2. Academic Validation
  3. Computational modeling and synthesis of pyridine variants of benzoyl-phenoxy-acetamide with high glioblastoma cytotoxicity and brain tumor penetration

Computational modeling and synthesis of pyridine variants of benzoyl-phenoxy-acetamide with high glioblastoma cytotoxicity and brain tumor penetration

  • Sci Rep. 2023 Jul 28;13(1):12236. doi: 10.1038/s41598-023-39236-w.
Charles H Ingraham 4th 1 2 3 4,  Joanna Stalinska 2 3 5,  Sean C Carson 1,  Susan B Colley 2 3 6,  Monika Rak 2 3 5,  Adam Lassak 2 3,  Francesca Peruzzi 2 3,  Krzysztof Reiss 7 8 9,  Branko S Jursic 10 11
Affiliations

Affiliations

  • 1 Department of Chemistry, University of New Orleans, New Orleans, LA, 70148, USA.
  • 2 Neurological Cancer Research, Department of Medicine, Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, 70112, USA.
  • 3 Neurological Cancer Research, Department of Interdisciplinary Oncology, LSU Health Sciences Center, New Orleans, LA, 70112, USA.
  • 4 WayPath Pharma, New Orleans BioInnovation Center (NOBIC), 1441 Canal Str., New Orleans, LA, 70112, USA.
  • 5 Department of Cell Biology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Cracow, Poland.
  • 6 Grants and Development Office, Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, 70112, USA.
  • 7 Neurological Cancer Research, Department of Medicine, Stanley S. Scott Cancer Center, LSU Health Sciences Center, New Orleans, LA, 70112, USA. kreiss@lsuhsc.edu.
  • 8 Neurological Cancer Research, Department of Interdisciplinary Oncology, LSU Health Sciences Center, New Orleans, LA, 70112, USA. kreiss@lsuhsc.edu.
  • 9 WayPath Pharma, New Orleans BioInnovation Center (NOBIC), 1441 Canal Str., New Orleans, LA, 70112, USA. kreiss@lsuhsc.edu.
  • 10 Department of Chemistry, University of New Orleans, New Orleans, LA, 70148, USA. bjursic1@uno.edu.
  • 11 Stepharm LLC., PO Box 24220, New Orleans, LA, 70184, USA. bjursic1@uno.edu.
PMID: 37507404 DOI: 10.1038/s41598-023-39236-w
Abstract

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.

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