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新型抗癌硫脲-氮杂环丁烷杂合体的发现：设计、合成、体外抗增殖、SAR、针对 VEGFR-2 的计算机分子对接、ADMET、毒性和 DFT 研究。

Discovery of new anticancer thiourea-azetidine hybrids: design, synthesis, in vitro antiproliferative, SAR, in silico molecular docking against VEGFR-2, ADMET, toxicity, and DFT studies.

机构信息

Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, India; Piramal Pharma Limited - Discovery Solutions, Plot no. 18, Pharmaceutical Special Economic Zone, Village Matoda, Ahmedabad, Gujarat, India.

Department of Chemistry, Faculty of Basic and Applied Sciences, Madhav University, Abu Road, Sirohi, Rajasthan, India.

出版信息

Bioorg Chem. 2021 Oct;115:105206. doi: 10.1016/j.bioorg.2021.105206. Epub 2021 Jul 27.

DOI:10.1016/j.bioorg.2021.105206
PMID:34339975
Abstract

With the aim to discover potent and novel antitumor agents, a series of thiourea compounds bearing 3-(4-methoxyphenyl)azetidine moiety were designed according to the essential pharmacophoric features of the reported VEGFR-2 inhibitors and synthesized. All the synthesized compounds were evaluated for their in vitro anticancer activity against various human cancer cell lines (lung (A549), prostate (PC3), breast (MCF-7), liver (HepG2), colon (HCT-116), ovarian (SKOV-3), skin (A431), brain (U251) and kidney (786-O)). 3-(4-Methoxy-3-(2-methoxypyridin-4-yl)phenyl)-N-(4-methoxyphenyl)azetidine-1-carbothioamide (3B) was found to be most potent member against PC3, U251, A431, and 786-O cancer cell lines with EC values 0.25, 0.6, 0.03, and 0.03 µM, respectively and showed more potency than Doxorubicin in PC3, A431, and 786-O cell lines. Compounds 1B to 7B showed EC values ranging from 0.03 to 12.55 µM in A431 cell line. Compound 3-(4-methoxy-3-(pyridin-4-yl)phenyl)-N-(4-methoxyphenyl)azetidine-1-carbothioamide (1B) was found to be highly efficient in A431 and 786-O cell line with EC values of 0.77 and 0.73 µM respectively. All the compounds exhibited good to moderate cytotoxic activity. The pharmacophoric features and molecular docking studies confirmed the potentialities of compounds 1B, 2B, 3B and 5B to be VEGFR-2 inhibitors. Moreover, in silico ADMET prediction indicated that most of the synthesized compounds have drug-like properties, possess low adverse effects and toxicity. In addition, the DFT studies for the most active compounds (1B and 3B) were carried out. In the end, our studies revealed that the compounds 1B and 3B represent promising anticancer potentialities through their VEGFR-2 inhibition.

摘要

为了发现有效的新型抗肿瘤药物，根据报道的 VEGFR-2 抑制剂的基本药效特征，设计了一系列含有 3-(4-甲氧基苯基)氮杂环丁烷部分的硫脲化合物，并进行了合成。所有合成的化合物都在体外针对各种人类癌细胞系（肺（A549）、前列腺（PC3）、乳腺（MCF-7）、肝（HepG2）、结肠（HCT-116）、卵巢（SKOV-3）、皮肤（A431）、脑（U251）和肾（786-O））进行了抗癌活性评估。发现 3-(4-甲氧基-3-(2-甲氧基吡啶-4-基)苯基)-N-(4-甲氧基苯基)氮杂环丁烷-1-甲脒（3B）对 PC3、U251、A431 和 786-O 癌细胞系的活性最强，EC 值分别为 0.25、0.6、0.03 和 0.03µM，并且在 PC3、A431 和 786-O 细胞系中的活性均强于多柔比星。化合物 1B 至 7B 在 A431 细胞系中的 EC 值范围为 0.03 至 12.55µM。发现 3-(4-甲氧基-3-(吡啶-4-基)苯基)-N-(4-甲氧基苯基)氮杂环丁烷-1-甲脒（1B）对 A431 和 786-O 细胞系具有高效活性，EC 值分别为 0.77 和 0.73µM。所有化合物均表现出良好至中等的细胞毒性活性。药效特征和分子对接研究证实了化合物 1B、2B、3B 和 5B 作为 VEGFR-2 抑制剂的潜力。此外，通过计算机预测 ADMET 表明，大多数合成化合物具有类药性，具有低副作用和毒性。此外，对最活跃的化合物（1B 和 3B）进行了 DFT 研究。最后，我们的研究表明，化合物 1B 和 3B 通过抑制 VEGFR-2 表现出有希望的抗肿瘤潜力。

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