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(-) 杜松烯新型倍半萜-芳基酯衍生物的细胞毒性、拓扑异构酶 I 抑制活性及计算机模拟研究。

Cytotoxic Activity, Topoisomerase I Inhibition and In Silico Studies of New Sesquiterpene-aryl Ester Derivatives of (-) Drimenol.

机构信息

Facultad de Farmacia, Escuela de Química y Farmacia, Universidad de Valparaíso, Av. Gran Bretaña 1093, Valparaíso 2340000, Chile.

Centro de Investigaciones Biomédicas, Escuela de Medicina, Facultad de Medicina, Universidad de Valparaíso, Viña del Mar 2520000, Chile.

出版信息

Molecules. 2023 May 8;28(9):3959. doi: 10.3390/molecules28093959.

DOI:10.3390/molecules28093959
PMID:37175368
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10179937/
Abstract

In this study, we aimed to evaluate two sets of sesquiterpene-aryl derivatives linked by an ester bond, their cytotoxic activities, and their capacity to activate caspases 3/7 and inhibit human topoisomerase I (TOP1). A total of 13 compounds were synthesized from the natural sesquiterpene (-)-drimenol and their cytotoxic activity was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and an immortalized non-tumoral cell line (MCF-10). From the results, it was observed that was the most promising compound due to its cytotoxic effect on three cancer cell lines and its selectivity, was 100-fold more selective than 5-FU in MCF-7 and 20-fold in PC-3. It was observed that also induced apoptosis by caspases 3/7 activity using a Capsase-Glo-3/7 assay kit and inhibited TOP1. A possible binding mode of in a complex with TOP1-DNA was proposed by docking and molecular dynamics studies. In addition, was predicted to have a good pharmacokinetic profile for oral administration. Therefore, through this study, it was demonstrated that the drimane scaffold should be considered in the search of new antitumoral agents.

摘要

在这项研究中，我们旨在评估通过酯键连接的两组倍半萜-芳基衍生物，它们的细胞毒性活性以及激活 Caspase 3/7 和抑制人拓扑异构酶 I（TOP1）的能力。共合成了 13 种从天然倍半萜（-）-drimenol 衍生而来的化合物，并在体外针对三种癌细胞系（PC-3（前列腺癌），HT-29（结肠癌），MCF-7（乳腺癌））和一种永生化非肿瘤细胞系（MCF-10）评估了它们的细胞毒性活性。结果表明，由于对三种癌细胞系的细胞毒性作用及其选择性，化合物 是最有前途的化合物，在 MCF-7 中比 5-FU 高 100 倍，在 PC-3 中高 20 倍。还观察到 通过 Caspase-Glo-3/7 测定试剂盒诱导 Caspase 3/7 活性引起的细胞凋亡，并抑制 TOP1。通过对接和分子动力学研究提出了 与 TOP1-DNA 形成复合物的可能结合模式。此外，还预测 口服给药具有良好的药代动力学特征。因此，通过这项研究，证明了在寻找新的抗肿瘤药物时应考虑戴马林支架。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/c0f51cc348a8/molecules-28-03959-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/7f2f7d6900ed/molecules-28-03959-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/1ac94a31816b/molecules-28-03959-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/3aaabd2ce733/molecules-28-03959-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/a06e03a12b2a/molecules-28-03959-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/99f1aa8e800d/molecules-28-03959-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/1228196503de/molecules-28-03959-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/779a27b4ae46/molecules-28-03959-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/c0f51cc348a8/molecules-28-03959-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/7f2f7d6900ed/molecules-28-03959-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/1ac94a31816b/molecules-28-03959-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/3aaabd2ce733/molecules-28-03959-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/a06e03a12b2a/molecules-28-03959-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/99f1aa8e800d/molecules-28-03959-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/1228196503de/molecules-28-03959-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/779a27b4ae46/molecules-28-03959-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/6f23/10179937/c0f51cc348a8/molecules-28-03959-g007.jpg

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