Structural optimization and biological evaluation of 1,5-disubstituted pyrazole-3-carboxamines as potent inhibitors of human 5-lipoxygenase

AbstractHuman 5-lipoxygenase (5-LOX) is a well-validated drug target and its inhibitors are potential drugs for treating leukotriene-related disorders. Our previous work on structural optimization of the hit compound 2 from our in-house collection identified two lead compounds, 3a and 3b, exhibiting a potent inhibitory profile against 5-LOX with IC50 values less than 1µmol/L in cell-based assays. Here, we further optimized these compounds to prepare a class of novel pyrazole derivatives by opening the fused-ring system. Several new compounds exhibited more potent inhibitory activity than the lead compounds against 5-LOX. In particular, compound 4e not only suppressed lipopolysaccharide-induced inflammation in brain inflammatory cells and protected neurons from oxidative toxicity, but also significantly decreased infarct damage in a mouse model of cerebral ischemia. Molecular docking analysis further confirmed the consistency of our theoretical results and experimental data. In conclusion, the excellent in vitro and in vivo inhibitory activities of these compounds against 5-LOX suggested that these novel chemical structures have a promising therapeutic potential to treat leukotriene-related disorders

Near-Infrared Electrochromic Behavior of Dibenzothiepin Derivatives Attached with Two Michler's Hydrol Blue Units

10,11-Bis[bis(4-dimethylaminophenyl)methylene]dibenzo[bf]thiepin (1) and -oxepin (2) were prepared as stable yellow crystalline compounds, which are the cyclic analogues of electron-donating hexaarylbutadienes. Upon two-electron oxidation, they are reversibly transformed into the title dications (1(2+) and 2(2+)) exhibiting near-infrared (NIR) absorptions, which were also isolated as stable salts. These redox pairs can serve as new entries into less well-explored organic NIR-electrochromic systems, and the separation of redox peaks (electrochemical bistability) was attained for 1/1(2+) and 2/2(2+), thanks to drastic geometrical changes between neutral and dicationic states, as revealed by a series of X-ray analyses. Thiepin-S,S-dioxide analogue (3/3(2+)) exhibits quite similar dynamic redox behavior due to nonaromatic nature of the dibenzothiepin and -oxepin unit in 1(2+) and 2(2+), whereas the thiepin-S-oxide derivative (4/4(2+)) does not exhibit bistability due to the smaller change in geometry upon electron transfer, showing that a subtle change of a bridging atom in the central seven-membered ring can modify the redox properties

Responsive Trimodal Probes for In Vivo Imaging of Liver Inflammation by Coassembly and GSH-Driven Disassembly

Noninvasive in vivo imaging of hepatic glutathione (GSH) levels is essential to early diagnosis and prognosis of acute hepatitis. Although GSH-responsive fluorescence imaging probes have been reported for evaluation of hepatitis conditions, the low penetration depth of light in liver tissue has impeded reliable GSH visualization in the human liver. We present a liver-targeted and GSH-responsive trimodal probe (GdNPs-Gal) for rapid evaluation of lipopolysaccharide- (LPS-) induced acute liver inflammation via noninvasive, real-time in vivo imaging of hepatic GSH depletion. GdNPs-Gal are formed by molecular coassembly of a GSH-responsive Gd(III)-based MRI probe (1-Gd) and a liver-targeted probe (1-Gal) at a mole ratio of 5/1 (1-Gd/1-Gal), which shows high r1 relaxivity with low fluorescence and fluorine magnetic resonance spectroscopic (19F-MRS) signals. Upon interaction with GSH, 1-Gd and 1-Gal are cleaved and GdNPs-Gal rapidly disassemble into small molecules 2-Gd, 2-Gal, and 3, producing a substantial decline in r1 relaxivity with compensatory enhancements in fluorescence and 19F-MRS. By combining in vivo magnetic resonance imaging (1H-MRI) with ex vivo fluorescence imaging and 19F-MRS analysis, GdNPs-Gal efficiently detect hepatic GSH using three independent modalities. We noninvasively visualized LPS-induced liver inflammation and longitudinally monitored its remediation in mice after treatment with an anti-inflammatory drug, dexamethasone (DEX). Findings highlight the potential of GdNPs-Gal for in vivo imaging of liver inflammation by integrating molecular coassembly with GSH-driven disassembly, which can be applied to other responsive molecular probes for improved in vivo imaging

Bioorthogonal cyclization-mediated in situ self-assembly of small-molecule probes for imaging caspase activity in vivo

