Author: Eissa, Ibrahim H. ; Elkaeed, Eslam B. ; Hagras, Mohamed ; Nofal, Ahmed ; Elkady, Hazem ; Mahdy, Hazem A. ; Dahab, Mohammed A. ; Elgammal, Walid E. ; Metwaly, Ahmed M. ; Alsfouk, Bshra A.

BACKGROUNDVascular endothelial growth factor receptor (VEGFR-2) inhibitors are critical in cancer therapy due to their role in suppressing tumor angiogenesis. Herein, we report a new series of thiadiazole-based derivatives as potential VEGFR-2 inhibitors with promising anticancer activity.METHODSThe synthesized compounds were evaluated for anti-proliferative activity against human cancer cell lines (HCT-116, MCF-7, and HepG-2), and WI-38 as normal cells. Sorafenib was used as a reference drug. VEGFR-2 inhibitory activity was determined, followed by cell cycle analysis, apoptosis assays, Q-RT-PCR analysis, and wound-healing assays. In silico molecular docking was conducted to explore binding interactions.RESULTSAmong the tested compounds, 13b exhibited potent anti-proliferative activity (IC₅₀: 3.98-11.81 µM) and strong VEGFR-2 inhibition (IC₅₀: 41.51 nM), surpassing sorafenib (IC₅₀: 53.32 nM). Cell cycle analysis revealed that 13b induced G2/M phase arrest in MCF-7 cells. Apoptosis levels increased from 2% to 52%, accompanied by a > 12-fold rise in the Bax/Bcl-2 ratio and activation of caspase-8/9. Additionally, 13b significantly suppressed MCF-7 cell migration, with only 5.28% wound closure. In silico studies confirmed its strong VEGFR-2 binding interactions.CONCLUSIONThiadiazole-based derivatives, particularly compound 13b, exhibit potent VEGFR-2 inhibition, anti-proliferative effects, apoptosis induction, and anti-migratory activity, supporting their potential as promising anticancer agents.

01 Apr 2025·Biomedical Chromatography

Development and Validation of a HPLC‐MS/MS Method for the Determination of Compound 13b in Rat Plasma and Its Application to a Pharmacokinetic Study

Article

Author: Hu, Shuang ; Jiang, Xiaowen ; Bi, Huichang ; Guo, Jiayin ; Bi, Guofang ; Yang, Xiao ; Yu, Qingqing ; Long, Yuhua ; Fang, Jian‐Hong ; Wu, Chenghua ; Zhang, Shuqing ; Wang, Peng

ABSTRACTCompound 13b, a newly identified anthraquinone derivative, has demonstrated potent efficacy against the Zika virus. To explore the bioavailability and pharmacokinetic properties of compound 13b, a robust and sensitive HPLC‐MS/MS method was established and verified to determine its plasma concentration in rats. Sample preparation involved protein precipitation using acetonitrile with testosterone as an internal standard. A Phenomenex Kinetex XB‐C18 column (2.1 × 100 mm, 2.6 μm) was utilized for sample separation with gradient elution. The mobile phase, consisting of water and acetonitrile, was dispensed at a flow rate of 1 mL/min. The multiple reaction monitoring mode (MRM) approach was used to detect compound 13b and testosterone, characterized by their respective ionization transitions: m/z 410.2 → 91.1 and m/z 289.2 → 109.2. The method demonstrated superior linearity within rat plasma samples, ranging from 2 to 400 ng/mL, and met all FDA guidelines for bioanalytical method validation. The pharmacokinetic properties were calculated by non‐compartmental approach following administration of compound 13b at 14 mg/kg in rats, and the absolute oral bioavailability was found to be 15.45%. Hence, a highly sensitive and rapid HPLC‐MS/MS method for measuring plasma concentration of compound 13b in rats has been successfully developed, rigorously validated, and subsequently utilized in a bioavailability and pharmacokinetic study.

01 Mar 2025·Bioorganic Chemistry

Isoxazole-pyrimidine derivatives as TACC3 inhibitors: A novel modality to targeted cancer therapy

Article

Author: Banoglu, Erden ; Saatci, Özge ; Çalışkan, Kübra ; Lengerli, Deniz ; Şahin, Özgür ; Çalışkan, Burcu ; Çalışkan, Özge Akbulut ; Vempati, Sridhar ; Lim, Chaemin

Inhibiting the function of transforming acidic coiled-coil 3 (TACC3) offers a promising therapeutic approach for various cancers, such as breast, ovarian, and lung cancers.Our previous work introduced BO-264 as a novel chemotype for inhibiting TACC3 function, though it exhibited relatively low metabolic stability. In this study, sixty-two compounds were designed and synthesized to modify the structure of BO-264 to improve its metabolic stability while maintaining its potency. The tractable SAR results obtained by these novel analogs indicated that appropriate substitutions on the left-end phenyl-isoxazole and right-end morpholine groups improved metabolic stability while preserving potency. Among these, compound 13b exhibited approximately sevenfold improvement in metabolic stability and bioavailability while maintaining strong potency and a favorable safety profile. 13b markedly increased the levels of p-Histone H3 (Ser10), cleaved PARP, and p-H2AX (Ser139), indicative of mitotic arrest, apoptosis, and DNA damage, respectively. In addition, the protein-drug binding assay, DARTS, identified TACC3 as a biologically significant target of 13b, positioning it as an advanced lead compound for further development of clinically relevant TACC3 inhibitors in cancers with elevated TACC3 expression.

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