Exploration of cytotoxicity of iodoquinazoline derivatives as inhibitors of both VEGFR-2 and EGFRT790M: Molecular docking, ADMET, design, and syntheses.

Novel inhibitors of epidermal growth factor receptor (EGFR)T790M/vascular endothelial growth factor receptor-2 (VEGFR-2) were synthesized based on the iodoquinazoline scaffold linked to different heteroaromatic, aromatic, and/or aliphatic moieties. The novel derivatives were in vitro examined for anticancer activities against A549, HCT116, michigan cancer foundation-7 (MCF-7), and HepG2 cells. Molecular modeling was applied to discover their orientation of binding with both VEGFR-2 and EGFR active sites. Compounds 8d, 8c, 6d, and 6c indicated the highest cytotoxicity with IC50 = 6.00, 6.90, 6.12 and 6.24 µM, 7.05, 7.35, 6.80, and 6.80 µM, 5.75, 7.50, 6.90, and 6.95 µM, and 6.55, 7.88, 7.44, and 7.10 µM against the A549, HepG2, HCT116, and MCF-7 cell lines, correspondingly. The cytotoxicity against normal VERO (normal african green monkey kidney cells) of the extremely active eight compounds 6a-d and 8a-d was evaluated. Our compounds exhibited low toxicity concerning normal VERO cells with IC50 = 45.66-51.83 µM. Furthermore, inhibition assays for both the EGFRT790M and VEGFR-2 enzymes were done for all compounds. Remarkable inhibition of EGFRT790M activity was achieved with compounds 6d, 8d, 6c, and 8c at IC50 = 0.35, 0.42, 0.48, and 0.50 µM correspondingly. Moreover, remarkable inhibition of VEGFR-2 activity was achieved with compounds 8d, 8c, 6d, and 6c at IC50 = 0.92, 0.95, 1.00, and 1.20 µM correspondingly. As planned, derivatives 6d, 8d, 6c, and 8c presented exceptional inhibition of both EGFRT790M/VEGFR-2 activities. Finally, in silico absorption, distribution, metabolism, excretion and toxicity (ADMET) studies were made for the highly active four compounds 6c, 6d, 8c, and 8d in comparison with erlotinib and sorafenib as reference standards.

Hepatic stearoyl-CoA desaturase-1 deficiency induces fibrosis and hepatocellular carcinoma-related gene activation under a high carbohydrate low fat diet.

Stearoyl-CoA desaturase-1 (SCD1) is a pivotal enzyme in lipogenesis, which catalyzes the synthesis of monounsaturated fatty acids (MUFA) from saturated fatty acids, whose ablation downregulates lipid synthesis, preventing steatosis and obesity. Yet deletion of SCD1 promotes hepatic inflammation and endoplasmic reticulum stress, raising the question of whether hepatic SCD1 deficiency promotes further liver damage, including fibrosis. To delineate whether SCD1 deficiency predisposes the liver to fibrosis, cirrhosis, and hepatocellular carcinoma (HCC), we employed in vivo SCD1 deficient global and liver-specific mouse models fed a high carbohydrate low-fat diet and in vitro established AML12 mouse cells. The absence of liver SCD1 remarkably increased the saturation of liver lipid species, as indicated by lipidomic analysis, and led to hepatic fibrosis. Consistently, SCD1 deficiency promoted hepatic gene expression related to fibrosis, cirrhosis, and HCC. Deletion of SCD1 increased the circulating levels of Osteopontin, known to be increased in fibrosis, and alpha-fetoprotein, often used as an early marker and a prognostic marker for patients with HCC. De novo lipogenesis or dietary supplementation of oleate, an SCD1-generated MUFA, restored the gene expression related to fibrosis, cirrhosis, and HCC. Although SCD1 deficient mice are protected against obesity and fatty liver, our results show that MUFA deprivation results in liver injury, including fibrosis, thus providing novel insights between MUFA insufficiency and pathways leading to fibrosis, cirrhosis, and HCC under lean non-steatotic conditions.

Anticancer evaluations of iodoquinazoline substituted with allyl and/or benzyl as dual inhibitors of EGFRWT and EGFRT790M: design, synthesis, ADMET and molecular docking.

