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吡咯并[2',3':3,4]环庚[1,2-][1,2]恶唑，一类新型抗有丝分裂剂，对多种恶性细胞类型具有活性。

Pyrrolo[2',3':3,4]cyclohepta[1,2-][1,2]oxazoles, a New Class of Antimitotic Agents Active against Multiple Malignant Cell Types.

机构信息

Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, 90123 Palermo, Italy.

Net4Science srl, Academic Spinoff, Università Magna Græcia di Catanzaro, Viale Europa, 88100 Catanzaro, Italy.

出版信息

J Med Chem. 2020 Oct 22;63(20):12023-12042. doi: 10.1021/acs.jmedchem.0c01315. Epub 2020 Oct 11.

DOI:10.1021/acs.jmedchem.0c01315
PMID:32986419
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7901646/
Abstract

A new class of pyrrolo[2',3':3,4]cyclohepta[1,2-][1,2]oxazoles was synthesized for the treatment of hyperproliferative pathologies, including neoplasms. The new compounds were screened in the 60 human cancer cell lines of the NCI drug screen and showed potent activity with GI values reaching the nanomolar level, with mean graph midpoints of 0.08-0.41 μM. All compounds were further tested on six lymphoma cell lines, and eight showed potent growth inhibitory effects with IC values lower than 500 nM. Mechanism of action studies showed the ability of the new [1,2]oxazoles to arrest cells in the G2/M phase in a concentration dependent manner and to induce apoptosis through the mitochondrial pathway. The most active compounds inhibited tubulin polymerization, with IC values of 1.9-8.2 μM, and appeared to bind to the colchicine site. The G2/M arrest was accompanied by apoptosis, mitochondrial depolarization, generation of reactive oxygen species, and PARP cleavage.

摘要

为治疗包括肿瘤在内的过度增殖性疾病，我们合成了一类新的吡咯并[2'，3':3，4]环庚[1,2-][1,2]恶唑。新化合物在 NCI 药物筛选的 60 个人类癌细胞系中进行了筛选，表现出很强的活性，GI 值达到纳摩尔水平，平均图中点为 0.08-0.41 μM。所有化合物均进一步在 6 个淋巴瘤细胞系中进行了测试，其中 8 种化合物表现出很强的生长抑制作用，IC 值低于 500 nM。作用机制研究表明，新的[1,2]恶唑类化合物能够以浓度依赖的方式将细胞阻滞在 G2/M 期，并通过线粒体途径诱导细胞凋亡。最活跃的化合物抑制微管蛋白聚合，IC 值为 1.9-8.2 μM，似乎与秋水仙碱结合位点结合。G2/M 期阻滞伴随着细胞凋亡、线粒体去极化、活性氧生成和 PARP 切割。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/4491d24ac3fa/jm0c01315_0010.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/4293e4afd315/jm0c01315_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/a6a64d63b2c4/jm0c01315_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/4491d24ac3fa/jm0c01315_0010.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/5ba425b29425/jm0c01315_0001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/b82de2ea5cdc/jm0c01315_0002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/7f0b32ed6832/jm0c01315_0011.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/88ed11add648/jm0c01315_0003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/26b630f19498/jm0c01315_0004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/937b50728e2d/jm0c01315_0005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/404c6614be70/jm0c01315_0006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/eacf6712a8b6/jm0c01315_0007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/4293e4afd315/jm0c01315_0008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/a6a64d63b2c4/jm0c01315_0009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1bc6/7901646/4491d24ac3fa/jm0c01315_0010.jpg

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本文引用的文献

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[2]
An overview on chemical structures as ΔF508-CFTR correctors.

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