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孕烯醇酮衍生物的合成、药理评价及作为人二氢叶酸还原酶抑制剂的分子建模研究。

Synthesis, pharmacological evaluation and Molecular modelling studies of pregnenolone derivatives as inhibitors of human dihydrofolate reductase.

机构信息

Department of Chemistry, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, KP, Pakistan.

Department of Pharmacy, COMSATS University Islamabad, Abbottabad Campus, 22060 Abbottabad, KP, Pakistan.

出版信息

Steroids. 2021 Apr;168:108801. doi: 10.1016/j.steroids.2021.108801. Epub 2021 Feb 5.

DOI:10.1016/j.steroids.2021.108801
PMID:33549543
Abstract

In current study, we synthesized chalcone derivatives (13a-c) via base-catalyzed Claisen-Schmidt condensation reaction. We further treated diamino compounds with synthesized chalcones to produce 3,4-dihydropyrimidin-2(1H)-one (18a-c), 3,4-dihydropyrimidin-2(1H)-thione (19a-c) and 2-aminopyrimidine (20a-c) derivatives of pregnenolone by cyclization reaction. Cell viability test of synthesized steroidal chalcones and their pyrimidine and thiopyrimidine derivatives against human breast (MCF-7), human lung (A549) and human prostate (PC-3) cancer cell lines was performed using (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), assay. Compounds were further evaluated for their inhibition potential against recombinant human DHFR (rhDHFR). All compounds showed activity from low micromolar to submicromolar range. Compound 20b with IC value of 180 nM emerged as most potent compound against rhDHFR. Interaction of the newly synthesized pregnenolone derivatives with hDHFR and estrogen receptor alpha (ERα) were also explored via docking simulations. The overall results of hDHFR inhibition have shown that these analogues can be further optimized and developed as potent anticancer agents.

摘要

在当前的研究中，我们通过碱催化的 Claisen-Schmidt 缩合反应合成了查尔酮衍生物（13a-c）。我们进一步将二氨基化合物与合成的查尔酮进行处理，通过环化反应生成孕烯醇酮的 3,4-二氢嘧啶-2(1H)-酮（18a-c）、3,4-二氢嘧啶-2(1H)-硫酮（19a-c）和 2-氨基嘧啶（20a-c）衍生物。我们使用（4,5-二甲基噻唑-2-基）-2,5-二苯基四氮唑溴盐（MTT）测定法对合成的甾体查尔酮及其嘧啶和噻嘧啶衍生物对人乳腺癌（MCF-7）、人肺癌（A549）和人前列腺癌（PC-3）癌细胞系的细胞活力进行了测试。此外，我们还评估了这些化合物对重组人二氢叶酸还原酶（rhDHFR）的抑制潜力。所有化合物的活性均在低微摩尔至亚微摩尔范围内。对 rhDHFR 具有 180 nM 的 IC 值的化合物 20b 表现出最强的活性。我们还通过对接模拟研究了新合成的孕烯醇酮衍生物与 hDHFR 和雌激素受体 alpha（ERα）的相互作用。hDHFR 抑制的总体结果表明，这些类似物可以进一步优化和开发为有效的抗癌药物。

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