Novel 3-Substituted-2H-Chromene Scaffold Based Fluorinated Hydrophobic Fragment as In-Vitro Antiproliferative Agents and Apoptosis Inducers Targeting Both VEGFR-2/BRAFV600E and h-DHFR With Molecular Docking Simulation

IF 3.5 4区 医学 Q2 CHEMISTRY, MEDICINAL
Mohamed A. Salem, Moustafa S. Abusaif, Nirvana A. Gohar, Yousry A. Ammar, Ahmed Ragab
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引用次数: 0

Abstract

Recently, there has been an increasing interest in the use of protein kinase inhibitors as a therapeutic strategy for the treatment of cancer. In this study, a new series of 2H-chromene derivatives (2-5 and 6-8) and 3H-benzo[f]chromene carbohydrazide derivative (9) were synthesized. The structure of the designed derivatives was characterized by IR, 1H/13C NMR, and elemental analysis. Moreover, the cytotoxic activity of the newly synthesized chromenes was evaluated against breast cancer cell lines (MDA-MB-231 and MCF-7) and a cervical cancer cell line (HeLa). The results of these evaluations demonstrated promising activity, ranging from good to moderate. Additionally, the lung fibroblast cell line (WI-38), as a normal cell line, was also utilized to assess the active derivatives' selectivity. Among the compounds tested, chromene derivative 3 demonstrated the highest potency, exhibiting IC50 values of 5.36 ± 0.50, 7.82 ± 0.60, and 9.28 ± 0.70 µM against the MDA-MB 231, MCF-7, and HeLa cell lines, respectively. The potential of chromone 3 as a multi-targeted anticancer agent was assessed by evaluating its activity against BRAF and VEGFR-2. Notably, the most promising chromene derivative 3 demonstrated significant VEGFR2 activity with an IC50 value of 0.224 µM compared to sorafenib's 0.045 µM, while exhibiting inhibitory activity against BRAF with an IC50 value of 1.695 µM relative to Vemurafenib's IC50 value of 0.468 µM. In addition, compound 3 inhibits the DHFR enzyme with an IC50 value of 2.217 ± 0.014 µM, compared to methotrexate (IC50 = 0.4315 ± 0.019 µM). These results revealed that the compound has multifaceted mechanisms of action that may augment its therapeutic effectiveness. In addition, compound 3 causes overexpression of caspase-3 and Bax by 6.13 and 8.85-fold, respectively. It also downregulates the antiapoptotic Bcl-2 level by 0.4775-fold compared to the untreated MDA-MB 231 cells. Flow cytometry analysis of MDA-MB-231 cells indicates that compound 3 induces cell cycle arrest in the G0-G1 phase, with an observed percentage of 73.15%. The in-silico toxicity prediction was evaluated and demonstrated a good toxicity profile. Finally, molecular docking studies supported these findings by confirming strong binding affinities of the derivatives to VEGFR-2, BRAF, and DHFR.

基于新型3-取代2h -铬支架的氟化疏水片段作为靶向VEGFR-2/BRAFV600E和h-DHFR的体外抗增殖剂和凋亡诱导剂的分子对接模拟
最近,人们对使用蛋白激酶抑制剂作为治疗癌症的一种治疗策略越来越感兴趣。本研究合成了一系列新的2h -铬烯衍生物(2-5和6-8)和3h -苯并[f]铬烯碳肼衍生物(9)。通过IR、1H/13C NMR和元素分析对所设计的衍生物进行了结构表征。此外,新合成的铬烯对乳腺癌细胞株(MDA-MB-231和MCF-7)和宫颈癌细胞株(HeLa)的细胞毒活性进行了评价。这些评价的结果显示出有希望的活动,范围从良好到中等。此外,作为正常细胞系的肺成纤维细胞系(WI-38)也被用来评估活性衍生物的选择性。其中,铬烯衍生物3对MDA-MB 231、MCF-7和HeLa细胞株的IC50值分别为5.36±0.50、7.82±0.60和9.28±0.70µM。通过评估其对BRAF和VEGFR-2的活性来评估3号染色体作为多靶点抗癌药物的潜力。值得注意的是,最有希望的色素衍生物3显示出显著的VEGFR2活性,IC50值为0.224µM,而索拉非尼的IC50值为0.045µM,而对BRAF的抑制活性为1.695µM,而Vemurafenib的IC50值为0.468µM。此外,化合物3抑制DHFR酶的IC50值为2.217±0.014µM,而甲氨蝶呤的IC50值为0.4315±0.019µM。这些结果表明,该化合物具有多方面的作用机制,可能会增加其治疗效果。此外,化合物3导致caspase-3和Bax分别过表达6.13倍和8.85倍。与未经处理的MDA-MB 231细胞相比,它还下调了抗凋亡Bcl-2水平0.4775倍。对MDA-MB-231细胞流式细胞术分析表明,化合物3诱导细胞周期阻滞在G0-G1期,阻滞率为73.15%。对硅毒性预测进行了评估,并证明了良好的毒性谱。最后,分子对接研究证实了这些衍生物与VEGFR-2、BRAF和DHFR的强结合亲和力,从而支持了这些发现。
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来源期刊
CiteScore
6.40
自引率
2.60%
发文量
104
审稿时长
6-12 weeks
期刊介绍: Drug Development Research focuses on research topics related to the discovery and development of new therapeutic entities. The journal publishes original research articles on medicinal chemistry, pharmacology, biotechnology and biopharmaceuticals, toxicology, and drug delivery, formulation, and pharmacokinetics. The journal welcomes manuscripts on new compounds and technologies in all areas focused on human therapeutics, as well as global management, health care policy, and regulatory issues involving the drug discovery and development process. In addition to full-length articles, Drug Development Research publishes Brief Reports on important and timely new research findings, as well as in-depth review articles. The journal also features periodic special thematic issues devoted to specific compound classes, new technologies, and broad aspects of drug discovery and development.
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