title: Derivatives of the pyrazolo[1,5-a]pyrimidine acetamide DPA-713 as translocator protein (TSPO) ligands and pro-apoptotic agents in human glioblastoma.
abstract: The 18kDa translocator protein (TSPO) is a target for novel glioblastoma therapies due to its upregulation in this cancer and relatively low levels of expression in the healthy cortex. The pyrazolo[1,5-a]pyrimidine acetamides, exemplified by DPA-713 and DPA-714, are a class of high affinity TSPO ligands with selectivity over the central benzodiazepine receptor. In this study we have explored the potential anti-glioblastoma activity of a library of DPA-713 and DPA-714 analogues, and investigated the effect of amending the alkyl ether chain on TSPO affinity and functional potential. All ligands demonstrated nanomolar affinity for TSPO, but showed diverse functional activity, for example DPA-713 and DPA-714 did not affect the proliferation or viability of human T98G glioblastoma cells, while the hexyl ether and benzyl ether derivatives decreased proliferation of T98G cells without affecting proliferation in human fetal glial SVGp12 cells. These ligands also induced apoptosis and dissipated T98G mitochondrial membrane potential. This suggests that the nature of the alkyl ether chain of pyrazolo[1,5-a]pyrimidine acetamides has little influence on TSPO affinity but is important for functional activity of this class of TSPO ligands.
authors.affiliation: Faculty of Health Sciences, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Eryn L
authors.initials: EL
authors.lastname: Werry
authors.affiliation: Discipline of Pharmacology, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: King
authors.affiliation: Faculty of Health Sciences, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Melissa L
authors.initials: ML
authors.lastname: Barron
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Banister
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Renee
authors.initials: R
authors.lastname: Sokias
authors.affiliation: School of Chemistry, The University of Sydney, Sydney, NSW, Australia. Electronic address: michael.kassiou@sydney.edu.au.
authors.forename: Michael
authors.initials: M
authors.lastname: Kassiou
mesh_terms: D000081:Acetamides / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D008024:Ligands; D011485:Protein Binding / Q000502:physiology; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D018079:Receptors, GABA / Q000378:metabolism*
chemical_list: D000081:Acetamides; D008024:Ligands; C507091:N,N-diethyl-2-(2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo(1,5-a)pyrimidin-3-yl)-acetamide; D011720:Pyrazoles; D011743:Pyrimidines; D018079:Receptors, GABA; C499229:TSPO protein, human
keywords: Apoptosis; DPA-713; Glioblastoma; Proliferation; Translocator protein