Fifteen new iodoquinazoline derivatives, 5a,b to 18, are reported in this study and their anticancer evaluation as dual inhibitors of EGFRWT and EGFRT790M. The new derivatives were designed according to the target of structural requirements of receptors. Cytotoxicity of our compounds was evaluated against MCF-7, A549, HCT116 and HepG2 cell lines using MTT assay. Compounds 18, 17 and 14b showed the highest anticancer effects with IC50 = 5.25, 6.46, 5.68 and 5.24 µM, 5.55, 6.85, 5.40 and 5.11 µM and 5.86, 7.03, 6.15 and 5.77 µM against HepG2, MCF-7, HCT116 and A549 cell lines, respectively. The eight highly effective compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 were inspected against VERO normal cell lines to evaluate their cytotoxicity. Our conclusion was that compounds 10, 13, 14a, 14b, 15, 16, 17 and 18 possessed low toxicity against VERO normal cells with IC50 increasing from 43.44 to 52.11 µM. All compounds were additionally assessed for their EGFRWT and EGFRT790M inhibitory activities. Additionally, their ability to bind with EGFRWT and EGFR receptors was confirmed by molecular docking. Compound 17 exhibited the same inhibitory activity as erlotinib. Compounds 10, 13, 14b, 16 and 18 excellently inhibited VEGFR-2 activity with IC50 ranging from 0.17 to 0.50 µM. Moreover, compounds 18, 17, 14b and 16 remarkably inhibited EGFRT790M activity with IC50 = 0.25, 0.30, 0.36 and 0.40 µM respectively. As planned, compounds 18, 17 and 14b showed excellent dual EGFRWT/EGFRT790M inhibitory activities. Finally, our compounds 18, 17 and 14b displayed good in silico ADMET calculated profiles.

N- and s-substituted Pyrazolopyrimidines: A promising new class of potent c-Src kinase inhibitors with prominent antitumor activity.

In this work, readily achievable synthetic pathways were utilized for construction of a library of N/S analogues based on the pyrazolopyrimidine scaffold with terminal alkyl or aryl fragments. Subsequently, we evaluated the anticancer effects of these novel analogs against the proliferation of various cancer cell lines, including breast, colon, and liver lines. The results were striking, most of the tested molecules exhibited strong and selective cytotoxic activity against the MDA-MB-231 cancer cell line; IC50 1.13 µM. Structure-activity relationship (SAR) analysis revealed that N-substituted derivatives generally enhanced the cytotoxic effect, particularly with aliphatic side chains that facilitated favorable target interactions. We also investigated apoptosis, DNA fragmentation, invasion assay, and anti-migration effects, and discussed their underlying molecular mechanisms for the most active compound 7c. We demonstrated that 7c N-propyl analogue could inhibit MDA-MB-231 TNBC cell proliferation by inducing apoptosis through the regulation of vital proteins, namely c-Src, p53, and Bax. In addition, our results also revealed the potential of these compounds against tumor metastasis by downregulating the invasion and migration modes. Moreover, the in vitro inhibitory effect of active analogs against c-Src kinase was studied and proved that might be the main cause of their antiproliferative effect. Overall, these compelling results point towards the therapeutic potential of these derivatives, particularly those with N-substitution as promising candidates for the treatment of TNBC type of breast cancer.

Retraction: Large Pleural Lipoma Manifesting With Chronic Shoulder Pain.

[This retracts the article DOI: 10.7759/cureus.21113.].

Iodoquinazoline-derived VEGFR-2 and EGFRT790M dual inhibitors: Design, synthesis, molecular docking and anticancer evaluations.

Herein, we report the synthesis of a series of new fourteen iodoquinazoline derivatives 7a-c to 13a-e and their evaluation as potential anticancer agents via dual targeting of EGFRT790M and VEGFR-2. The new derivatives were designed according to the target receptors structural requirements. The compounds were evaluated for their cytotoxicity against HepG2, MCF-7, HCT116 and A549 cancer cell lines using MTT assay. Compound 13e showed the highest anticancer activities with IC50 = 5.70, 7.15, 5.76 and 6.50 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Compounds 7c, 9b and 13a-d exhibited very good anticancer effects against the tested cancer cell lines. The highly effective six derivatives 7c, 10, 13b, 13c, 13d and 13e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Our conclusion revealed that compounds 7c, 10, 13b, 13c, 13d and 13e possessed low toxicity against VERO normal cells with IC50 prolonging from 41.66 to 53.99 µM. Also compounds 7a-c to 13a-e were further evaluated for their inhibitory activity against EGFRT790M and VEGFR-2. Also, their ability to bind with both EGFR and VEGFR-2 receptors was examined by molecular modeling. Compounds 13e, 13d, 7c and 13c excellently inhibited VEGFR-2 activity with IC50 = 0.90, 1.00, 1.25 and 1.50 µM respectively. Moreover, Compounds 13e, 7c, 10 and 13d excellently inhibited EGFRT790M activity with IC50 = 0.30, 0.35, 0.45 and 0.47 µM respectively. Finally, our derivatives 7b, 13d and 13e showed good in silico calculated ADMET profile.

