyrimidine 12 and 13, and pyrazolo[3,4-c]pyrazole 14 derivatives were synthesized to evaluate their anticancer activity against HEPG2 human cancer cell lines compared to erlotinib and sorafenib as reference drugs. Seven compounds 1, 2, 4, 8, 11, 12, and 15 showed nearly 10 fold higher activity than erlotinib (10.6 μM) with IC50 ranging from 0.31 to 0.71 μM. In vitro EGFR and VEGFR-2 inhibitory activity were performed for the synthesized compounds, and the results identified compound 3 as the most potent EGFR inhibitor (IC50 = 0.06 μM) and compound 9 as the most potent VEGFR-2 inhibitor (IC50 = 0.22 μM). Moreover, compounds 9 and 12 revealed potent dual EGFR and VEGFR-2 inhibition, and these results were supported by docking studies of these two compounds within the active sites of both enzymes.

Highlights

Cancer is considered a worldwide health risk nowadays
Multicomponent reactions (MCRs), or one-pot reactions in which at least three different substrates join through the covalent bonds, have been of great interest in synthetic organic chemistry due to the efficiency of giving higher overall yields (Musonda et al, 2004; Dekamin et al, 2013a,b; Dekamin and Eslami, 2014; Rotstein et al, 2014; Sudhapriya et al, 2014; Oshiro et al, 2015; Aly, 2016; Aly et al, 2018)
A literature survey reveals that numerous methods were developed for the synthesis of dihydropyrano[2,3-c]pyrazoles (Sudhapriya et al, 2014; Ambethkar et al, 2015; Pati Tripathi et al, 2017)

Summary

Introduction

Cancer is considered a worldwide health risk nowadays. It is the second driving cause of death in the world, and it is anticipated to be the primary cause of death in the upcoming years (Harding et al, 2018). In spite of the indispensable advances accomplished over the last decades in the design and development of assorted anticancer agents, current accessible treatments still have two significant limitations, the primary being the shortage of selectivity for cancer tissues (Shafei et al, 2017), inflicting unwanted side effects (Cavero-Redondo et al, 2015; Brewer et al, 2016; Decalf et al, 2017). Unwanted side effects of anticancer medication can be overcome with agents capable of discriminating tumor cells from normal cells. Hepatocellular carcinoma is taken into account because it is the third most common cancer in males, the seventh in females, and the third most prevalent cause of mortality associated with cancer round the world, and this is why early diagnosis is of great importance (Wen et al, 2019)

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