Aberrant expression or dysfunction of Cyclin-dependent kinase 7(CDK7) and Histone deacetylase 1 (HDAC1) are associated with the occurrence and progression of various cancers. In this study, we developed a series of dual-target inhibitors by designing and synthesizing compounds that incorporate the pharmacophores of THZ2 and SAHA. The most potent dual-target inhibitor displayed robust inhibitory activity against several types of cancer cells and demonstrated promising inhibitory effects on both CDK7 and HDAC1. After further mechanistic studies, it was discovered that this inhibitor effectively arrested HCT-116 cells at the G2 phase and induced apoptosis. Additionally, it also significantly hindered the migration of HCT-116 cells and exhibited notable anti-tumor effects. These findings offer strong support for the development of dual-target inhibitors of CDK7 and HDAC1 and provide a promising avenue for future cancer therapy.
Monthly Archives: October 2023
Moving out of the CF3‐land: synthesis, receptor affinity and in silico studies of NK1‐receptor ligands containing pentafluorosulfanyl (SF5) group
The NK1 receptor (NK1R) is a molecular target for both approved and experimental drugs intended for a variety of conditions, including i.a. emesis, pain or cancers. While contemplating modifications to the typical NK1R pharmacophore, we wondered whether the CF3 groups common for many NK1R ligands, could be replaced with some other moiety. Our attention was drawn by the SF5-group, and so we designed, synthesized and tested for NK1R affinity ten novel SF5-containing compounds. All the novel analogues exhibit detectable NK1R binding, with the best of them, compound 5a, binding only slightly worse (IC50 = 34.3 nM) than the approved NK1R-targeting drug, aprepitant (IC50 = 27.7 nM). Molecular docking provided structural explanation of SAR. According to our analysis, the SF5 group in our compounds occupies a position similar to that of one of CF3 groups of aprepitant as found in the crystal structure. Additionally, we checked on whether the docking scoring function or energies derived from Fragment Molecular Orbital quantum chemical calculations may be helpful in explaining and predicting the experimental receptor affinities for our analogues. Both these methods produce moderately good results. Overall, this is the first demonstration of the utility of the SF5-group in the design of NK1R ligands.
Protein–Porphyrin Complex Photosensitizers for Anticancer and Antimicrobial Photodynamic Therapies
Photodynamic therapy (PDT) efficiently induces apoptosis through visible-light irradiation of photosensitizers (PSs) within tumors and microbial cells. Porphyrin analogues serve as widely utilized photosensitizing agents with their theranostic abilities being governed by molecular structures and central metal ions. However, these macrocyclic compounds tend to agglutinate and form stacks in aqueous environments, resulting in a loss of photochemical activity. To overcome this limitation, encapsulation within liposomes and polymer micelles enables the dispersion of porphyrins as monomolecular entities in aqueous solutions, preventing undesirable deactivation. Recently, the use reconstituted hemoproteins containing various metal-porphyrins and protein cages incorporating porphyrins have garnered significant interest as a new generation of biocompatible PSs. In this concept paper, we provide a comprehensive review of recent developments and trends of protein–porphyrin complex PSs for applications in anticancer and antimicrobial PDTs.
Phosphinine vs Pyridine in Luminescent Cu(I) Complex and Application in Lifetime‐Based Molecular Thermometer
Luminescent Cu(I) complexes have attracted significant interest due to their adjustable emission properties, diverse structures, and reasonable cost. In this work, two class of complexes, namely phosphinine and pyridine ligated Cu(I) complexes that differ by only one atom, were synthesized and characterized. Photophysical analysis and theoretical studies reveal an emissive phosphinine-localized triplet states for Cu(I) phosphinine complexes, and a temperature-dependent interplay between metal-to-ligand charge-transfer (MLCT) singlet and triplet states for Cu(I) pyridine complexes. In general, the Cu(I) phosphinine complexes exhibit a longer lifetime and greater temperature-dependent lifetime changes than the pyridine complexes. A molecular thermometer incorporating Cu(I) phosphinine complexes 2c as indicator was fabricated. This thermometer exhibits a rare linear correlation between temperature and lifetime ranging from 77–297 K with a high sensitivity of –13.5 μs K–1.
Anti‐inflammatory and antioxidant activity of Titanium dioxide nanotubes conjugated with Quercetin.
