Synthesis, bioactivity assessment, molecular docking and ADMET studies of new chromone congeners exhibiting potent anticancer activity.

In consideration of the chromones' therapeutic potential and anticancer activity, a new series of chromanone derivatives have been synthesized through a straightforward reaction between 6-formyl-7-hydroxy-5-methoxy-2-methylchromone (2) and various organic active compounds. The cytotoxic activity of the newly synthesized congeners was investigated against MCF-7 (human breast cancer), HCT-116 (colon cancer), HepG2 (liver cancer), and normal skin fibroblast cells (BJ1). The obtained data indicated that compounds 14b, 17, and 19 induce cytotoxic activity in the breast MCF7, while compounds 6a, 6b, 11 and 14c showed highly potent activity in the colon cancer cell lines. Overall, the results demonstrate that the potential cytotoxic effects of the studied compounds may be based on their ability to induce DNA fragmentation in cancer cell lines, down-regulate the expression level of CDK4 as well as the anti-apoptotic gene Bcl-2 and up-regulate the expression of the pro-apoptotic genes P53 and Bax. Furthermore, compounds 14b and 14c showed a dual mechanism of action by inducing apoptosis and cell cycle arrest. The docking studies showed that the binding affinity of the most active cytotoxic compounds within the active pocket of the CDK4 enzyme is stronger due to hydrophobic and H-bonding interactions. These results were found to be consistent with the experimental results.

Multi-decadal coastal change detection using remote sensing: the Mediterranean coast of Egypt between El-Dabaa and Ras El-Hekma.

A key source of information for many decision support systems is identifying land use and land cover (LULC) based on remote sensing data. Land conservation, sustainable development, and water resource management all benefit from the knowledge obtained from detecting changes in land use and land cover. The present study aims to investigate the multi-decadal coastal change detection for Ras El-Hekma and El-Dabaa area along the Mediterranean coast of Egypt, a multi-sectoral development area. Besides, the superiority of the area is highly dependent on its proximity to three development projects: the tourism and urban growth pole at Ras El-Hekma, the beachfront Alamain New Mega City, and the Nuclear Power Plant at El Dabaa. This study utilized multi-spectral Landsat satellite images covering 1990, 2010, and 2020 to perceive the post-classification change detection analysis of the land use and land cover changes (LULCC) over 30 years. The results of the supervised classification from 1990 to 2020 showed a 47.33 km2 (4.13%) expansion of the agricultural land area, whereas the bare soil land area shrunk to 73.13 km2 (6.24%). On the other hand, the built-up activities in the area launched in 2010 and escalated to 20.51 km2(1.77%) in 2020. The change in land use reveals the shift in the economic growth pattern in the last decade toward tourism and urban development. Meanwhile, it indicates that no conflict has yet arisen regarding the land use between the expanded socioeconomic main sectors (i.e., agriculture, and tourism). Therefore, the best practices of land use management and active participation of the stakeholders and the local community should be enhanced to achieve sustainability and avoid future conflicts. An area-specific plan including resource conservation measures and the provision of livelihood alternatives should be formulated within the National Integrated Coastal Zone Management (ICZM) plan with the participation of the main stakeholders and beneficiaries. The findings of the present work may be considered useful for sustainable management and supportive to the decision-making process for the sustainable development of this area.

Camptothecin structure simplification elaborated new imidazo[2,1-b]quinazoline derivative as a human topoisomerase I inhibitor with efficacy against bone cancer cells and colon adenocarcinoma.

