@article{
author = "Stojković, Pavle and Stepanović, Ana and Lupšić, Ema and Terzić Jovanović, Nataša and Novaković, Miroslav and Nedialkov, Paraskev and Trendafilova, Antoaneta and Pešić, Milica and Opsenica, Igor M.",
year = "2023",
abstract = "The synthesis of 24 hybrid molecules, consisting of naturally occurring sclareol (SCL) and synthetic 1,2,4-triazolo
[1,5-a]pyrimidines (TPs), is described. New compounds were designed with the aim of improving the cytotoxic
properties, activity, and selectivity of the parent compounds. Six analogs (12a-f) contained 4-benzylpiperazine
linkage, while 4-benzyldiamine linkage was present in eighteen derivatives (12g-r and 13a-f). Hybrids 13a-f
consist of two TP units. After purification, all hybrids (12a-r and 13a-f), as well as their precursors (9a-e and
11a-c), were tested on human glioblastoma U87 cells. More than half of the tested synthesized molecules, 16 out
of 31, caused a significant reduction of U87 cell viability (more than 75% reduction) at 30 μM. The
concentration-dependent cytotoxicity of these 16 compounds was also examined on U87 cells, corresponding
multidrug-resistant (MDR) U87-TxR cells with increased P-glycoprotein (P-gp) expression and activity, and
normal lung fibroblasts MRC-5. Importantly, 12l and 12r were active in the nanomolar range, while seven
compounds (11b, 11c, 12i, 12l, 12n, 12q, and 12r) were more selective towards glioblastoma cells than SCL. All
compounds except 12r evaded MDR, showing even better cytotoxicity in U87-TxR cells. In particular, 11c, 12a,
12g, 12j, 12k, 12m, 12n, and SCL showed collateral sensitivity. Hybrid compounds 12l, 12q, and 12r decreased
P-gp activity to the same extent as a well-known P-gp inhibitor - tariquidar (TQ). Hybrid compound 12l and its
precursor 11c affected different cellular processes including the cell cycle, cell death, and mitochondrial
membrane potential, and changed the levels of reactive oxygen and nitrogen species (ROS/RNS) in glioblastoma
cells. Collateral sensitivity towards MDR glioblastoma cells was caused by the modulation of oxidative stress
accompanied by inhibition of mitochondria.",
publisher = "Academic Press Inc.",
journal = "Bioorganic Chemistry",
title = "Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells",
volume = "138",
doi = "10.1016/j.bioorg.2023.106605",
pages = "106605"
}
