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噻唑烷-2,4-二酮类衍生物与 1,2-二氢喹啉酮和 2-氧代吲哚的设计与合成及其作为潜在 VEGFR-2 抑制剂的抗癌活性评价与研究

Design and synthesis of thiazolidine-2,4-diones hybrids with 1,2-dihydroquinolones and 2-oxindoles as potential VEGFR-2 inhibitors: anticancer evaluation and studies.

机构信息

Pharmaceutical Medicinal Chemistry & Drug Design Department, Faculty of Pharmacy (Boys), Al-Azhar University, Cairo, Egypt.

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.

出版信息

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1903-1917. doi: 10.1080/14756366.2022.2085693.

DOI:10.1080/14756366.2022.2085693
PMID:35801403
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9272924/
Abstract

A thiazolidine-2,4-dione nucleus was molecularly hybridised with the effective antitumor moieties; 2-oxo-1,2-dihydroquinoline and 2-oxoindoline to obtain new hybrids with potential activity against VEGFR-2. The cytotoxic effects of the synthesised derivatives against Caco-2, HepG-2, and MDA-MB-231 cell lines were investigated. Compound was found to be the most potent candidate against the investigated cell lines with IC values of 2, 10, and 40 µM, respectively. Furthermore, the synthesised derivatives were tested for their VEGFR-2 inhibitory activity showing strong inhibition. Moreover, an viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. Compound was further investigated for its apoptotic behaviour by assessing the gene expression of four genes (Bcl2, Bcl-xl, TGF, and Survivin). Molecular dynamic simulations authenticated the high affinity, accurate binding, and perfect dynamics of compound against VEGFR-2.

摘要

噻唑烷-2,4-二酮核与有效的抗肿瘤部分；2-氧代-1,2-二氢喹啉和 2-氧代吲哚啉进行分子杂交，得到对 VEGFR-2 具有潜在活性的新杂合子。研究了合成衍生物对 Caco-2、HepG-2 和 MDA-MB-231 细胞系的细胞毒性作用。发现化合物 对所研究的细胞系具有最强的活性，IC 值分别为 2、10 和 40µM。此外，还测试了合成衍生物对 VEGFR-2 的抑制活性，结果显示出强烈的抑制作用。此外，还研究了它们对非癌细胞系 Vero 的活性，结果反映出所有测试化合物均具有很高的安全性。进一步研究了化合物 的凋亡行为，评估了四个基因（Bcl2、Bcl-xl、TGF 和 Survivin）的基因表达。分子动力学模拟证实了化合物 与 VEGFR-2 的高亲和力、准确结合和完美动力学。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/b1b2442b679d/IENZ_A_2085693_F0010_C.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/27c9dc055601/IENZ_A_2085693_F0009_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/b1b2442b679d/IENZ_A_2085693_F0010_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/b31bd941999f/IENZ_A_2085693_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/39d279089183/IENZ_A_2085693_SCH0001_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/773f7bfe2ef6/IENZ_A_2085693_SCH0002_B.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/21df90ed1452/IENZ_A_2085693_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/e9ef92aca65f/IENZ_A_2085693_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/b14991f7d321/IENZ_A_2085693_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/d384493dd9c3/IENZ_A_2085693_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/8b6aa895a3ff/IENZ_A_2085693_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/3c4d0ccd2808/IENZ_A_2085693_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/a9aaa16dcd7b/IENZ_A_2085693_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/27c9dc055601/IENZ_A_2085693_F0009_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e9af/9272924/b1b2442b679d/IENZ_A_2085693_F0010_C.jpg

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