Inflammation is closely associated with cancer and leads to the formation of various malignancies. Quercetin is a naturally occurring flavonoid, with numerous pharmaceutical activities like anti-oxidant, anti-inflammatory, and anti-tumor effects. Due to its partial solubility in an aqueous solution, its consumption is limited. We recently showed the physicochemical characterization of titanium dioxide nanotubes (TNT) conjugated with quercetin and we found that quercetin conjugated with TNT enhances the anticancer activity in B16F10 cells and induced apoptosis. In the present study, we stimulated the efficiency of quercetin conjugated with titanium dioxide nanotubes and studies their anti-oxidant, anti-inflammatory activity. TNT conjugated with quercetin (showed less cytotoxic effect towards RAW264.7 macrophages than quercetin alone. The inflammatory stimulation of RAW264.7 with LPS induced the pro-inflammatory cytokine IL-6 and inducible nitric synthase mRNA which were significantly inhibited by treating with TNT-Qu without causing any toxicity than quercetin and TNT alone. These results suggested that the potential of TNT conjugated with quercetin are better than quercetin and TNT alone and TNT may provide protection against inflammation by down regulating IL-6 and iNOS.
Mechanochemical Oxidative Coupling of Amine to Azo‐based Polymers by Hypervalent Iodine Oxidant
Among porous organic polymers (POPs), azo-linked POPs represent a crucial class of materials, making them the focus of numerous catalytic systems proposed for their synthesis. However, the synthetic process is limited to metal-catalyzed, high-temperature, and liquid-phase reactions. In this study, we employ mechanochemical oxidative metal-free systems to encompass various syntheses of azo-based polymers. Drawing inspiration from the "rule of six" principle (six or more carbons on azide group render the organic compound relatively safe), an azo compound featuring significant steric hindrance is obtained using the hypervalent iodine oxidation strategy. Furthermore, during the polymerization process, steric hindrance is enhanced in monomers to effectively prevent explosions resulting from direct contact between hypervalent iodine oxidants and primary amines. Indeed, this approach provides a facile and innovative solid-phase synthesis method for synthesizing azo-based materials.
Photo‐Catalyzed α‐Arylation of Enol Acetate Using Recyclable Silica‐Supported Heteroleptic and Homoleptic Copper(I) Photosensitizers
Homoleptic and heteroleptic copper(I) complexes were anchored on silica nanoparticles and used for the visible-light mediated α-arylation of enol acetate.Photo-Catalyzed alpha-Arylation of Enol Acetate Using Recyclable Silica-Supported Heteroleptic and Homoleptic Copper(I) Photosensitizers (Troian-Gautier, Riant, Hermans et al.)
Abstract
Earth-abundant photosensitizers are highly sought after for light-mediated applications, such as photoredox catalysis, depollution and energy conversion schemes. Homoleptic and heteroleptic copper(I) complexes are promising candidates in this field, as copper is abundant and the corresponding complexes are easily obtained in smooth conditions. However, some heteroleptic copper(I) complexes suffer from low (photo)stability that leads to the gradual formation of the corresponding homoleptic complex. Such degradation pathways are detrimental, especially when recyclability is desired. This study reports a novel approach for the heterogenization of homoleptic and heteroleptic Cu complexes on silica nanoparticles. In both cases, the photophysical properties upon surface immobilization were only slightly affected. Excited-state quenching with aryl diazonium derivatives occurred efficiently (108–1010 M−1 s−1) with heterogeneous and homogeneous photosensitizers. Moderate but almost identical yields were obtained for the α-arylation of enol acetate using the homoleptic complex in homogeneous or heterogeneous conditions. Importantly, the silica-supported photocatalysts were recycled with moderate loss in photoactivity over multiple experiments. Transient absorption spectroscopy confirmed that excited-state electron transfer occurred from the homogeneous and heterogeneous homoleptic copper(I) complexes to aryl diazonium derivatives, generating the corresponding copper(II) center that persisted for several hundreds of microseconds, compatible with photoredox catalysis applications.
Nitrogen‐Doped Graphene Quantum Dots as Electrochemiluminescence‐Emitting Species for Sensitive Detection of KRAS G12C Mutation via PET‐RAFT
Nitrogen-doped graphene quantum dots (NGQDs) synthesized from different ratios of carbon and nitrogen sources have been systematically explored for their electrochemiluminescence (ECL) properties for the first time. And NGQDs as signal molecules combined with photo-induced electron/energy transfer reversible addition-fragment chain transfer (PET-RAFT) signal amplification strategy to construct a ECL biosensor for sensitive detection of KRAS G12C mutation was first reported.
