Styrylquinazoline derivatives as ABL inhibitors selective for different DFG orientations

Among tyrosine kinase inhibitors, quinazoline-based compounds represent a large and well-known group of multi-target agents. Our previous studies have shown interesting kinases inhibition activity for a series of 4-aminostyrylquinazolines based on the CP-31398 scaffold. Here, we synthesised a new series of styrylquinazolines with a thioaryl moiety in the C4 position and evaluated in detail their biological activity. Our results showed high inhibition potential against non-receptor tyrosine kinases for several compounds. Molecular docking studies showed differential binding to the DFG conformational states of ABL kinase for two derivatives. The compounds showed sub-micromolar activity against leukaemia. Finally, in-depth cellular studies revealed the full landscape of the mechanism of action of the most active compounds. We conclude that S4-substituted styrylquinazolines can be considered as a promising scaffold for the development of multi-kinase inhibitors targeting a desired binding mode to kinases as effective anticancer drugs.</p

Pyrrolidinium-Based Ionic Liquids as Sustainable Media in Heat-Transfer Processes

Ionic liquids are viewed as green media for many engineering applications and exhibit exceptional properties, including negligible vapor pressure, null flammability, wide liquid range, and high thermal and chemical stabilities. We present new thermophysical properties of 1-alkyl-1-methylpyrrolidinium bis­(trifluoromethylsulfonyl)­imides ([C_<i>n</i>C₁pyr]­[NTf₂] with <i>n</i> = 3, 4) for future application them as heat-transfer media. The speed of sound was measured at pressures up to 100 MPa and at temperatures from 293 K to 318 K. The <i>p</i>ρ<i>T</i>, <i>pC</i>_<i>p</i><i>T</i> data, and derived thermophysical properties were determined using the acoustic method. TGA of [C_<i>n</i>C₁pyr]­[NTf₂] and cytotoxicity of [C_<i>n</i>C₁pyr]­[NTf₂] and their imidazolium counterparts ([C_<i>n</i>C₁im]­[NTf₂]) are investigated. The physicochemical properties of [C_<i>n</i>C₁pyr]­[NTf₂] are compared with those of [C_<i>n</i>C₁im]­[NTf₂] and commercial heat-transfer fluids (Therminol VP-1, Therminol 66, Marlotherm SH). [C₃C₁pyr]­[NTf₂] and [C₄C₁pyr]­[NTf₂] have a wide liquid range of ∼480 K and high decomposition onset temperatures of 771 and 776 K, respectively. [C_<i>n</i>C₁pyr]­[NTf₂] exhibit high energy storage density of ∼1.98 MJ m^–3 K^–1, which is slightly dependent on temperature and pressure. The thermal conductivity of [C_<i>n</i>C₁pyr]­[NTf₂] is comparable to that of commercial heat-transfer fluids. [C_<i>n</i>C₁pyr]­[NTf₂] have lower toxicity for normal human dermal fibroblast cells than [C_<i>n</i>C₁im]­[NTf₂]. Thus, [C_<i>n</i>C₁pyr]­[NTf₂] are promising heat-transfer fluid candidates

Tubulin level (a) and PARP cleavage (b) in HCT-116 cells for 6b (0, 10, 20, 40 μM) and 17b (0, 10, 20, 40, μM).

<p>Tubulin level (a) and PARP cleavage (b) in HCT-116 cells for 6b (0, 10, 20, 40 μM) and 17b (0, 10, 20, 40, μM).</p

Synthesis of the compounds that were studied.

<p>Synthesis of the compounds that were studied.</p

Quinolines and analogs with a marked anticancer activity.

<p>Quinolines and analogs with a marked anticancer activity.</p

<i>In vitro</i> staining of HCT116 cells treated with 6b (CH I.) and MitoTracker Orange CMTMRos dye (CH II.).

<p><i>In vitro</i> staining of HCT116 cells treated with 6b (CH I.) and MitoTracker Orange CMTMRos dye (CH II.).</p

Anti-cancer activity of the studied compounds (ND—not determined).

<p>Results are expressed as mean ± SD of at least three independent experiments. IC₅₀ values below 10 μM are bolded.</p><p>Anti-cancer activity of the studied compounds (ND—not determined).</p

Absorption spectra of 2c, 3c, 5b, 6b, CP-31398 and doxorubicin without CT-DNA (solid line) and with CT-DNA (dotted line).

<p>Absorption spectra of 2c, 3c, 5b, 6b, CP-31398 and doxorubicin without CT-DNA (solid line) and with CT-DNA (dotted line).</p

Activity (as—logIC₅₀) vs logP of the compounds that were tested.

<p>Activity (as—logIC₅₀) vs logP of the compounds that were tested.</p

Selective hydrolysis of styrylquinolines.

<p>For example, compare <b>2b</b>, <b>3b</b> and <b>18b</b>.</p