Furan- and Furopyrimidine-Based Derivatives: Synthesis, VEGFR-2 Inhibition, and In Vitro Cytotoxicity.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-11-25 eCollection Date: 2024-12-12 DOI:10.1021/acsmedchemlett.4c00438

Akram H Abd El-Haleem, Manar Abd El-Karim Kassem, Mohamed R Elnagar, Safinaz E-S Abbas, Ahmed M El Kerdawy, Ahmed K B A W Farouk

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Abstract

New derivatives 4a-d, 6, 7a-d, 8a-c, 9, 11a, 11b, 12a-f, 13a-c, and 14 were synthesized and evaluated for their VEGFR-2 inhibition. Compounds 4c, 7b, and 7c showed remarkable enzyme inhibition (IC₅₀ = 57.1, 42.5, and 52.5 nM, respectively) relative to sorafenib (IC₅₀ = 41.1 nM) and were assessed for their cytotoxicity versus HepG2, MCF-7, A549, HT-29, and PC3 cancer cell lines in addition to WI-38. Compound 7b displayed nearly equipotent cytotoxicity against A549 and HT-29 (IC₅₀ = 6.66 and 8.51 μM) compared to sorafenib (IC₅₀ = 6.60 and 8.78 μM). Cell cycle analysis and apoptotic assay of 7b in the HT-29 cell line showed cellular growth arrest at the G2/M phase in addition to the induction of apoptosis. Western blot analysis of compound 7b revealed the deactivation of VEGFR-2. Moreover, a wound healing assay of 7b showed inhibition of wound closure. Additionally, molecular modeling studies of compounds 4c, 7b, and 7c were carried out.

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呋喃和呋喃嘧啶衍生物：合成、VEGFR-2抑制和体外细胞毒性。

合成了新的衍生物4a-d、6、7a-d、8a-c、9、11a、11b、12a-f、13a-c和14，并对其VEGFR-2抑制作用进行了评价。与索拉非尼（IC50 = 41.1 nM）相比，化合物4c、7b和7c表现出显著的酶抑制作用（IC50分别为57.1、42.5和52.5 nM），并评估了它们对HepG2、MCF-7、A549、HT-29和PC3癌细胞的细胞毒性。化合物7b对A549和HT-29的IC50分别为6.66和8.51 μM，与sorafenib的IC50分别为6.60和8.78 μM相比，具有相当的细胞毒性。在HT-29细胞系中，7b的细胞周期分析和凋亡实验显示，7b在G2/M期阻滞细胞生长，并诱导细胞凋亡。Western blot分析化合物7b显示VEGFR-2失活。此外，伤口愈合试验显示7b对伤口愈合有抑制作用。此外，对化合物4c、7b和7c进行了分子模拟研究。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.