The effect of substituent position and solvent on thermal Z‒E isomerization of dihydroquinolylazotetrazole dyes: kinetic, thermodynamic, and spectral approaches.

Kinetic and thermodynamic parameters have been investigated for the thermal Z‒E isomerization of dihydroquinolylazotetrazole dyes with alkyl substituents (Me, t-Bu, and Adm) at positions 1 (dyes 2) and 2 (dyes 3) of the tetrazole moiety in two solvents of different polarity, acetonitrile (MeCN) and toluene. The experimental results show crucial dependence of these parameters on a substituent position in the tetrazole moiety and on a solvent. For dyes 2, Eact and ΔH‡ are lower in MeCN than in toluene that results in a high increase in the lifetimes of the Z isomers: from milliseconds in MeCN to minutes in toluene. For dyes 3, the difference in Eact and ΔH‡ in the two solvents is opposite: Eact and ΔH‡ are by more than 20 kJ mol-1 higher in MeCN, nevertheless, the rate constants for 3 in toluene are comparable with those in MeCN at the ambient temperature and the difference in the behavior is determined by the value of negative entropy of activation. Quantum-chemical calculations of the thermal Z‒E isomerization show the possibility of the process to occur via crossing from the S0 to the thermally induced T1 state. The contribution of this path is highest for 3 in toluene. The analysis of the absorption spectra demonstrates that for the E isomers, the n‒π* and π‒π* transitions are within the long-wavelength absorption band and their positions relative each other are opposite in the solvents: the n‒π* transition is blue-shifted relative to the π‒π* transition in MeCN and is red-shifted in toluene.

Benzimidazolyl-pyrazolo[3,4-b]pyridinones, Selective Inhibitors of MOLT-4 Leukemia Cell Growth and Sea Urchin Embryo Spiculogenesis: Target Quest.

1,3-Substituted pyrazolo[3,4-b]pyridinones 11-18 were synthesized by a three-component condensation of Meldrum's acid with aryl aldehydes and 1,3-substituted 5-aminopyrazoles. Their biological activity was evaluated using the in vivo phenotypic sea urchin embryo assay and the in vitro cytotoxicity screen against human cancer cell lines. In the sea urchin embryo model, 1-benzimidazolyl-pyrazolo[3,4-b]pyridinones 11 caused inhibition of hatching and spiculogenesis at sub-micromolar concentrations. These compounds also selectively and potently inhibited growth of the MOLT-4 leukemia cell line. Subsequent structure-activity relationship studies determined the benzimidazolyl fragment as an essential pharmacophore for both effects. We applied numerous techniques for target identification. A preliminary QSAR target identification search did not result in tangible leads. Attempts to prepare a relevant photoaffinity probe that retained potency in both assays were not successful. Compounds 11 were further characterized for their activity in a wild-type versus Notch-mutant leukemia cell lines, and in in vitro panels of kinases and matrix metalloproteinases. Using a series of diverse modulators of spiculogenesis as standards, we excluded multiple signaling networks including Notch, Wnt/ß-catenin, receptor tyrosine kinases (VEGF/VEGFR, FGF/FGFR), PI3K, and Raf-MEK-ERK as possible targets of 11. On the other hand, matrix metalloproteinase-9/hatching enzyme was identified as one potential target.

Novel hetarylazo dyes containing tetrazole and hydroquinoline moieties: spectral characteristics, solvatochromism and photochemistry.

Novel hetarylazo dyes containing tetrazole and tetra- or dihydroquinoline moieties were synthesized and their spectral properties in solvents of different polarities and H-bonding abilities were examined. The dyes exhibit solvatochromism dramatically depending on the proton accepting ability of solvents: (DMSO > H2O > MeOH > ACN > CH2Cl2) and the dye concentration. Upon dilution the absorption maximum of the visible band shows a blue shift and the absorption coefficient of the maximum decreases. This was accounted for by complex formation either between the dye molecules or between the dye and solvent molecules. The H-bond with partial proton transfer is formed between the acidic NH group of the tetrazole moiety of a dye molecule and the basic NH group of the hydroquinoline moiety of the other dye molecule or with a solvent with proton accepting ability. Upon dilution the equilibrium shifts to the complex with a solvent. The coexistence of several forms of the dye molecules with different absorption spectra was demonstrated in pulse photolysis upon excitation by light with different wavelengths. Three forms of cis-isomers were registered. The photogenerated cis-isomers decay with lifetimes from 200 µs to 5 ms. The fast cis-trans dark isomerization determines the photostability of the dyes.