Design, synthesis, docking, ADMET and anticancer evaluations of N-alkyl substituted iodoquinazoline derivatives as dual VEGFR-2 and EGFR inhibitors.

Fifteen new 1-alkyl-6-iodoquinazoline derivatives 5a-d to 9a-e were designed and synthesized and their anticancer activities were evaluated against HepG2, MCF-7, HCT116 and A549 cancer cell lines via dual targeting of EGFR and VEGFR-2. The newly synthesized compounds were designed based on the structure requirements of the target receptors and were confirmed using spectral data. Compound 9c showed the highest anticancer activities with EC50 = 5.00, 6.00, 5.17 and 5.25 µM against HepG2, MCF-7, HCT116 and A549 cell lines correspondingly. Moreover, compounds 5d, 8b, 9a, 9b, 9d, and 9e exhibited very good anticancer effects against the tested cancer cell lines. The highly effective seven derivatives 5d, 8b, 9a-e were examined against VERO normal cell lines to estimate their cytotoxic capabilities. Compounds 9c, 9b, 9d, 9a, 9e and 5d excellently inhibited VEGFR-2 activity with IC50 = 0.85, 0.90, 0.90, 1.00, 1.20 and 1.25 µM respectively. Moreover, compounds 9c, 9d, 9e, 5d, 8b and 9b excellently inhibited EGFRT790M activity with IC50 = 0.22, 0.26, 0.30, 0.40, 0.45 and 0.50 µM respectively. Also, compounds 9c, 9d and 9e excellently inhibited EGFRWT activity with IC50 = 0.15, 0.20 and 0.25 µM respectively. As planned, compound 9c showed excellent dual EGFR/VEGFR-2 inhibitory activities. Consonantly, ADMET study was calculated in silico for the supreme three worthwhile compounds 9b, 9c and 9e in contrast to sorafenib and erlotinib as reference drugs. The obtained results concluded that, our compounds might be useful as prototype for design, optimization, adaptation and investigation to have more powerful and selective dual VEGFR-2/EGFRT790M inhibitors with higher antitumor activity.

Development of Novel Class of Phenylpyrazolo[3,4-d]pyrimidine-Based Analogs with Potent Anticancer Activity and Multitarget Enzyme Inhibition Supported by Docking Studies.

Phenylpyrazolo[3,4-d]pyrimidine is considered a milestone scaffold known to possess various biological activities such as antiparasitic, antifungal, antimicrobial, and antiproliferative activities. In addition, the urgent need for selective and potent novel anticancer agents represents a major route in the drug discovery process. Herein, new aryl analogs were synthesized and evaluated for their anticancer effects on a panel of cancer cell lines: MCF-7, HCT116, and HePG-2. Some of these compounds showed potent cytotoxicity, with variable degrees of potency and cell line selectivity in antiproliferative assays with low resistance. As the analogs carry the pyrazolopyrimidine scaffold, which looks structurally very similar to tyrosine and receptor kinase inhibitors, the potent compounds were evaluated for their inhibitory effects on three essential cancer targets: EGFRWT, EGFRT790M, VGFR2, and Top-II. The data obtained revealed that most of these compounds were potent, with variable degrees of target selectivity and dual EGFR/VGFR2 inhibitors at the IC50 value range, i.e., 0.3-24 µM. Among these, compound 5i was the most potent non-selective dual EGFR/VGFR2 inhibitor, with inhibitory concentrations of 0.3 and 7.60 µM, respectively. When 5i was tested in an MCF-7 model, it effectively inhibited tumor growth, strongly induced cancer cell apoptosis, inhibited cell migration, and suppressed cell cycle progression leading to DNA fragmentation. Molecular docking studies were performed to explore the binding mode and mechanism of such compounds on protein targets and mapped with reference ligands. The results of our studies indicate that the newly discovered phenylpyrazolo[3,4-d]pyrimidine-based multitarget inhibitors have significant potential for anticancer treatment.

