Mohamed N. El-Bayaa

The growth of a tumor and the development of metastases are facilitated by tumor angiogenesis, and vascular endothelial growth factor receptor 2 (VEGFR-2) plays an essential role in the process of angiogenesis. Receptor tyrosine kinases involved in the process of angiogenesis have become the primary focus of anticancer drug design. This review focuses on the role of VEGFR-2 in breast, lung, and colorectal cancers; solid and hematologic tumors; and leukemia. In addition, it provides a summary of recent findings regarding the medicinal chemistry of VEGFR-2 inhibitors. This review is organized by ten heterocyclic scaffolds, including imidazole, quinazoline, pyridine, pyrimidine, indole, purine, indazole, quinoline, quinoxaline, and triazole, and outlines SAR and pharmacophore contributions. The ten most active compounds were evaluated using docking. The results of this evaluation showed that most of the identified compounds were more active than sorafenib in displacing the DFG motif and the hydrophobic binding pocket and interacting with the hydrophobic binding pocket rather than the typical hinge-region bond. The last section of this review outlines some possible approaches to develop new, more selective and clinically relevant VEGFR-2 inhibitors. These approaches include the use of mutant-specific inhibitors and structure-based design in combination with molecular hybridization.

1. There are serious risks associated with numerous human diseases such as diabetes, Alzheimer’s disease and inflammation, that are rationalized with each other as a result of different driving fac...

The discovery of novel compounds as potential cancer drug candidates has garnered significant interest and widespread attention. A novel series of benzimidazole-1,2,3-triazole-pyridine-glycosyl hybrids was rationally designed and synthesized to explore their potential anticancer activity. The targeted compounds were achieved via click chemistry. The acetylated N¹-glycosyl-1,2,3-triazoles were deprotected, producing the free hydroxy glycosides. Their cytotoxicity was evaluated against human colorectal (HCT-116), hepatic (HepG-2), and breast (MCF-7) cancers. Molecular docking and dynamics, in addition to Density functional theory (DFT) calculations, were studied. Glycosyl-1,2,3-triazoles 15 and 17 exhibited the highest cytotoxic activity among the tested compounds, while others demonstrated selective efficacy against specific cancer cell lines. Notably, compound 17 showed a 1.808-fold increase in cytotoxicity compared to doxorubicin when tested on MCF-7 breast cancer cells (IC₅₀ = 33.32 µM). Molecular docking studies with the epidermal growth factor receptor (EGFR) indicated favorable-binding interactions and potential inhibitory effects. Molecular dynamics further confirmed the stable integration of 17 within the EGFR active site, preserving the structural integrity of its catalytic domain. DFT calculations provided insights into the electronic structure, molecular orbitals, and electrostatic potential of compound 17.

A series of novel functionalized pyrazolopyridine derivatives bearing arylidene side chains was synthesized through efficient heterocyclization methods. Additionally, alkyl‐substituted imidazo‐pyrazolopyridine (tetraazacyclopenta[ a ]indene) compounds and tetracyclic pyrazolopyridine–imidazopyrimidine hybrids (pentaazaindeno[1,2‐ a ]inden‐2‐one) were prepared. The cytotoxicity of these compounds was assessed against human colorectal (HCT‐116) and breast (MCF‐7) cancer cell lines, revealing that compounds 9 and 16 have exhibited the most potent activity. Other derivatives showed selective cytotoxic effects toward one of the two cell lines. Molecular docking studies were conducted to explore the binding interactions of compounds 9 and 16 within the active site of EGFR (epidermal growth factor receptor). To further investigate the binding stability of compound 16 , molecular dynamics (MD) simulations were performed using EGFR (PDB ID: 1M17), providing insight into the stability and structural integrity of the protein‐ligand complex. Additionally, density functional theory (DFT) analysis was carried out to examine the electronic structure of compound 16 , including its molecular orbitals and electrostatic potential. The HOMO–LUMO analysis supported the compound's electron‐donating properties, aligning with its strong binding affinity and cytotoxic performance observed in the docking and MD studies.

New pyridine-O-glycosides and their acyclic nucleoside analogues were prepared by heterocyclization and glycosylation. The anticancer activity against HCT-116, HepG2 and MCF-7 human cancer cells and BJ-1 cell revealed that the galacto- and xylopyranosyl glycosides possessing 4-bromophenyl have superior cytotoxic activities against HepG2 cell while glycosides 7-9 resulted in superior cytotoxic activities regarding MCF-7 breast cell. In case of HCT-116 colorectal carcinoma cells, two products and the derived glycosides and acyclic analogues showed potent activities. The most potent compounds were investigated for their possible binding affinities to the active site of CDK2 enzyme via in silico molecular docking simulation in addition to computational studies. The results support the antiproliferative effect and elucidate the interactions of 3a and 8 with catalytic sites.

