Bcl-2 x VEGFR2

Flubendiamide (FBD) is a well-known insecticide, known to cause organo-toxicity in non-targeted living beings. This experiment was aimed at examining the progression of cardiac injuries across different doses of FBD in Sprague Dawley rats. Thirty-six rats were apportioned into four groups i.e., control, FBD low dose (125 mgkg^-1), FBD moderate dose (250 mgkg^-1), and FBD high dose (500 mgkg^-1) treated group. Our findings revealed that FBD perturbed the angiogenesis pathway by increasing the expression of VEGFA and angiopoietin- 2 (ANGPT2) while downregulating the expression of platelet-derived growth factor B (PDGFB), VEGF receptor 2 (VEGFR2), and nitric oxide-synthase 3 (NOS3/eNOS). It was found that cardiac redox homeostasis was severely impaired, as indicated by the inhibition of catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx), glutathione (GSH), glutathione reductase (GSR), glutathione S-transferase (GST), and heme oxygenase-1 (HO-1) and a sudden escalation in the levels of reactive oxygen species (ROS) and malondialdehyde. Moreover, FBD provoked the levels of creatine kinase-MB (CK-MB), creatine phosphokinase (CPK), troponin-I, troponin-T, lactate dehydrogenase (LDH), brain natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP) and C-reactive protein (CRP). Echocardiographic evaluation showed FBD induced bradycardia, thickening of the interventricular septal, ventricular dilation, enlargement of the posterior wall, and dysfunctional of systolic and diastolic functions in dose-dependent manners. Moreover, FBD exposure elevated the levels of Bax and caspase-3, and caspase-9 while inhibiting the levels of Bcl-2. A sudden upregulation in the levels of nuclear factor-kappa B (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), interleukin-6 (IL-6), and cyclooxygenase-2 (COX-2) was found after FBD intoxication. Besides, FBD administration disrupted histoarchitecture of cardiac tissues. Taken together, these results indicate that FBD has strong dose-effective cardiotoxicity by altering angiogenic signaling, oxidative homeostasis, apoptotic, and inflammatory responses.

A library of new methoxyquinazoline sulfonamide derivatives was synthesized through two main structural modifications: either by introducing methoxy groups at the quinazoline ring, or S-alkylation with acetamide moieties bearing differently substituted aromatic groups to explore the structure-activity relationship. The synthesized compounds were assessed for their cytotoxic effects against A549, MDA-MB-231 and HepG-2 cancer cell lines, as well as WI-38 and MCF-10A normal cell lines. Among these derivatives, the trimethoxy-substituted quinazolines 9a-c showed the highest cytotoxic potency, with compound 9a emerging as the lead candidate. Compound 9a displayed strong inhibitory activity against VEGFR-2, with an IC₅₀ value of 0.23 ± 0.03 μM, comparable to that of sorafenib. It inhibited HepG-2 cell migration in a wound healing assay, which correlated with a reduction in Akt phosphorylation (p-Akt), suggesting its potential to modulate VEGFR-2-mediated signaling pathways involved in angiogenesis. Compound 9a induced apoptosis, evidenced by caspase-3 activation, upregulation of Bax, downregulation of Bcl-2 and a marked increase in Bax/Bcl-2 ratio. Cell cycle analysis demonstrated G2/M phase arrest, supporting its antiproliferative activity. It also revealed enhanced radiation-induced cytotoxicity when combined with a single 8 Gy dose of gamma radiation. Docking within the VEGFR-2 active site supported the biological findings by revealing promising binding interactions. Besides, ADME analysis supports the design strategy and suggests that these derivatives possess promising pharmacokinetic properties.

In this work, a new series of N-arylmethylene/heterylmethylene-2-(4-oxo-1-phenyl-1,4-dihydro-5H-pyrazolo[3,4-d]pyrimidin-5-yl)acetohydrazide 8a-l was synthesized via the condensation reaction of acetohydrazide 6 with various aromatic aldehydes 7a-l. The cytotoxic activity of these compounds was evaluated in vitro using against three human cancer cell lines: hepatocellular carcinoma (HepG2), prostate cancer (PC-3) and colorectal carcinoma (HCT-116). Among the synthesized series, compound 8g exhibited the highest potency, with IC₅₀ values of 3.93 μM, 9.56 μM, and 6.30 μM against HepG2, PC-3, and HCT-116, respectively, surpassing the reference drugs doxorubicin (4.50 μM against HepG2) and sorafenib (9.18 μM against HepG2). Mechanistically, 8g demonstrated strong inhibition of VEGFR2 (IC₅₀ = 0.38 μM), but it outperformed PD-L1 inhibition compared to Bavencio (IC₅₀ = 134.41 pg/mL and 217.74 pg/mL, respectively). In contrast, it enhanced INF-γ secretion in comparison to the reference drug. Cell cycle analysis revealed arrest at G0/G1with apoptosis induction at 29.41%. The apoptotic enzyme assay showed upregulation of BAX and Caspase-3, and downregulation of Bcl-2, confirming the activation of the intrinsic apoptotic pathway. In silico molecular docking and dynamic simulation assisted data strongly correlated with the experimental approach that compound 8g exerts multi-targeted anticancer activity via VEGFR2 and PD-L1 inhibition. In conclusion, 8g is a promising candidate recommended for further therapeutic development.