Modulation of NRF2/KEAP1-Mediated Oxidative Stress for Cancer Treatment by Natural Products Using Pharmacophore-Based Screening, Molecular Docking, and Molecular Dynamics Studies.

Oxidative stress plays a significant role in the development of cancer. Inhibiting the protein-protein interaction (PPI) between Keap1 and Nrf2 offers a promising strategy to activate the Nrf2 antioxidant pathway, which is normally suppressed by the binding of Keap1 to Nrf2. This study aimed to identify natural compounds capable of targeting the kelch domain of KEAP1 using structure-based drug design methods. A pharmacophore model was constructed based on the KEAP1-inhibitor complex, leading to the selection of 6178 compounds that matched the model. Subsequently, docking and MM/GBSA analyses were conducted, resulting in the identification of 10 compounds with superior binding energies compared to the reference compound. From these, three compounds (ZINC000002123788, ZINC000002111341, and ZINC000002125904) were chosen for further investigation. Ligand-residue interaction analysis revealed specific interactions between these compounds and key residues, indicating their stability within the binding site. ADMET analysis confirmed that the selected compounds possessed desirable drug-like properties. Furthermore, molecular dynamics simulations were performed, demonstrating the stability of the ligand-protein complexes over a 100 ns duration. These findings underscore the potential of the selected natural compounds as agents targeting KEAP1 and provide valuable insights for future experimental studies.

Hepatic oleate regulates one-carbon metabolism during high carbohydrate feeding.

Obesity is a major risk factor for type 2 diabetes, coronary heart disease, and strok. These diseases are associated with profound alterations in gene expression in metabolic tissues. Epigenetic-mediated regulation of gene expression is one mechanism through which environmental factors, such as diet, modify gene expression and disease predisposition. However, epigenetic control of gene expression in obesity and insulin resistance is not fully characterized. We discovered that liver-specific stearoyl-CoA desaturase-1 (Scd1) knockout mice (LKO) fed a high-carbohydrate low-fat diet exhibit dramatic changes in hepatic gene expression and metabolites of the folate cycle and one-carbon metabolism respectively for the synthesis of S-adenosylmethionine (SAM). LKO mice show an increased ratio of S-adenosylmethionine to S-adenosylhomocysteine, a marker for increased cellular methylation capacity. Furthermore, expression of DNA and histone methyltransferase genes is up-regulated while the mRNA and protein levels of the non-DNA methyltransferases including phosphatidylethanolamine methyltransferase (PEMT), Betaine homocysteine methyltransferase (Bhmt), and the SAM-utilizing enzymes such as glycine-N-methyltransferase (Gnmt) and guanidinoacetate methyltransferase (Gamt) are generally down-regulated. Feeding LKO mice a high carbohydrate diet supplemented with triolein, but not tristearin, and increased endogenous hepatic synthesis of oleate but not palmitoleate in Scd1 global knockout mice normalized one carbon gene expression and metabolite levels. Additionally, changes in one carbon gene expression are independent of the PGC-1α-mediated ER stress response previously reported in the LKO mice. Together, these results highlight the important role of oleate in maintaining one-carbon cycle homeostasis and point to observed changes in one-carbon metabolism as a novel mediator of the Scd1 deficiency-induced liver phenotype.

Cytological Changes and Immunocytochemistry Expression of P53 in Oral Mucosa Among Waterpipe Users in the Kingdom of Saudi Arabia.