New 1,3,4-thiadiazole thioglycosides linked to a substituted arylidine system were synthesized via heterocyclization via click 1,3-dipolar cycloaddition. The click strategy was used for the synthesis of new 1,3,4-thiadiazole and 1,2,3-triazole hybrid glycoside-based indolyl systems as novel hybrid molecules by reacting azide derivatives with the corresponding acetylated glycosyl terminal acetylenes. The cytotoxic activities of the compounds were studied against HCT-116 (human colorectal carcinoma) and MCF-7 (human breast adenocarcinoma) cell lines using the MTT assay. The results showed that the key thiadiazolethione compounds, the triazole glycosides linked to p-methoxyarylidine derivatives and the free hydroxyl glycoside had potent activity comparable to the reference drug, doxorubicin, against MCF-7 human cancer cells. Docking simulation studies were performed to check the binding patterns of the synthesized compounds. Enzyme inhibition assay studies were also conducted for the epidermal growth factor receptor (EGFR), and the results explained the activity of a number of derivatives.

New Furan, 1,3,4-thiadiazole and 1,2,4-triazole hybrid compounds and their 1,3,4-oxadiazole hybrid derivatives were synthesized. The thioglycoside derivatives of the synthesized hybrid compounds were synthesized via glycosylation of the triazole-5-thione and 1,3,4-oxadiazole-5-thione derivatives. The hydrazinyl sugar derivative of the thiadiazole system and hydroxyalkylamino derivative of the 1,2,4-triazole compound were also prepared. The cytotoxic activities of the synthesized compounds were studied against MCF-7 (human breast adenocarcinoma) cancer cell and RPE-1 (human normal Retina pigmented epithelium) cell lines using the MTT assay. The obtained results showed that a number of the synthesized compounds revealed good activities comparable to that observed for the reference drug doxorubicin against the MCF-7 cancer cell lines.

Background & Objective: Glycosyl heterocycles, being as nucleoside analogs with modified glycon and hybrid heterocycle motifs, are of considerable interest, and thus, the targeted compounds were synthesized via a convenient and efficient approach. Methods: New indolyl-thiadiazolyl thioglycosides scaffolds were synthesized, starting with the reaction of indole-3-carbaldehyde with 2-aminothiadiazole-5-thiole followed by glycosylation and deprotection. Likewise, new molecular hybrids comprising indole, thiadiazole, triazole and glycosyl moieties were synthesized utilizing click chemistry strategy. The cytotoxic activities of the newly synthesized compounds were studied on colon carcinoma HCT116, breast carcinoma MCF-7, lung carcinoma A549 and hepatocellular carcinoma HepG2 cell lines using Sulphorhodamine-B (SRB) assay. Results: The 1,3,4-thiadiazole thioglycoside and the 1,2,3-triazole N¹-glycoside possessing xylose moiety, compounds 8 and 15 revealed the most potent bio-activity among the new chemical entities; therefore, they undertook for further analysis of apoptosis. Conclusion: IC₅₀s of Compound 8 were 38, 36, 33 and 158μg/ml, while they were 41, 44, 32 and 25μg/ml for compound 15 on HepG2, MCF7, HCT116 and A549 cell lines, respectively; furthermore, the total apoptosis rate (%) for control untreated cells were 9.63, 28.4, 25.4 (%), compounds 8 and 15 respectively, they produced a significant increase in total and early apoptosis rate (%) compared to control (P=0.0001). At the same time, no significant difference was detected in the late apoptosis rate (%), which means that both derivatives have the potential to be developed into potent anticancer agents.

New sugar hydrazones and their derived oxadiazolyl acyclic nucleoside analogs in addition to the derived thioglycosides incorporating pyridine, furan or thiophene have been synthesized via a multi-component reaction (MCR). The acetylated derivatives of hydrazones and the derived deprotected thioglycosides of the prepared acetylated analogs have been also synthesized. Anticancer activity of the products has been tested against adenocarcinomic human alveolar basal epithelial (A549), human prostatic adenocarcinoma (PC3) and human colorectal carcinoma (HCT116) cell lines in addition to their effect on human normal retinal pigmented epithelial cell line (RPE1) using the MTT assay. Three products: acid hydrazide, sugar hydrazine and glycoside are characterized by high activity against three cancer cell lines.