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Background Several plants have not been investigated for their endophytes, such as the medicinal plant Ficus carica for which anticancer activity has been confirmed. The endophyte Aspergillus neoniger was selected for investigation of its metabolites since it exerted anticancer activities in preliminary screening assays. Results Bioactivity-guided chromatographic fractionation was performed on the endophytic extract and resulted in the identification of asperazine and asperazine A through spectroscopic analysis. Moderate cytotoxicity against HeLa cell lines (CC50 = 18.4 µg mL−1) and moderate antiproliferative effects against HUVEC and K-562 cell lines (GI50 = 31.5 and 24.8 µg mL−1, respectively) were observed for asperazine. Asperazine A on the other hand showed weak cytotoxic activity against HeLa cell lines (CC50 = 34.6 µg mL−1) as well as weak cytostatic activities against HUVEC and K-562 cell lines (GI50 = 40.7 and 50.2 µg mL−1, respectively) while no antimicrobial activity was detected for both compounds. Conclusions These results suggest contribution of A. neoniger to the reported anticancer activity of the host plant and provides a new source of anticancer metabolites with therapeutic potential.

Targeting the EGFR with small-molecule inhibitors is a confirmed valid strategy in cancer therapy. Since the FDA approval of the first EGFR-TKI, erlotinib, great efforts have been devoted to the discovery of new potent inhibitors. Until now, fourteen EGFR small-molecule inhibitors have been globally approved for the treatment of different types of cancers. Although these drugs showed high efficacy in cancer therapy, EGFR mutations have emerged as a big challenge for these drugs. In this review, we focus on the EGFR small-molecule inhibitors that have been approved for clinical uses in cancer therapy. These drugs are classified based on their chemical structures, target kinases, and pharmacological uses. The synthetic routes of these drugs are also discussed. The crystal structures of these drugs with their target kinases are also summarized and their bonding modes and interactions are visualized. Based on their binding interactions with the EGFR, these drugs are also classified into reversible and irreversible inhibitors. The cytotoxicity of these drugs against different types of cancer cell lines is also summarized. In addition, the proposed metabolic pathways and metabolites of the fourteen drugs are discussed, with a primary focus on the active and reactive metabolites. Taken together, this review highlights the syntheses, target kinases, crystal structures, binding interactions, cytotoxicity, and metabolism of the fourteen globally approved EGFR inhibitors. These data should greatly help in the design of new EGFR inhibitors.

In the current study, eight new hybrids of the NSAIDs, ibuprofen and ketoprofen with five pyrrolizine/indolizine derivatives were designed and synthesized. The chemical structures of these hybrids were confirmed by spectral and elemental analyses. The antiproliferative activities of these hybrids (5 μM) was investigated against MCF-7, A549, and HT-29 cancer cell lines using the cell viability assay, MTT assay. The results revealed 4–71% inhibition of the growth of the three cancer cell lines, where 8a,e,f were the most active. In addition, an investigation of the antiproliferative activity of 8a,e,f against MCF-7 cells revealed IC50 values of 7.61, 1.07, and 3.16 μM, respectively. Cell cycle analysis of MCF-7 cells treated with the three hybrids at 5 μM revealed a pro-apoptotic increase in cells at preG1 and cell cycle arrest at the G1 and S phases. In addition, the three hybrids induced early apoptotic events in MCF-7 cells. The results of the molecular docking of the three hybrids into COX-1/2 revealed higher binding free energies than their parent compounds 5a,c and the co-crystallized ligands, ibuprofen and SC-558. The results also indicated higher binding free energies toward COX-2 over COX-1. Moreover, analysis of the binding modes of 8a,e,f into COX-2 revealed partial superposition with the co-crystallized ligand, SC-558 with the formation of essential hydrogen bonds, electrostatic, or hydrophobic interactions with the key amino acid His90 and Arg513. The new hybrids also showed drug-likeness scores in the range of 1.06–2.03 compared to ibuprofen (0.65) and ketoprofen (0.57). These results above indicated that compounds 8a,e,f deserve additional investigation as potential anticancer candidates.

In the current study, we report the synthesis and cytotoxic evaluation of a new series of S-benzo[4,5]thiazolo[2,3-c][1,2,4]triazole-based derivatives 8-12. Cytotoxicity of the new compounds was investigated in A549, MCF-7, and Hep3B cancer cell lines. Among these derivatives, compound 12 bearing an isatin moiety was the most active derivative (IC50 = 2.40-3.53 µM). A mechanistic study of compound 12 was performed using the kinase profiling test to explore its inhibitory activity against 10 types of the oncogenic kinases and the potential activation of caspase 3/7 enzymes. The results revealed that compound 12 showed moderate inhibition of the EGFR and LCK kinases. Moreover, compound 12 also activated caspase-3/7 in A549 cells. The docking study of compound 12 into EGFR ATP-active site revealed that it fits nicely with good binding affinity. Together, the results indicated that compound 12 could serve as a good lead for developing new potential anticancer agents.

Ten new pyridine linked various substituted thiazole hybrids through (hydrazonomethyl)phenoxy-acetamide spacer were synthesized. The synthetic strategy was based on the reaction of the precursor 2-(4-((2-carbamothioylhydrazono)methyl)phenoxy)-N-(pyridin-2-yl)acetamide (3) with various α-halogenated carbonyl compounds (namely; phenacyl bromides, ethyl bromoacetate, diethyl bromomalonate and 3-chloropentane-2,4-dione). Moreover, the cytotoxicity properties of the synthesized compounds have been studied against liver carcinoma (HepG2), laryngeal carcinoma (Hep-2), prostate cancer (PC3), breast cancer (MCF-7) and normal fibroblast cells (WI38). The pyridine-thiazole compounds 7 and 10 revealed promising anticancer activity against MCF-7 and HepG2 cell lines with IC50 values in the range 5.36–8.76 μM compared to the activity of 5-fluorouracil. Docking study provided valuable insights for binding sites of the synthesized compounds with Rho-associated protein kinase (ROCK-1).

A novel set of S-benzo[4,5]thiazolo[2,3-c][1,2,4]triazoles was synthesized. Cytotoxicity of these compounds was evaluated against three cancer cell lines of different origins, Hep3B, A549, and MCF-7. Three of these compounds were screened by NCI for growth inhibitory activities against 60 cancer cell lines. The results revealed significant cytotoxic activities for compounds 13a-i. Among these derivatives, compounds 13c and 13f-13i exhibited the highest cytotoxicity against the selected cancer cell lines with IC50 values between 3.17 and 14.18 μM. The structure-activity relationship of compounds 13a-i indicated favorable cytotoxic results on the expansion of the cyclic amine and the substitution with aminothiazole moiety. A mechanistic study revealed the activation of caspase-3/7 in A549 cells on treatment with compounds 13f-i at 5–20 μM. Moreover, the results of flow cytometric analysis suggested that compound 13i efficiently induced apoptosis in a dose-dependent manner. Compounds 13f,g,i also exhibited a weak to moderate inhibition of multiple kinases where compound 13i was the most active in inhibiting the activity of CDK2/Cyclin A1 (IC50 = 4.65 μM). The current work provided a novel set of compounds with cytotoxic, kinase inhibition, and apoptosis-inducing activities, which can serve as a lead for further optimization.