Development of pyridazine derivatives as potential EGFR inhibitors and apoptosis inducers: Design, synthesis, anticancer evaluation, and molecular modeling studies
Graphical abstract
Introduction
Despite the rapid advance in drug discovery, the lack of effectiveness, safety and selectivity of anticancer drugs currently available remained as the most important unsolved issue [1]. Targeted therapy, a special type of chemotherapy, is a useful method for preventing the growth and spread of cancer cells by targeting specific genes or proteins [2]. Advancing our knowledge of molecular and cellular biology enhances our ability to target specific cancer cell functions [3]. The human epidermal growth factor receptor (EGFR) is a tyrosine kinase (RTK) transmembrane receptor consisting of a single polypeptide chain of 1186 amino acids [4], [5]. This receptor belongs to the receptor family ErbB (human epidermal receptor, HER) which comprises four structurally related members EGFR (ErbB1), ErbB2 (HER2), ErbB3 (HER3) and ErbB4 (HER4) [6]. EGFR and members of its family play crucial roles in controlling many cellular processes including cell migration, survival, and proliferation [7]. EGFR may be triggered aberrantly by mutations or over-expression, leading to cell proliferation, angiogenesis, metastasis, and anti-apoptosis. EGFR is over-expressed in a variety of epidermal cancers including head and neck, chest, prostate, breast, cervical, brain and pancreatic cancers [8], [9], [10]. Considering that EGFR is a rational target for antitumor strategies, one of the most effective methods of inhibiting EGFR is blocking tyrosine kinase by small-molecule inhibitors at the ATP-binding site in the cytoplasmic domain [6].
In recent years, various nitrogen heterocyclic rings have remarkably complex biological properties and belong to one of the most important classes of medicinal chemistry compounds [11]. Pyrazole motif shows many applications in the field of pharmaceutical and medicinal chemistry. They have anti-inflammatory [12], fungistatic [13], analgesic [14], antibacterial [15], and potent antitumor activities [16], [17], [18], [19], [20], [21]. A series of novel compounds containing the pyrazole motifs were reported as potent anticancer agents targeting EGFR tyrosine kinase [22], [23], [24], [25], [26]. Furthermore, pyrazoline nucleus represent an important core for triaryl substituted derivatives such as compound 1 (Fig. 1) that had been reported to exhibit powerful cytotoxic activity against different cancer cell lines [27]. In addition, the strategy of hybridization of pyrazoline core with different heterocyclic nuclei such as thiophene (compound 2) [18] and pyrimidine (compound 3) [17] proved effective in production of potent antiproliferative analogs. Therefore, the pyrazoline ring is an advantageous choice for the synthesis of pharmaceutical compounds with diverse biological activities and good safety profiles [28], [29], [30]. On the other hand, pyridazine is considered a significant group of heterocyclic compounds which contains two adjacent nitrogen atoms. In recent years, there has been an increasing interest in the pyridazine ring system due its diverse biological activities and other beneficial applications [31], [32]. Various pyridazine derivatives have been reported to possess increasing attention in the synthesis and evaluation of their biological properties. This indicates that various substituted pyridazine compounds possess different types of pharmacological activities, such as antidiabetic [33], antimicrobial [34], antihypertensive [35], anti-inflammatory [36], and antiproliferative agents [37], [38], [39], [40]. Pyridazine 4 (Fig. 1) revealed promising cytotoxic activity [41]. A series of novel compounds containing the pyridazine moiety were reported as potent anticancer agents targeting EGFR tyrosine kinase [42]. Finally, from the molecular design point of view, the combination of two pharmacophores into one single molecule represents one of the most important methods that can be used to synthesize new anticancer molecules [43], [44], [45].
This work therefore adopted the hybridization of pyrazoline and pyridazine core with triaryl substitution for the synthesis of a novel pyrazoline/pyridazine hybrids IXa-n, aiming to obtain new promising antiproliferative compounds (Fig. 1). The newly synthesized target compounds were sent to the National Cancer Institute (NCI) for assessment of their anticancer activity. Additionally, the most active candidates have been tested against target EGFR tyrosine kinase inhibition. Also, this study determined annexin V-FITC apoptosis assay. Moreover, the cell cycle activity was detected for the most potent compounds, to get an overview about the possible stage at which the new derivatives could suppress the growth of cancer cells. Furthermore, levels of Bax, Bcl2 and caspase-3 was also determined in this study.
Section snippets
Chemistry
Compound III was prepared via the reaction of acetophenone I with glyoxilic acid II in the presence of hydrazine hydrate [46]. Furthermore, the reaction between phosphorous oxychloride and compound III afford 3-chloropyridazine IV which has been reacted with hydrazine hydrate to obtain V (Scheme 1) [47].
On the other hand, Chalcones derivatives VIIIa-n were prepared by the Claisene Schmidt condensation between acetophenones VIa or VIb and appropriate aldehyde derivatives VII [48], [49], [50],
Chemistry
IR spectra had been measured on a Perkin Elmer-9712 spectrophotometer. Elemental microanalysis was performed at the Micro-analytical Laboratory at Cairo University, Egypt. 1H NMR spectrometer and 13C NMR spectra were measured on Bruker 400 MHz NMR. For the evaluation of mass spectra, a Shimadzu Qp-2010 Plus was used. 6-phenylpyridazines V [46], [47] and Chalcones VIII [48], [49], [50], [51], [52], [53], [54], [55], [56], [57] have been prepared according to the procedures indicated.
Conclusion
New series of pyridazine hybridized with pyrazoline derivatives were designed and synthesized based on targeting EGFR. Preliminarily screening results at NCI, USA showed the sensitivity of Ovarian cancer IGROV1, Breast cancer T-47D, Renal cancer CAKI-1 and UO-31 cell lines to almost all screened compounds. EGFR inhibition for the promising cytotoxic compounds showed that compounds IXn, IXg, IXb and IXl exhibited inhibition effect more than Erlotinib. Also, compounds IXg and IXn showed high cell
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgement
The authors would like to extend their sincere appreciation to Taif University Researchers Supporting Project number (TURSP-2020/56), Taif University, Taif, Saudi Arabia. Authors are thankful to the Developmental Therapeutics Program of the United States, National Cancer Institute for performing the anticancer testing.
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