Spectroscopic and computational study of the interaction of Pt(II) pyrrole-imine chelates with human serum albumin

Three bis(pyrrolide-imine) Pt(II) chelates were synthesised and characterized with different bridging alkyl groups, specifically 2-hydroxypropyl (1), 2,2-dimethylpropyl (2), and 1,2-(S,S)-(+)-cyclohexyl (3). Novel compounds 1 and 2 were analysed by single-crystal X-ray diffraction (space group P[1 with combining macron]). The asymmetric unit of 1 comprises three independent molecules linked by hydrogen bonds involving the OH groups, forming a trimeric supramolecular structure. The Pt(II) chelates were reacted with human serum albumin (HSA) to investigate how the ligand bound to the Pt(II) ion influences the compound's affinity for HSA. Fluorescence quenching data obtained for native HSA and HSA bound to site-specific probes (warfarin, subdomain IIA; ibuprofen, subdomain IIIA) indicated that the three Pt(II) chelates bind close enough (within ∼30 Å) to Trp-214 to quench its intrinsic fluorescence. The bimolecular quenching constant (kq) was 103–104 -fold higher than the maximum diffusion-controlled collision constant in water (1010 M s−1) at 310 K, while the affinity constants, Ka, ranged from ∼5 × 103 to ∼5 × 105 at 310 K, and followed the order 1 > 3 > 2. The reactions of 1 and 3 with HSA were enthalpically driven, while that for 2 was entropically driven. Macromolecular docking simulations (Glide XP) and binding site specificity assays employing site-specific probes and UV-vis CD spectroscopy indicated that 1 and 2 target Sudlow's site II in subdomain IIIA, minimally perturbing the tertiary structure of the protein. Well-resolved induced CD signals from 1 and 2 bound to HSA in subdomain IIIA were adequately simulated by hybrid QM:MM TD-DFT methods. We conclude that the structure of the bis(pyrrolide-imine) Pt(II) chelate measurably affects its uptake by HSA without detectable decomposition or demetallation. Such compounds could thus serve as metallodrug candidates capable of utilising an HSA-mediated cellular uptake pathway

Synthesis, X-ray structure determination and germination studies on some smoke-derived karrikins

AbstractThe discovery of the karrikin class of plant growth regulators (PGRs) is a milestone accomplishment in plant biochemistry and physiology, with significant potential in agriculture and horticulture. These compounds have in common a fused furano-pyran ring system featuring various permutations of methyl substitution. Chief amongst these compounds is karrikinolide (KAR1), identified as the key germination stimulant present in plant-derived smoke, which together with five other closely-related structures (KAR2–KAR6) make up the karrikin class of PGRs. By contrast, the germination inhibitor 3,4,5-trimethyl-2(5H)-furanone has also been identified in plant-derived smoke. Various synthetic endeavours have been undertaken for structure–activity relationship study purposes as well as to probe the molecular mechanics of these compounds. In this study, syntheses of KAR1, KAR3 and S-KAR1 were carried out and their structures verified by X-ray crystallography. Effects on germination were measured against the inhibitor 3,4,5-trimethyl-2(5H)-furanone in Grand Rapids lettuce seeds. X-ray crystallographic data and germination promotory activity for S-KAR1 are described for the first time

Synthesis and characterization of C2-symmetric bis(carboxamide) pincer ligands

Tridentate bis(carboxamide) pincers are key ligands used in catalysis, investigational medicinal inorganic compounds, and materials science. This study examined the atropisomerism of a group of bis(carboxamide) pincers with C2 symmetry to elucidate their physical, chemical, and structural behaviour, paving the way for the application of their metal complexes in different fields. One of the five compounds structurally elucidated by X-ray crystallography, 1c, has a pair of intramolecularly constrained isoquinoline ring substituents and crystallized enantiomerically pure in a chiral Sohncke space group. PM6 calculations of the 3-D potential energy surface for the main atropisomerisation reaction coordinate of 1c indicated that the lowest-energy conformer (atropisomer) has the isoquinoline rings canted out-of-plane by almost +30° and −30° relative to the central pyridine ring. The X-ray structure of 1c is located close to this energy minimum. Circular dichroism (CD) spectroscopy on bulk solid samples confirmed the presence of an excess population of one enantiomer (C2-symmetric atropisomer), most notably for compounds 1c, 1e, and 1f. CD spectra could be recorded for all compounds in solution, similarly reflecting an excess population of one atropisomer. The experimental spectra were confirmed by TD-DFT simulations at the CAM-B3LYP/def2-tzvp level of theory. We conclude that the present group of ligands are worthy of further investigation as chelating agents for metal ions with applications in chiral catalysis or biology

