Novel hybrids of sclareol and 1,2,4-triazolo[1,5-a]pyrimidine show collateral sensitivity in multidrug-resistant glioblastoma cells

by Selleckchem | Jul 13 2023

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.

Comments:

The passage describes the synthesis and evaluation of hybrid molecules derived from sclareol (SCL), a naturally occurring compound, and synthetic 1,2,4-triazolo[1,5-a]pyrimidines (TPs). The goal of this research was to enhance the cytotoxic properties, activity, and selectivity of the parent compounds.

A total of 24 hybrid molecules were synthesized, consisting of combinations of SCL and TPs. These hybrids were designed with structural variations, including the presence of a 4-benzylpiperazine linkage in six analogs (12a-f) and a 4-benzyldiamine linkage in eighteen derivatives (12g-r and 13a-f). Hybrids 13a-f were unique in that they contained two TP units.

Following purification, all synthesized hybrids (12a-r and 13a-f) and their precursors (9a-e and 11a-c) were tested on human glioblastoma U87 cells. Among the tested molecules, more than half (16 out of 31) demonstrated significant reduction of U87 cell viability, exceeding 75% reduction at a concentration of 30 µM.

The concentration-dependent cytotoxicity of these 16 compounds was further examined on U87 cells, multidrug-resistant (MDR) U87-TxR cells with increased expression and activity of P-glycoprotein (P-gp), and normal lung fibroblasts MRC-5. Notably, compounds 12l and 12r exhibited activity in the nanomolar range. Additionally, seven compounds (11b, 11c, 12i, 12l, 12n, 12q, and 12r) displayed greater selectivity toward glioblastoma cells compared to SCL. Except for 12r, all compounds evaded MDR and showed improved cytotoxicity in U87-TxR cells. Specifically, compounds 11c, 12a, 12g, 12j, 12k, 12m, 12n, and SCL exhibited collateral sensitivity.

Furthermore, hybrid compounds 12l, 12q, and 12r demonstrated a reduction in P-gp activity similar to that of a well-known P-gp inhibitor called tariquidar (TQ). Compound 12l and its precursor 11c affected various cellular processes, including the cell cycle, cell death, mitochondrial membrane potential, and levels of reactive oxygen and nitrogen species (ROS/RNS) in glioblastoma cells. The collateral sensitivity observed in MDR glioblastoma cells was attributed to the modulation of oxidative stress, accompanied by mitochondrial inhibition.