TY  - JOUR
AU  - Stojković, Pavle
AU  - Kostić, Ana
AU  - Lupšić, Ema
AU  - Jovanović, Nataša Terzić
AU  - Novaković, Miroslav M.
AU  - Nedialkov, Paraskev
AU  - Trendafilova, Antoaneta
AU  - Pešić, Milica
AU  - Opsenica, Igor 
PY  - 2023
UR  - http://cherry.chem.bg.ac.rs/handle/123456789/6258
AB  - 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.
PB  - Elsevier
T2  - Bioorganic Chemistry
T1  - Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells
VL  - 138
SP  - 106605
DO  - 10.1016/j.bioorg.2023.106605
ER  - 

@article{
author = "Stojković, Pavle and Kostić, Ana and Lupšić, Ema and Jovanović, Nataša Terzić and Novaković, Miroslav M. and Nedialkov, Paraskev and Trendafilova, Antoaneta and Pešić, Milica and Opsenica, Igor ",
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 = "Elsevier",
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",
pages = "106605",
doi = "10.1016/j.bioorg.2023.106605"
}

Stojković, P., Kostić, A., Lupšić, E., Jovanović, N. T., Novaković, M. M., Nedialkov, P., Trendafilova, A., Pešić, M.,& Opsenica, I.. (2023). Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells. in Bioorganic Chemistry
Elsevier., 138, 106605.
https://doi.org/10.1016/j.bioorg.2023.106605

Stojković P, Kostić A, Lupšić E, Jovanović NT, Novaković MM, Nedialkov P, Trendafilova A, Pešić M, Opsenica I. Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells. in Bioorganic Chemistry. 2023;138:106605.
doi:10.1016/j.bioorg.2023.106605 .

Stojković, Pavle, Kostić, Ana, Lupšić, Ema, Jovanović, Nataša Terzić, Novaković, Miroslav M., Nedialkov, Paraskev, Trendafilova, Antoaneta, Pešić, Milica, Opsenica, Igor , "Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells" in Bioorganic Chemistry, 138 (2023):106605,
https://doi.org/10.1016/j.bioorg.2023.106605 . .