Chiral Au(iii) chelates exhibit unique NCI-60 cytotoxicity profiles and interactions with human serum albumin

Au(III) bis(pyrrolide-imine) chelates are emerging as a class of versatile, efficacious metallodrug candidates. Here, we synthesised two enantiopure chiral ligands H₂L1 and H₂L2 (tetradentate cyclohexane-1,2-diamine-bridged bis(pyrrole-imine) derivatives). Metallation of the ligands with Au(III) afforded the chiral cationic complexes AuL1 and AuL2. The in vitro cytotoxicities of AuL1 and AuL2 determined in the NCI-60 single-dose drug screen were 56.5% and 89.1%, respectively. AuL1 was subsequently selected for a five-dose NCI-60 screen, attaining GI₅₀, IC₅₀, and LC₅₀ values of 4.7, 9.3 and 39.8 μM, respectively. Hierarchical cluster analysis of the NCI-60 data indicated that the profile for AuL1 was similar to that of vinblastine sulfate, a microtubule-targeting vinca alkaloid. Reactions of AuL1 with glutathione (GSH) in vitro confirmed its susceptibility to reduction, Au(III) → Au(I), by intracellular thiols. Because human serum albumin (HSA) is responsible for transporting clinically deployed and investigational drugs, we studied the uptake of AuL1 and AuL2 by HSA to delineate how chirality impacts their protein-binding affinity. Steady-state fluorescence quenching data acquired on the native protein and data from site-specific probes showed that the compounds bind at sites close enough to Trp-214 (subdomain IIA) of HSA to quench the fluorophore. The bimolecular quenching rate constants, Kq, were ca. 10² times higher than the maximum diffusion-controlled collision constant of a biomolecule in water (10¹⁰ M⁻¹ s⁻¹), confirming that static fluorescence quenching was the dominant mechanism. The Stern–Volmer constants, KSV, were ∼10⁴ M⁻¹ at 37 °C, while the affinity constants, Ka (37 °C), measured ∼2.1 × 10⁴ M⁻¹ (AuL1) and ∼1.2 × 10⁴ M⁻¹ (AuL2) for enthalpy-driven ligand uptake targeting Sudlow's site I. Although far- and near-UV CD spectroscopy indicated that both complexes minimally perturb the secondary and tertiary structure of HSA, substantial shifts in the CD spectra were recorded for both protein-bound ligands. This study highlights the role of chirality in determining the cytotoxicity profiles and protein binding behaviour of enantiomeric Au(III) chelates

Structural basis for Cu(ii) metallocycle hexamer formation

NNN bis-aryl amide pincer ligands may be designed to meet the structural requirements for Cu(II) metallocycle hexamer formation, giving supramolecular crystals containing solvent-accesible voids

A Survey of the Angular Distortion Landscape in the Coordination Geometries of High-Spin Iron(II) 2,6-Bis(pyrazolyl)pyridine Complexes

