Computational modeling and synthesis of pyridine variants of benzoyl-phenoxy-acetamide with high glioblastoma cytotoxicity and brain tumor penetration.
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
28 07 2023
28 07 2023
Historique:
received:
03
04
2023
accepted:
21
07
2023
medline:
31
7
2023
pubmed:
29
7
2023
entrez:
28
7
2023
Statut:
epublish
Résumé
Glioblastomas are highly aggressive brain tumors for which therapeutic options are very limited. In a quest for new anti-glioblastoma drugs, we focused on specific structural modifications to the benzoyl-phenoxy-acetamide (BPA) structure present in a common lipid-lowering drug, fenofibrate, and in our first prototype glioblastoma drug, PP1. Here, we propose extensive computational analyses to improve the selection of the most effective glioblastoma drug candidates. Initially, over 100 structural BPA variations were analyzed and their physicochemical properties, such as water solubility (- logS), calculated partition coefficient (ClogP), probability for BBB crossing (BBB_SCORE), probability for CNS penetration (CNS-MPO) and calculated cardiotoxicity (hERG), were evaluated. This integrated approach allowed us to select pyridine variants of BPA that show improved BBB penetration, water solubility, and low cardiotoxicity. Herein the top 24 compounds were synthesized and analyzed in cell culture. Six of them demonstrated glioblastoma toxicity with IC50 ranging from 0.59 to 3.24 µM. Importantly, one of the compounds, HR68, accumulated in the brain tumor tissue at 3.7 ± 0.5 µM, which exceeds its glioblastoma IC50 (1.17 µM) by over threefold.
Identifiants
pubmed: 37507404
doi: 10.1038/s41598-023-39236-w
pii: 10.1038/s41598-023-39236-w
pmc: PMC10382599
doi:
Substances chimiques
Acetamides
0
Pyridines
0
Water
059QF0KO0R
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
12236Subventions
Organisme : NIGMS NIH HHS
ID : P20 GM121288
Pays : United States
Organisme : NCI NIH HHS
ID : R41 CA275433
Pays : United States
Organisme : NCI NIH HHS
ID : 1R41CA275433
Pays : United States
Commentaires et corrections
Type : UpdateOf
Informations de copyright
© 2023. The Author(s).
Références
Cell Cycle. 2012 Jul 15;11(14):2660-71
pubmed: 22732497
Nat Rev Drug Discov. 2015 Jun;14(6):387-404
pubmed: 25907346
BMC Bioinformatics. 2019 May 29;20(Suppl 10):250
pubmed: 31138104
JACS Au. 2022 Jun 16;2(6):1383-1394
pubmed: 35783161
Mol Cell Biol. 2015 Jan;35(1):182-98
pubmed: 25332241
FEBS J. 2020 Mar;287(5):1005-1034
pubmed: 31545550
ACS Chem Neurosci. 2021 Nov 3;12(21):4090-4112
pubmed: 34652128
J Med Chem. 2019 Nov 14;62(21):9824-9836
pubmed: 31603678
Cells. 2022 Aug 15;11(16):
pubmed: 36010607
Carcinogenesis. 2019 Jul 20;40(7):853-860
pubmed: 30877769
Mini Rev Med Chem. 2022;22(2):248-272
pubmed: 34126914
Int J Mol Sci. 2016 Jan 26;17(2):
pubmed: 26821017
World Neurosurg. 2018 Dec;120:302-315
pubmed: 30196171
Sci Rep. 2019 Apr 16;9(1):6117
pubmed: 30992465
Surg Neurol Int. 2010 Dec 25;1:96
pubmed: 21246059
Transl Oncol. 2019 Jul;12(7):895-907
pubmed: 31078963
Front Cell Neurosci. 2019 Jun 06;13:230
pubmed: 31244605
Sci Rep. 2019 Nov 19;9(1):17021
pubmed: 31745126
J Virol. 2006 May;80(10):4833-46
pubmed: 16641275
Cancer Drug Resist. 2021;4:17-43
pubmed: 34337348
Nature. 2013 Feb 6;494(7438):506
pubmed: 23389443
Perspect Medicin Chem. 2014 Jun 16;6:11-24
pubmed: 24963272
Cancers (Basel). 2022 Jan 17;14(2):
pubmed: 35053605
Molecules. 2015 Oct 07;20(10):18279-351
pubmed: 26457702
ACS Chem Neurosci. 2016 Jun 15;7(6):767-75
pubmed: 26991242
Nature. 2020 Apr;580(7801):71-75
pubmed: 32238943
Neurochem Int. 2021 Mar;144:104952
pubmed: 33400964
Adv Drug Deliv Rev. 2001 Mar 1;46(1-3):3-26
pubmed: 11259830
Am J Pathol. 2007 May;170(5):1445-53
pubmed: 17456751
J Mol Model. 2012 Sep;18(9):4367-80
pubmed: 22585356
Cancer Genomics Proteomics. 2018 Sep-Oct;15(5):421-436
pubmed: 30194083
Cell. 2013 Oct 10;155(2):462-77
pubmed: 24120142
Nat Rev Cancer. 2020 Jan;20(1):26-41
pubmed: 31601988
Curr Protoc Pharmacol. 2011 Mar;Chapter 14:Unit 14.16
pubmed: 21743824
Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2203936119
pubmed: 36161947
J Med Chem. 2017 Mar 9;60(5):1662-1664
pubmed: 28234469
Nucleic Acids Res. 2022 Jul 5;50(W1):W115-W123
pubmed: 35536252
J Comput Aided Mol Des. 2022 Dec;36(12):837-849
pubmed: 36305984
J Nutr Metab. 2015;2015:760689
pubmed: 26167297
J Cheminform. 2019 Jan 5;11(1):2
pubmed: 30612223
J Chem Inf Comput Sci. 2003 Jan-Feb;43(1):120-5
pubmed: 12546544
Nat Rev Drug Discov. 2018 Oct 30;17(11):777
pubmed: 30374178
J Lab Autom. 2015 Apr;20(2):107-26
pubmed: 25586998
Front Endocrinol (Lausanne). 2016 Feb 02;7:5
pubmed: 26869992
Tetrahedron Lett. 2021 Jan 19;63:
pubmed: 33456089
Nature. 2018 Sep;561(7724):S40-S41
pubmed: 30258156
RSC Adv. 2022 May 20;12(24):15385-15406
pubmed: 35693235
Neuro Oncol. 2021 Aug 2;23(8):1231-1251
pubmed: 34185076
J Neuropathol Exp Neurol. 2022 Apr 27;81(5):312-329
pubmed: 35446393
J Physiol Pharmacol. 2015 Apr;66(2):233-47
pubmed: 25903954
Pharmacol Ther. 2020 Jan;205:107419
pubmed: 31629009
Toxicol In Vitro. 2005 Apr;19(3):299-334
pubmed: 15713540
J Proteome Res. 2019 Mar 1;18(3):960-969
pubmed: 30596429
Eur J Med Chem. 2020 Jun 1;195:112290
pubmed: 32283295
Sci Rep. 2022 Mar 1;12(1):3384
pubmed: 35232976
Front Oncol. 2018 Oct 23;8:464
pubmed: 30406030