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酿酒单孢菌素A的启发；作为潜在PIM激酶抑制剂的强效类似物的合成。

Saccharomonosporine A inspiration; synthesis of potent analogues as potential PIM kinase inhibitors.

作者信息

AboulMagd Asmaa M, Hassan Hossam M, Sayed Ahmed M, Abdelmohsen Usama Ramadan, Abdel-Rahman Hamdy M

机构信息

Pharmaceutical Chemistry Department, Faculty of Pharmacy, Nahda University Beni Suef Egypt

Pharmacognosy Department, Faculty of Pharmacy, Beni-Suef University Beni-Suef Egypt.

出版信息

RSC Adv. 2020 Feb 13;10(12):6752-6762. doi: 10.1039/c9ra10216g.

DOI:10.1039/c9ra10216g
PMID:35493904
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9049778/
Abstract

Saccharomonosporine A was recently reported as a natural anti-cancer agent working through inhibition of a Proviral integration site for Moloney murine leukemia virus-1 (PIM-1) kinase. Structural bioisosteres of this natural product were synthesized and tested against PIM kinase enzymes. They showed potent inhibitory activity against all the known PIM kinases (PIM-1, 2 and 3) with IC values ranging from 0.22 to 2.46 μM. Compound 5 was the most potent -inhibitor with IC values of 0.37, 0.41, and 0.3 μM, against PIM-1, 2, 3 respectively. Compounds 4-6 were tested for their cytotoxic activities against 3 cell lines: H1650, HT-29, and HL-60. Compound 5 exhibited significant cytotoxic activity against human colon adenocarcinoma HT-29 and the human promyelocytic leukemia HL-60, with IC μM values of 1.4 and 1.7 respectively. Molecular docking and homology modeling studies were carried out to confirm the affinity of these synthesized compounds to the three different PIM kinases. Additionally, a number of predictions, ADME/Tox, were adopted to evaluate their drug-likeness.

摘要

最近有报道称，嗜糖单孢菌素A是一种天然抗癌剂，其作用机制是抑制莫洛尼氏鼠白血病病毒1型原病毒整合位点（PIM-1）激酶。合成了该天然产物的结构生物电子等排体，并对PIM激酶进行了测试。它们对所有已知的PIM激酶（PIM-1、2和3）均显示出强效抑制活性，IC值范围为0.22至2.46μM。化合物5是最有效的抑制剂，对PIM-1、2、3的IC值分别为0.37、0.41和0.3μM。测试了化合物4-6对3种细胞系（H1650、HT-29和HL-60）的细胞毒性活性。化合物5对人结肠腺癌HT-29和人早幼粒细胞白血病HL-60表现出显著的细胞毒性活性，IC50值分别为1.4和1.7μM。进行了分子对接和同源建模研究，以确认这些合成化合物对三种不同PIM激酶的亲和力。此外，采用了一些ADME/Tox预测来评估它们的类药性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/2d33ea4e8854/c9ra10216g-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/ab3d1d483cf9/c9ra10216g-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/4e4537c2b85c/c9ra10216g-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/faf96e98dc1e/c9ra10216g-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/d92af77c478a/c9ra10216g-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/5e2ddfcfb0bb/c9ra10216g-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/47da68a091c8/c9ra10216g-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/2d33ea4e8854/c9ra10216g-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/ab3d1d483cf9/c9ra10216g-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/4e4537c2b85c/c9ra10216g-s1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/faf96e98dc1e/c9ra10216g-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/d92af77c478a/c9ra10216g-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/5e2ddfcfb0bb/c9ra10216g-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/47da68a091c8/c9ra10216g-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/44cb/9049778/2d33ea4e8854/c9ra10216g-f6.jpg

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