Directed self-assembly of small molecules in living systems could enable a myriad of applications in biology and medicine, and already this has been used widely to synthesize supramolecules and nano/microstructures in solution and in living cells. However, controlling the self-assembly of synthetic small molecules in living animals is challenging because of the complex and dynamic in vivo physiological environment. Here we employ an optimized first-order bioorthogonal cyclization reaction to control the self-assembly of a fluorescent small molecule, and demonstrate its in vivo applicability by imaging caspase-3/7 activity in human tumour xenograft mouse models of chemotherapy. The fluorescent nanoparticles assembled in situ were imaged successfully in both apoptotic cells and tumour tissues using three-dimensional structured illumination microscopy. This strategy combines the advantages offered by small molecules with those of nanomaterials and should find widespread use for non-invasive imaging of enzyme activity in vivo

Engineering of electrochromic materials as activatable probes for molecular imaging and photodynamic therapy

Electrochromic materials (EMs) are widely used color-switchable materials, but their applications as stimuli-responsive biomaterials to monitor and control biological processes remain unexplored. This study reports the engineering of an organic π-electron structure-based EM (dicationic 1,1,4,4-tetraarylbutadiene, 12+) as a unique hydrogen sulfide (H2S)-responsive chromophore amenable to build H2S-activatable fluorescent probes (12+-semiconducting polymer nanoparticles, 12+-SNPs) for in vivo H2S detection. We demonstrate that EM 12+, with a strong absorption (500–850 nm), efficiently quenches the fluorescence (580, 700, or 830 nm) of different fluorophores within 12+-SNPs, while the selective conversion into colorless diene 2 via H2S-mediated two-electron reduction significantly recovers fluorescence, allowing for non-invasive imaging of hepatic and tumor H2S in mice in real time. Strikingly, EM 12+ is further applied to design a near-infrared photosensitizer with tumor-targeting and H2S-activatable ability for effective photodynamic therapy (PDT) of H2S-related tumors in mice. This study demonstrates promise for applying EMs to build activatable probes for molecular imaging of H2S and selective PDT of tumors, which may lead to the development of new EMs capable of detecting and regulating essential biological processes in vivo

Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis

Non-invasive detection of caspase-3/7 activity in vivo has provided invaluable predictive information regarding tumor therapeutic efficacy and anti-tumor drug selection. Although a number of caspase-3/7 targeted fluorescence and positron emission tomography (PET) imaging probes have been developed, there is still a lack of gadolinium (Gd)-based magnetic resonance imaging (MRI) probes that enable high spatial resolution detection of caspase-3/7 activity in vivo. Here we employ a self-assembly approach and develop a caspase-3/7 activatable Gd-based MRI probe for monitoring tumor apoptosis in mice. Upon reduction and caspase-3/7 activation, the caspase-sensitive nano-aggregation MR probe (C-SNAM: 1) undergoes biocompatible intramolecular cyclization and subsequent self-assembly into Gd-nanoparticles (GdNPs). This results in enhanced r1 relaxivity-19.0 (post-activation) vs. 10.2 mM-1 s-1 (pre-activation) at 1 T in solution-and prolonged accumulation in chemotherapy-induced apoptotic cells and tumors that express active caspase-3/7. We demonstrate that C-SNAM reports caspase-3/7 activity by generating a significantly brighter T1-weighted MR signal compared to non-treated tumors following intravenous administration of C-SNAM, providing great potential for high-resolution imaging of tumor apoptosis in vivo

Caspase-responsive smart gadolinium-based contrast agent for magnetic resonance imaging of drug-induced apoptosis

Non-invasive detection of caspase-3/7 activity in vivo has provided invaluable predictive information regarding tumor therapeutic efficacy and anti-tumor drug selection. Although a number of caspase-3/7 targeted fluorescence and positron emission tomography (PET) imaging probes have been developed, there is still a lack of gadolinium (Gd)-based magnetic resonance imaging (MRI) probes that enable high spatial resolution detection of caspase-3/7 activity in vivo. Here we employ a self-assembly approach and develop a caspase-3/7 activatable Gd-based MRI probe for monitoring tumor apoptosis in mice. Upon reduction and caspase-3/7 activation, the caspase-sensitive nano-aggregation MR probe (C-SNAM: 1) undergoes biocompatible intramolecular cyclization and subsequent self-assembly into Gd-nanoparticles (GdNPs). This results in enhanced r(1) relaxivity—19.0 (post-activation) vs. 10.2 mM(−1) s(−1) (pre-activation) at 1 T in solution—and prolonged accumulation in chemotherapy-induced apoptotic cells and tumors that express active caspase-3/7. We demonstrate that C-SNAM reports caspase-3/7 activity by generating a significantly brighter T(1)-weighted MR signal compared to non-treated tumors following intravenous administration of C-SNAM, providing great potential for high-resolution imaging of tumor apoptosis in vivo