Abstract
The levels of KRAS G12C point mutation is recognized to be closely related to the earlier diagnosis of non-small cell lung cancer (NSCLC). Here, based on nitrogen-doped graphene quantum dots (NGQDs) and photo-induced electron/energy transfer reversible addition-fragment chain transfer (PET-RAFT) signal amplification strategy, we fabricated a novel electrochemiluminescence (ECL) biosensor for the detection of KRAS G12C mutation for the first time. NGQDs as ECL-emitting species with cathodic ECL were prepared by a simple calcination method. Firstly, KRAS G12C mutation DNA, i. e., target DNA (tDNA), was captured by specific identification with hairpin DNA (hDNA). Then, PET-RAFT was initiated by blue light, and large numbers of monomers were successfully polymerized to form controllable polymer chains. Lastly, massive NGQDs was introduced via amidation reaction with N-(3-aminopropyl)methacrylamide hydrochloride (APMA), which significantly amplified the ECL signal intensity. Under optimal conditions, this biosensor achieved a good linear relationship between ECL intensity and logarithm of the levels of KRAS G12C mutation in the range from 10 fM to 10 nM. Moreover, this strategy exhibited high selectivity and excellent applicability for KRAS G12C mutation detection in the serum samples. Therefore, this biosensor has great potential in clinical diagnosis and practical application.
Synthesis of Defective Wheel‐Shaped Nanographdiynes
The synthesis and optical properties of wheel-shaped nanographdiynes that has lost some butadiyne spokes were reported. These defective wheel-shaped nanographdiynes possess butadiyne-bridged metacyclophanes with para-bis(phenylbutadiynyl)-benzene units as the axis. The optimized geometries of the defective wheel-shaped nanographdiynes along with their vibrational spectra, HOMO and LUMO orbitals were calculated at B3LYP/6-311G(d,p) level. HOMO and LUMO orbitals are delocalized mainly over the para-bis(phenylbutadiynyl)-benzene axis, with weak contribution from the attached ethynyl units. The π-conjugation extension and quantity increase of the para axis influenced the optical properties of these graphdiyne substructures, leading to the change of bandgap from 2.88 eV to 2.56 eV as reflected by optical spectroscopy. The defective wheel-shaped nanographdiynes lost the characteristic intensive sharp absorption peak at low energy region, which indicated that the fusion of adjacent dehydrobenzo [18] annulenes are crucial for the bulk properties of graphdiyne.
Slow Magnetization Relaxation in a Family of Triangular {CoIII2LnIII} Clusters: The Effect of Diamagnetic CoIII Ions on the LnIII Magnetic Dynamics
A new family of heterometallic complexes, [CoIII 2LnIII(OMe)2(naph)2(O2CMe)3(MeOH)2] (Ln=Tb (1), Dy (2), and Er (3)), possessing a rare {CoIII 2Ln(μ3-OMe)}8+ triangular core, have been prepared; compounds 2 and 3, as well as the magnetic diluted analogue {Co2Dy0.05Y0.95} (2 a), behave as mononuclear single-molecule magnets (SMMs) with Ueff up to ~90 K.
Abstract
The first use of the Schiff base chelate N-naphthalidene-o-aminophenol (naphH2) in Co/Ln chemistry has afforded a family of isostructural [CoIII 2LnIII(OMe)2(naph)2(O2CMe)3(MeOH)2] (Ln=Tb, Dy and Er) complexes, revealing a rare {CoIII 2Ln(μ3-OMe)}8+ triangular core composed of two diamagnetic CoIII ions and a 4f-ion with slightly distorted square antiprismatic geometry. Alternating current (ac) magnetic susceptibility studies revealed that {Co2Dy}, and its magnetic diluted analogue {Co2Dy0.05Y0.95}, behave as mononuclear single-molecule magnets (SMMs) with similar energy barriers for the magnetization reversal, Ueff , of ~85-90 K. SMM properties were also detected for {Co2Er}, with the compound exhibiting a Ueff of 18.7 K under an applied magnetic field of 800 Oe. To interpret the experimental magnetic results, ab initio CASSCF/RASSI-SO and DFT calculations were performed as a means of exploring the single-ion characteristics of LnIII ions and comprehend the role of the diamagnetic CoIII ions in the magnetization relaxation of the three heterometallic compounds.