Objective In this study, we aimed to assess cytological changes and p53 expression in oral mucosa among waterpipe users in the Kingdom of Saudi Arabia (KSA). Methodology A case-control study was conducted in KSA from January to October 2022. Two cytologic oral smear samples each were taken from 500 volunteers; 300 were waterpipe users (case) while 200 did not use a waterpipe (control). They were then stained using the Papanicolaou staining procedure and immunocytochemical method to show the expression of P53. Results The interpretation of the Papanicolaou staining outcomes showed the presence of four results with different proportions: inflammation, infection, atypia, and keratinization. Cytological inflammation was identified among 77/300 (25.6%) waterpipe smokers, which was higher than that among non-users (12/200, 6%). The reverse cytological infection and atypia were also higher in waterpipe smokers compared with controls (9% vs. 4.5% and 4.3% vs. 0.5%, respectively), and keratinization was detected only in waterpipe users (3.6%) compared with controls. Waterpipe users had higher p53 protein expression than non-users. Conclusion Using a waterpipe is an effective way to change the oral mucosa. In atypia and keratinization, there was high p53 expression. These results could indicate that p53 is involved in both the change from normal to cancerous cells and the growth of new cells, but the presence or absence of p53 staining could not be used to predict the outcome of potentially cancerous oral mucosal lesions.

Large Pleural Lipoma Manifesting With Chronic Shoulder Pain.

Musculoskeletal symptoms related to orthopedic conditions are highly prevalent worldwide and are a leading cause of morbidity. However, non-orthopedic conditions may also present with musculoskeletal symptoms. For example, shoulder pain may be caused by gastrointestinal, hepatobiliary, cardiac, and neurological pathologies. We report the case of a 32-year-old man who presented to the orthopedic clinic with a complaint of left shoulder pain for the past three months. He described the pain as sharp in nature. The pain was constant and was not related to the shoulder movements. It was not associated with morning stiffness. He had no history of preceding trauma. On examination, both shoulders were symmetrical with no evidence of deformities. Palpation over the shoulder region did not elicit any tenderness. The range of motion in both the active and passive movements was intact. The Neer and Jobe tests were negative. Also, the sensory examination was intact, and laboratory findings were normal. The patient underwent a plain frontal radiograph of the chest, which revealed a large well-circumscribed lobulated mass lesion in the left hemithorax, arising from the pleural lining. A thoracic CT scan was then performed to provide further characterization of the mass lesion and it re-demonstrated the mass as having homogeneous fat-attenuation with thin septations, probably representing pleural lipoma. The tumor was successfully resected via open thoracotomy. The patient's symptoms resolved and he had no recurrence after one year of follow-up. Pleural lipoma is a very rare benign mesenchymal tumor. The case highlights the importance of considering non-orthopedic conditions in the differential diagnosis of shoulder pain in patients with normal physical examination findings. A CT scan is vital to make the diagnosis and can show the accurate anatomic relations with respect to the tumor for surgical planning.

Identification of Novel Benzoxa-[2,1,3]-diazole Substituted Amino Acid Hydrazides as Potential Anti-Tubercular Agents.

Discovery and development of new therapeutic options for the treatment of Mycobacterium tuberculosis (Mtb) infection are desperately needed to tackle the continuing global burden of this disease and the efficacy and cost limitations associated with current medicines. Herein, we report the synthesis of a series of novel benzoxa-[2,1,3]-diazole substituted amino acid hydrazides in a two-step synthesis and evaluate their inhibitory activity against Mtb and selected bacterial strains of clinical importance utilising an end point-determined REMA assay. Alongside this, their potential for undesired cytotoxicity against mammalian cells was assessed employing standard MTT assay methodologies. It has been demonstrated using modification at three sites (the hydrazine, amino acid, and the benzodiazole) it is possible to change both the antibacterial activity and cytotoxicity of these molecules whilst not affecting their microbial selectivity, making them attractive architectures for further exploitation as novel antibacterial agents.

Ousting RAGE in melanoma: A viable therapeutic target?

Melanoma remains an important health concern, given the steady increase in incidence and acquisition of resistance to systemic therapies. The receptor for advanced glycation end products (RAGE) initially identified for its binding to advanced glycation end products was subsequently acknowledged as a pattern recognition receptor given its ability to recognize similar structural elements within numerous ligands. Recent studies have elucidated a plausible role of RAGE in melanoma progression through modulation of inflammatory, proliferative and invasive cellular responses. Several of its ligands including the S100 proteins and HMGB1 are being investigated for their involvement in melanoma metastasis and as potential biomarkers of the disease. Targeting RAGE signaling represents a viable therapeutic strategy which remains underexplored in cutaneous malignancies. Here we have summarized current knowledge on the functionality of RAGE with special focus on specific ligands enumerated in various in vitro and in vivo melanoma models.