{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yu J"],"funding":["Fundamental Research Funds for the Central Universities","Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences","Science and Technology Project of Tianjin"],"pagination":["952-972"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC8942544"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["37(1)"],"pubmed_abstract":["The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors cannot cross the blood-brain barrier, thus limiting their application in the central nervous system. Here, 55 benzodiazepines were designed and synthesised to screen brain penetrating PARP-1 inhibitors. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with better activity were selected for further assays <i>in vitro</i>. Among them, compounds <b>H34</b>, <b>H42</b>, <b>H48</b>, and <b>H52</b> displayed acceptable inhibition effects on breast cancer cells. Also, computational prediction together with the permeability assays <i>in vitro</i> and <i>in vivo</i> proved that the benzodiazepine PARP-1 inhibitors we synthesised were brain permeable. Compound <b>H52</b> exhibited a B/P ratio of 40 times higher than that of Rucaparib and would be selected to develop its potential use in neurodegenerative diseases. Our study provided potential lead compounds and design strategies for the development of brain penetrating PARP-1 inhibitors.HIGHLIGHTSStructural fusion was used to screen brain penetrating PARP-1 inhibitors.55 benzodiazepines were evaluated for their PARP-1 inhibition activity.Four compounds displayed acceptable inhibition effects on breast cancer cells.The benzodiazepine PARP-1 inhibitors were proved to be brain permeable."],"journal":["Journal of enzyme inhibition and medicinal chemistry"],"pubmed_title":["Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors."],"pmcid":["PMC8942544"],"funding_grant_id":["18ZXXYSY00110","3332020057","CIFMS 2016-I2M-3-022"],"pubmed_authors":["Li Y","Cui Y","Luo L","Gou W","Sun T","Shang H","Yu J","Sun X","Hou W"],"additional_accession":[]},"is_claimable":false,"name":"Design and synthesis of benzodiazepines as brain penetrating PARP-1 inhibitors.","description":"The poly (ADP-ribose) polymerase (PARP) inhibitors play a crucial role in cancer therapy. However, most approved PARP inhibitors cannot cross the blood-brain barrier, thus limiting their application in the central nervous system. Here, 55 benzodiazepines were designed and synthesised to screen brain penetrating PARP-1 inhibitors. All target compounds were evaluated for their PARP-1 inhibition activity, and compounds with better activity were selected for further assays <i>in vitro</i>. Among them, compounds <b>H34</b>, <b>H42</b>, <b>H48</b>, and <b>H52</b> displayed acceptable inhibition effects on breast cancer cells. Also, computational prediction together with the permeability assays <i>in vitro</i> and <i>in vivo</i> proved that the benzodiazepine PARP-1 inhibitors we synthesised were brain permeable. Compound <b>H52</b> exhibited a B/P ratio of 40 times higher than that of Rucaparib and would be selected to develop its potential use in neurodegenerative diseases. Our study provided potential lead compounds and design strategies for the development of brain penetrating PARP-1 inhibitors.HIGHLIGHTSStructural fusion was used to screen brain penetrating PARP-1 inhibitors.55 benzodiazepines were evaluated for their PARP-1 inhibition activity.Four compounds displayed acceptable inhibition effects on breast cancer cells.The benzodiazepine PARP-1 inhibitors were proved to be brain permeable.","dates":{"release":"2022-01-01T00:00:00Z","publication":"2022 Dec","modification":"2026-05-30T15:10:20.137Z","creation":"2024-11-13T00:59:27.441Z"},"accession":"S-EPMC8942544","cross_references":{"pubmed":["35317687"],"doi":["10.1080/14756366.2022.2053524"]}}