ABSTRACT
BACKGROUND: VEGFR-2 has emerged as a prominent positive regulator of cancer progression. AIM: Discovery of new anticancer agents and apoptotic inducers targeting VEGFR-2. METHODS: Design and synthesis of new thiazolidine-2,4-diones followed by extensive in vitro studies, including VEGFR-2 inhibition assay, MTT assay, apoptosis analysis, and cell migration assay. In silico investigations including docking, MD simulations, ADMET, toxicity, and DFT studies were performed. RESULTS: Compound 15 showed the strongest VEGFR-2 inhibitory activity with an IC50 value of 0.066 µM. Additionally, most of the synthesized compounds showed anti-proliferative activity against HepG2 and MCF-7 cancer cell lines at the micromolar range with IC50 values ranging from 0.04 to 4.71 µM, relative to sorafenib (IC50 = 2.24 ± 0.06 and 3.17 ± 0.01 µM against HepG2 and MCF-7, respectively). Also, compound 15 showed selectivity indices of 1.36 and 2.08 against HepG2 and MCF-7, respectively. Furthermore, compound 15 showed a significant apoptotic effect and arrested the cell cycle of MCF-7 cells at the S phase. Moreover, compound 15 had a significant inhibitory effect on the ability of MCF-7 cells to heal from. Docking studies revealed that the synthesized thiazolidine-2,4-diones have a binding pattern approaching sorafenib. MD simulations indicated the stability of compound 15 in the active pocket of VEGFR-2 for 200 ns. ADMET and toxicity studies indicated an acceptable pharmacokinetic profile. DFT studies confirmed the ability of compound 15 to interact with VEGFR-2. CONCLUSION: Compound 15 has promising anticancer activity targeting VEGFR-2 with significant activity as an apoptosis inducer.
Subject(s)
Antineoplastic Agents , Apoptosis , Cell Proliferation , Drug Design , Molecular Docking Simulation , Thiazolidinediones , Vascular Endothelial Growth Factor Receptor-2 , Humans , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Vascular Endothelial Growth Factor Receptor-2/metabolism , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Thiazolidinediones/pharmacology , Thiazolidinediones/chemistry , Thiazolidinediones/chemical synthesis , MCF-7 Cells , Hep G2 Cells , Cell Proliferation/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Drug Screening Assays, Antitumor , Sorafenib/pharmacology , Sorafenib/chemistry , Molecular Dynamics Simulation , Cell Movement/drug effectsABSTRACT
Plant tissue culture technology offers a solution for meeting the increasing commercial demand on economically important plants such as rice, a widespread dietary staple. However, significant genotype-specific morphogenetic responses constitute a considerable on rice regeneration in plant biotechnology contexts. Aside from genotype dependency, the components of the nutrient media including gelling agents have an important impact on regeneration efficiency. The current study explores the effect of different gelling agents on various stages of rice regeneration in two Egyptian rice cultivars-Sakha104 and Giza178. Media solidified with varying concentrations of a variety of gelling agents (agar, bacto agar, gelrite and phytagel) were tested for their impact on the frequency of callus induction, shoot regeneration and rooting. The results indicated gellan gum (gelrite and phytagel) was superior to agar products (agar and bacto agar) for callus induction. By contrast, no significant differences were found between different gelling agents for shoot regeneration. Gellan gum and media solidified with bacto agar were found to lead to significantly higher root regeneration than agar. The Sakha104 cultivar showed better responses than Giza 178 for callus induction and similar performance to the Giza 178 cultivar for root regeneration irrespective of the gelling agent. This work provides insights into the impact of different gelling agents on the morphogenetic response of two rice cultivars and can be used to help maximize the frequency of rice regeneration.
ABSTRACT
Frequent episodes of heat threaten sustainable agriculture in Egypt. This study is an urgent call to select tolerant genotypes of heat and discover the predicted screening phenotypic parameters. Here, twenty spring wheat genotypes were exposed to heat stress under field conditions for screening heat tolerance. Stress environments were simulated by delaying the sowing date by 53 and 58 days than the normal environments for two successive seasons. Stressed plants received the highest peak of heat during the reproductive growth stage. Eight phenotypic parameters were measured to evaluate genotype tolerance. Mean performance, reduction percentage/trait, and heat susceptibility index parameters were calculated. Additionally, the pollen grain viability during spike emergence and the germinability of producing grains were investigated. Results demonstrated: (1) Highly significant differences (P < 0.01) between genotypes, treatments and genotypes by treatments in grain yield and other traits in both studied seasons, (2) significant reduction in all studied traits compared to the non-stress environment, (3) the overall yield reduction, based on grain yield/m2, was 40.17, 41.19 % in the first and second seasons, respectively, and the most tolerant genotypes were Masr2, Sids1, Giza 171 and Line 9, (4) limited impact of heat has detected on pollen grains viability and germinability, and (5) grain yield as a selection criterion for heat stress remains the most reliable yardstick.