Reaction of 2,4,6-trifluoropyridine with sodium 3,4-dimethoxybenzenethiolate and 2 equiv of sodium pyrazolate in tetrahydrofuran at room temperature affords 4-(3,4-dimethoxyphenylsulfanyl)-2,6-di(pyrazol-1-yl)pyridine (L), in 30% yield. The iron(II) complexes [FeL2][BF4]2 (1a) and [FeL2][ClO4]2 (1b) are high-spin with a highly distorted six-coordinate geometry. This structural deviation from ideal D2d symmetry is common in high-spin [Fe(bpp)2]2+ (bpp = di{pyrazol-1-yl}pyridine) derivatives, which are important in spin-crossover materials research. The magnitude of the distortion in 1a and 1b is the largest yet discovered for a mononuclear complex. Gas-phase DFT calculations at the ω-B97X-D/6-311G** level of theory identified four minimum or local minimum structural pathways across the distortion landscape, all of which are observed experimentally in different complexes. Small distortions from D2d symmetry are energetically favorable in complexes with electron-donating ligand substituents, including sulfanyl groups, which also have smaller energy penalties associated with the lowest energy distortion pathway. Natural population analysis showed that these differences reflect greater changes to the Fe–N{pyridyl} σ-bonding as the distortion proceeds, in the presence of more electron-rich pyridyl donors. The results imply that [Fe(bpp)2]2+ derivatives with electron-donating pyridyl substituents are more likely to undergo cooperative spin transitions in the solid state. The high-spin salt [Fe(bpp)2][CF3SO3]2, which also has a strong angular distortion, is also briefly described and included in the analysis

Revealing key structural features for developing new agonists targeting δ opioid receptor: Combined machine learning and molecular modeling perspective

Despite being the most widely prescribed and misused type of medication, opioids continue to function as robust pain relief agents; however, overdosing is a significant cause of fatalities among opioid users. The δ-opioid receptor (DOR) has immense promise in treating long-term pain by producing anxiolytic and antidepressant-like outcomes. Although DOR agonists play a crucial role, their clinical implementation is restricted because of the probable manifestation of severe, life-threatening complications. A Python-based machine learning approach was employed to develop a quantitative structure–activity relationship (QSAR) model in this study. To address this, 4217 compounds and their associated biological inhibition activities were retrieved from the gpcrdb database. The K-best features selection method revealed three key structural features such as SLOGPVSA2, Chi6ch, and S17 contributed significantly to the best model performance. Statistical analysis, K-fold cross-validation, applicability domain analysis, and external validation using 38 unseen FDA-approved drug data confirmed the robustness of the predictive model. A molecular docking study in along with Ligand–Receptor Contact Fingerprints (LRCFs) using the essential chemical interactions described for analog ligands releaved the key contact interactions of Asp 128, Tyr 129, Met 132, Trp 274, Ile 277, and Tyr 308 residues in the total binding affinities upon complexation. Our combinatorial study using regression QSAR and ligand–receptor Contact, analysis could serve in the design of more rational compounds for drug discovery targeting DOR

An 8-aminoquinoline-naphthyl copper complex causes apoptotic cell death by modulating the expression of apoptotic regulatory proteins in breast cancer cells

Breast cancer is one of the most common cancers globally and a leading cause of cancer-related deaths among women. Despite the combination of chemotherapy with targeted therapy, including monoclonal antibodies and kinase inhibitors, drug resistance and treatment failure remain a common occurrence. Copper, complexed to various organic ligands, has gained attention as potential chemotherapeutic agents due to its perceived decreased toxicity to normal cells. The cytotoxic efficacy and the mechanism of cell death of an 8-aminoquinoline-naphthyl copper complex (Cu8AqN) in MCF-7 and MDA-MB-231 breast cancer cell lines was investigated. The complex inhibited the growth of MCF-7 and MDA-MB-231 cells with IC50 values of 2.54 ± 0.69 μM and 3.31 ± 0.06 μM, respectively. Nuclear fragmentation, annexin V binding, and increased caspase-3/7 activity indicated apoptotic cell death. The loss of mitochondrial membrane potential, an increase in caspase-9 activity, the absence of active caspase-8 and a decrease of tumour necrosis factor receptor 1(TNFR1) expression supported activation of the intrinsic apoptotic pathway. Increased ROS formation and increased expression of haem oxygenase-1 (HMOX-1) indicated activation of cellular stress pathways. Expression of p21 protein in the nuclei was increased indicating cell cycle arrest, whilst the expression of inhibitor of apoptosis proteins (IAPs); cIAP1, XIAP and survivin were decreased, creating a pro-apoptotic environment. Phosphorylated p53 species; phospho-p53(S15), phospho-p53(S46), and phospho-p53(S392) accumulated in MCF-7 cells indicating the potential of Cu8AqN to restore p53 function in the cells. In combination, the data indicates that Cu8AqN is a useful lead molecule worthy of further exploration as a potential anti-cancer drug