Design, synthesis and biological evaluation of novel 1,3,4-thiadiazole derivatives as anti-glioblastoma agents targeting the AKT pathway

Monika Szeliga; Monika Karpińska; Radosław Rola; Andrzej Niewiadomy

doi:10.1016/j.bioorg.2020.104362

Design, synthesis and biological evaluation of novel 1,3,4-thiadiazole derivatives as anti-glioblastoma agents targeting the AKT pathway

Bioorg Chem. 2020 Dec:105:104362. doi: 10.1016/j.bioorg.2020.104362. Epub 2020 Oct 9.

Authors

Monika Szeliga¹, Monika Karpińska², Radosław Rola³, Andrzej Niewiadomy⁴

Affiliations

¹ Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 5 Pawinskiego Str, 02-106 Warsaw, Poland. Electronic address: [email protected].
² Łukasiewicz Research Network - Institute of Industrial Organic Chemistry, 6 Annopol Str., 03-236 Warsaw, Poland. Electronic address: [email protected].
³ Department of Neurosurgery and Paediatric Neurosurgery of the Lublin Medical University, 8 Jaczewskiego Str, 20-090 Lublin, Poland. Electronic address: [email protected].
⁴ Łukasiewicz Research Network - Institute of Industrial Organic Chemistry, 6 Annopol Str., 03-236 Warsaw, Poland. Electronic address: [email protected].

PMID: 33074121
DOI: 10.1016/j.bioorg.2020.104362

Abstract

In spite of progress in understanding biology of glioblastoma (GBM), this tumor remains incurable with a median survival rate of 15 months. Previous studies have shown that 2-(4-fluorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (FPDT) and 2-(3-chlorophenyloamino)-5-(2,4-dihydroxyphenyl)-1,3,4-thiadiazole (CPDT) diminished viability of cancer cell lines of different origin. In the current study, we have examined activity of these compounds in several GBM cell lines and patient-derived GBM cells. We have also designed, synthesized and evaluated anti-GBM activity of novel 1,3,4-thiadiazole derivatives containing additional Cl or CH₂CH₃ substitute at C5-position of 2,4-dihydroxyphenyl. The tested compounds presented a considerable cytotoxicity against all GBM cell lines examined as well as patient-derived GBM cells. They were 15-110 times more potent than temozolomide, the first-line chemotherapeutic agent for GBM. Notably, in anticancer concentrations three of the derivatives were not toxic to human astrocytes. FPDT appeared to be the most promising compound with IC₅₀ values between 45 μM and 68 μM for GBM cells and >100 μM for astrocytes. It augmented activity of temozolomide and inhibited proliferation migration and invasion of GBM cells. Treatment with FPDT diminished phosphorylation level of GSK3β and AKT. Pretreatment with PDGF-BB, an AKT activator, partially protected cells from death caused by FPDT, indicating that FPDT-mediated decrease in cell viability is causatively related to the inhibition of the AKT pathway.

Keywords: AKT pathway; Anti-glioblastoma compound; Glioblastoma; Proliferation; Thiadiazole derivative; Viability.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Brain Neoplasms / drug therapy*
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Design*
Drug Screening Assays, Antitumor
Glioblastoma / drug therapy*
Glioblastoma / metabolism
Glioblastoma / pathology
Humans
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
Proto-Oncogene Proteins c-akt / metabolism
Structure-Activity Relationship
Thiadiazoles / chemical synthesis
Thiadiazoles / chemistry
Thiadiazoles / pharmacology*

Substances

Antineoplastic Agents
Protein Kinase Inhibitors
Thiadiazoles
1,3,4-thiadiazole
Proto-Oncogene Proteins c-akt