Camptothecin is a pentacyclic natural alkaloid that inhibits the hTop1 enzyme involved in DNA transcription and cancer cell growth. Camptothecin structure pitfalls prompted us to design new congeners using a structure simplification strategy to reduce the ring extension number from pentacyclic to tetracyclic while maintaining potential stacking of the new compounds with the DNA base pairs at the Top1-mediated cleavage complex and aqueous solubility, as well as minimizing compound-liver toxicity. The principal axis of this study was the verification of hTop1 inhibiting activity as a possible mechanism of action and the elaboration of new simplified inhibitors with improved pharmacodynamic and pharmacokinetic profiling using three structure panels (A-C) of (isoquinolinoimidazoquinazoline), (imidazoquinazoline), and (imidazoisoquinoline), respectively. DNA relaxation assay identified five compounds as hTop1 inhibitors belonging to the imidazoisoquinolines 3a,b, the imidazoquinazolines 12, and the isoquinolinoimidazoquinazolines 7a,b. In an MTT cytotoxicity assay against different cancer cell lines, compound 12 was the most potent against HOS bone cancer cells (IC50 = 1.47 µM). At the same time, the other inhibitors had no detectable activity against any cancer cell type. Compound (12) demonstrated great penetrating power in the HOS cancer cells' 3D-multicellular tumor spheroid model. Bioinformatics research of the hTop1 gene revealed that the TP53 cell proliferative gene is in the network of hTop1. The finding is confirmed empirically using the gene expression assay that proved the increase in p53 expression. The impact of structure simplification on compound 12 profile, characterized by the absence of acute oral liver toxicity when compared to Doxorubicin as a standard inhibitor, the lethal dose measured on Swiss Albino female mice and reported at LD50 = 250 mg/kg, and therapeutic significance in reducing colon adenocarcinoma tumor volume by 75.36 % after five weeks of treatment with compound 12. The molecular docking solutions of the active CPT-based derivative 12 and the inactive congener 14 into the active site of hTop1 and the activity cliffing of such MMP directed us to recommend the addition of HBD and HBA variables to compound 12 imidazoquinazoline core scaffold to enhance the potency via hydrogen bond formation with the major groove amino acids (Asp533, Lys532) as well as maintaining the hydrogen bond with the minor groove amino acid Arg364.

Association between single nucleotide polymorphism of human angiotensin-converting enzyme 2 gene locus and clinical severity of COVID-19.

Background: Coronavirus disease 2019 (COVID-19) is a devastating pandemic-causing disease with a variable severity among populations. Genetic studies have pinpointed angiotensin-converting enzyme 2 (ACE2), a key enzyme for viral entry, for its possible linkage to the disease progression. The present study aimed to investigate the potential association between single nucleotide polymorphisms (SNPs) of human ACE2 gene with the severity and outcomes of COVID-19 for better patient management. Methods: In this observational cross-sectional study, COVID-19 confirmed patients were classified into moderate and severe cases according to the "Ain Shams University Hospitals Pocket Guide for COVID-19 Diagnosis." Genetic analysis of ACE2 SNP rs2048683 was carried out using a TaqMan assay with the real-time polymerase chain reaction (PCR) technique. Results: Among 90 confirmed COVID-19 patients, 78.9% (71/90) were classified as severe, and 21.1% (19/90) were classified as moderate. Laboratory biomarkers were significantly (P = 0.000) higher in the severe group than in the moderate group. Similarly, associated comorbidities such as hypertension were significant (P = 0.000) in the severe group, whereas asthma and deep venous thrombosis were significant in the moderate group (P = 0.007 and 0.006, respectively). Elevated serum ferritin level (odds ratio (OR) 162.589, 95% confidence interval (CI) 8.108-3260.293) and ACE2 rs2048683 genotype GG/G (OR 5.852, 95% CI 1.586-21.591) were both considered independent risk factors for severe disease. Conclusion: The findings of the present study provide preliminary evidence of an association between ACE2 rs2048683 SNPs and COVID-19 severity in the Egyptian population, which may inform the need for targeted management. Supplementary Information: The online version contains supplementary material available at 10.1186/s43042-022-00331-8.

Temporal distribution of trace metals pollution load index in the Nile Delta coastal surface sediments.

The Mediterranean coastal area of the Nile Delta is socio-economically vital, however, it is under significant environmental stress due to pollution from land-based activities. The study investigates the temporal variations of trace metals to assess the development of the anthropogenic pollution status in the coastal sediments. The average concentrations, the enrichment factor, and the geoaccumulation index revealed that Cr, V, Ni, and Co are pollutants of concern. Trace metals are particularly accumulating in the sediments further offshore and in the middle and eastern sectors of the Nile Delta coast. The temporal patterns of the pollution load index (PLI) along the Nile Delta coastal indicate that pollution hotspots are increasingly exposed to trace metals pollution over time. This is linked to discharges from anthropogenic land-based activities and controlled by sedimentological factors. A conceptual model for the accumulation of trace metals in sediments is proposed based on this study.