Exploring the anticancer properties of indole pyrimidine derivatives: Synthesis, structural insights, docking analysis, and in vitro evaluation

IF 3.8 Q2 CHEMISTRY, PHYSICAL Chemical Physics Impact Pub Date : 2024-09-10 DOI:10.1016/j.chphi.2024.100730
HM Pallavi , VH Kameshwar , Fares Hezam Al-Ostoot , Shaukath Ara Khanum
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引用次数: 0

Abstract

The nitrogen containing heterocyclic and chalcones moiety widely recognized as favorable combination of diagnostic and therapeutic facilities in medicinal chemistry. In particular, indole analogs play a very important medicinal role in pharmacology activities, hence, drugs like pindolol, indomethacin, oxypertine, ellipticine, arbidol and ate viridine are well known in market. In this view, the title compounds 4(a-j) were synthesized in good yield. The purified compounds were explained by spectroscopic procedures (FT-IR, 1H NMR, 13CNMR, and LC-MS), and lastly, all synthetic compounds have in-vitro efficacy assessed against the HeLa human cervical cancer and MCF-7 human breast cancer cell lines, and their efficacy was compared to that of the well-known anticancer drug methotrexate (Methotrexate). Compounds 4a, 4b, 4c, and 4e from the series (4a-j) demonstrated the most notable inhibitory activity. The cytotoxicity evaluation of these newly synthesized compounds revealed that 4a, 4b, 4c, and 4e were the most toxic to HeLa cells, with IC50 values for growth inhibition of 20.41 ± 3.14, 23.54 ± 3.27, 24.77 ± 2.14, and 26.10 ± 1.58, respectively. These compounds exhibited an even stronger growth-inhibitory effect on MCF-7 cells, with IC50 values of 18.84 ± 2.69, 19.45 ± 3.14, 22.83 ± 2.68, and 21.80 ± 1.68, respectively. In comparison, methotrexate (Methotrexate) showed IC50 values of 28.29 ± 1.0 for HeLa cells and 45.08 ± 2.61 for MCF-7 cells. Additionally, compounds 4a, 4b, 4c, and 4e played a crucial role in interacting with the catalytic domain of PDE3, demonstrating IC50 values for PDE3A inhibition of 8.05 ± 1.27, 7.55 ± 2.14, 15.09 ± 1.54, and 17.12 ± 3.14, respectively. These results are compared with Cilostazol, a known PDE inhibitor, which exhibited an IC50 of 0.00368 ± 3.14. In-silico studies revealed that compounds (4a, 4b, and 4c) are comparatively very efficient in binding with PDE3A which was further validated with MMGBSA and MDSs.

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探索吲哚嘧啶衍生物的抗癌特性:合成、结构洞察、对接分析和体外评估
含氮杂环和查耳酮分子被广泛认为是药物化学中诊断和治疗的有利结合。特别是,吲哚类似物在药理学活动中发挥着非常重要的药用作用,因此,像平度洛尔、吲哚美辛、奥沙利哌啶、鞣酸平、阿比多尔和阿特金刚碱等药物在市场上广为人知。有鉴于此,我们以良好的收率合成了标题化合物 4(a-j)。最后,所有合成化合物都对 HeLa 人宫颈癌细胞系和 MCF-7 人乳腺癌细胞系进行了体外药效评估,并与知名抗癌药物甲氨蝶呤(Methotrexate)的药效进行了比较。系列化合物(4a-j)中的化合物 4a、4b、4c 和 4e 表现出了最显著的抑制活性。对这些新合成化合物进行的细胞毒性评估显示,4a、4b、4c 和 4e 对 HeLa 细胞的毒性最强,其抑制生长的 IC50 值分别为 20.41 ± 3.14、23.54 ± 3.27、24.77 ± 2.14 和 26.10 ± 1.58。这些化合物对 MCF-7 细胞的生长抑制作用更强,IC50 值分别为 18.84 ± 2.69、19.45 ± 3.14、22.83 ± 2.68 和 21.80 ± 1.68。相比之下,甲氨蝶呤(Methotrexate)对 HeLa 细胞的 IC50 值为 28.29 ± 1.0,对 MCF-7 细胞的 IC50 值为 45.08 ± 2.61。此外,化合物 4a、4b、4c 和 4e 在与 PDE3 的催化结构域相互作用方面发挥了关键作用,对 PDE3A 抑制作用的 IC50 值分别为 8.05 ± 1.27、7.55 ± 2.14、15.09 ± 1.54 和 17.12 ± 3.14。这些结果与已知的 PDE 抑制剂西洛他唑进行了比较,后者的 IC50 为 0.00368 ± 3.14。室内研究显示,化合物(4a、4b 和 4c)与 PDE3A 的结合效率相对较高,这一点通过 MMGBSA 和 MDSs 得到了进一步验证。
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来源期刊
Chemical Physics Impact
Chemical Physics Impact Materials Science-Materials Science (miscellaneous)
CiteScore
2.60
自引率
0.00%
发文量
65
审稿时长
46 days
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