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具有强大抗癌活性的环氧化酶抑制铂（IV）前药

Cyclooxygenase-Inhibiting Platinum(IV) Prodrugs with Potent Anticancer Activity.

作者信息

Khoury Aleen, Sakoff Jennette A, Gilbert Jayne, Scott Kieran F, Karan Shawan, Gordon Christopher P, Aldrich-Wright Janice R

机构信息

School of Science, Western Sydney University, Locked Bag 1797, Penrith South, NSW 2751, Australia.

Calvary Mater Hospital, Waratah, NSW 2298, Australia.

出版信息

Pharmaceutics. 2022 Apr 3;14(4):787. doi: 10.3390/pharmaceutics14040787.

DOI:10.3390/pharmaceutics14040787
PMID:35456621
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9029360/
Abstract

Platinum(IV) prodrugs of the [Pt(P)(A)(COXi)(OH)] type scaffold (where P is 1,10-phenanthroline or 5,6-dimethyl-1,10-phenanthroline, A is 1,2-diaminocyclohexane, and COXi is a COX inhibitor, either indomethacin or aspirin) were synthesised and characterised, and their biological activity was explored. MTT assays showed that these complexes exhibit outstanding activity against a range of cancer cell lines, and nanomolar activities were observed. The most potent complex, , exhibited a GI of 3 nM in the Du145 prostate cancer cell line and was observed to display a 1614-fold increased activity against the HT29 colon cancer cell line relative to cisplatin. ICP-MS studies showed a linear correlation between increased cellular accumulation of the complexes and increased cytotoxicity, while an enzyme immunoassay showed that and inhibited COX-2 at 14 and 1.4 µM, respectively, which is comparable to the inhibition exhibited by indomethacin. These results suggest that while the cytotoxicity of prodrugs - was influenced by cellular uptake, it was not entirely dependent on either COX inhibition or lipophilicity.

摘要

合成并表征了[Pt(P)(A)(COXi)(OH)]型支架的铂(IV)前药（其中P为1,10-菲咯啉或5,6-二甲基-1,10-菲咯啉，A为1,2-二氨基环己烷，COXi为COX抑制剂，即吲哚美辛或阿司匹林），并探索了它们的生物活性。MTT分析表明，这些配合物对一系列癌细胞系表现出优异的活性，并观察到纳摩尔活性。最有效的配合物，在Du145前列腺癌细胞系中表现出3 nM的GI，并且观察到相对于顺铂，其对HT29结肠癌细胞系的活性增加了1614倍。电感耦合等离子体质谱研究表明，配合物细胞内积累的增加与细胞毒性的增加之间存在线性相关性，而酶免疫分析表明，和分别在14和1.4 μM时抑制COX-2，这与吲哚美辛表现出的抑制作用相当。这些结果表明，虽然前药的细胞毒性受到细胞摄取的影响，但它并不完全依赖于COX抑制或亲脂性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/070c0214908f/pharmaceutics-14-00787-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/67c777a8326c/pharmaceutics-14-00787-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/825e46b321aa/pharmaceutics-14-00787-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/52f5f92ced6a/pharmaceutics-14-00787-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/f1333f2b8af9/pharmaceutics-14-00787-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/ccd6aaf4208d/pharmaceutics-14-00787-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/daefd3d9aa54/pharmaceutics-14-00787-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/f5ef1498a1a6/pharmaceutics-14-00787-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/20fa058dbeb6/pharmaceutics-14-00787-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/f2783cdfb26a/pharmaceutics-14-00787-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/070c0214908f/pharmaceutics-14-00787-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/67c777a8326c/pharmaceutics-14-00787-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/825e46b321aa/pharmaceutics-14-00787-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/52f5f92ced6a/pharmaceutics-14-00787-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/f1333f2b8af9/pharmaceutics-14-00787-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/ccd6aaf4208d/pharmaceutics-14-00787-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/daefd3d9aa54/pharmaceutics-14-00787-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/f5ef1498a1a6/pharmaceutics-14-00787-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/20fa058dbeb6/pharmaceutics-14-00787-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/f2783cdfb26a/pharmaceutics-14-00787-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/64bf/9029360/070c0214908f/pharmaceutics-14-00787-g009.jpg

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