X-ray Crystallography Research Articles

Quinizarin Gold(I) N-Heterocyclic Carbene Complexes with Synergistic Activity Against Anthracycline-Resistant Leukaemia Cells: Synthesis and Biological Activity Studies.

New, asymmetric quinizarin-Au(I)-NHC complexes were designed, isolated, and fully characterised including by single crystal X-ray crystallography. Cytotoxicity studies showed effective growth inhibition in HeLa cervical cancer cells with IC50 values ranging from 2.4 μM to 5.3 μM. The successful cellular uptake was evidenced by X-ray fluorescence imaging on cryo-preserved whole HeLa cells and the sub-cellular localisation was monitored by live-cell fluorescence microscopy. Notably, complex 2 b showed circumvention of acquired anthracycline resistance in K562 leukaemia cells as well as synergistic activity with doxorubicin against both wild-type and anthracycline-resistant Nalm-6 leukaemia cells. Interestingly, sub-cellular localisation towards mitochondria proved to be more important than the compounds' overall cytotoxicity for potent antiproliferative activity and to achieve effective resistance circumvention.

Secupyritines A-C, Three Natural Propellane Securinega Alkaloids: Structure Elucidation and Total Synthesis Based on Biogenetic Building Blocks.

Secupyritines A-C are unique polycyclic Securinega alkaloids isolated from medicinal plant Flueggea suffruticosa. They feature a distinctive 6/6/6/5/6 fused pentacyclic ring system with a highly strained 2-oxa-6-aza[4.4.3]propellane core. Their structures with absolute configurations were elucidated through a comprehensive approach involving nuclear magnetic resonance (NMR) spectroscopy, single-crystal X-ray crystallography, electronic circular dichroism (ECD) calculations, and total synthesis. The total synthesis of secupyritines A-C was achieved in 14 or 16 steps, employing a synthesis strategy based on biogenetic building blocks. Key elements of the synthetic procedures include a vinylogous Mannich-type reaction to construct the sp3-sp2 attached-ring system, a Suzuki coupling reaction to build the piperidine ring, and an intramolecular aza-Michael addition reaction to establish the propellane skeleton. Formal asymmetric synthesis of secupyritines A-C was also presented.

Impact of Structural Subtleties on Chirality Induction and Amplification in Trizinc(II)Porphyrin Trimers.

Herein, we report the precise control of molecular to supramolecular chirality induction at the single-molecule level just upon subtle modification in an achiral 'nano-size' trizinc(II) porphyrin trimer. A slight variation in the projection of the substituent at the periphery of the central porphyrin unit in a porphyrin trimer (host) resulted in pronounced changes in the interchromophoric arrangement, leading to distinct 'open' and 'closed' conformations. While 'open' form generates 'monomeric' complex with low CD amplitude, 'closed' form produces exclusive 'polymer' with large, amplified CD signal with opposite sign due to stronger intermolecular excitonic coupling. Also, the sign of the CD couplets is just opposite between R and S substrates for both polymer and monomer which suggest that the chirality is predominantly governed by the stereogenic projection of the chiral center. X-ray structures of the host and polymer have been reported here. Crystallographic characterization offers a detailed perspective on the structural and geometrical transformations in the polymer, enabling a systematic understanding of its optical properties. DFT and TD-DFT calculations strongly corroborate with the experimental findings.

Dinuclear iridium complexes ligated by lithium-ion endohedral fullerene Li+@C60.

The diiridium complexes of lithium-ion endohedral fullerene Li+@C60 were synthesised in high yields. X-ray crystallography revealed the η2:η2-coordination of Li+@C60 and the disorder of the Li+ ion over two sites close to the coordinated carbons. 13C NMR study suggested the presence of dynamic behaviour via haptotropic rearrangements. UV/Vis and CV characteristics were also investigated experimentally and theoretically.

Indium-catalyzed hydrosilylation of nitroarenes to aromatic amines.

Herein, we report the synthesis of three indium complexes (1-3) supported by different chelating ligands (L1-L3). The indium metal complexes were characterized by using multinuclear NMR, and their solid-state structures were confirmed by single-crystal X-ray crystallography. The indium complex 1 (5 mol%) effectively reduced nitroarenes in the presence of phenylsilane and NaI. Nitroarenes containing different functionalities were reduced under standard conditions to give the corresponding amines in good yields.

Thianthrene 5,5,10,10-tetraoxide-based phosphorescent platinum(II) complexes for solution-processed organic light-emitting diode (OLED) with external quantum efficiency approach 25 %

Pt(II) complexes have great potential in realizing high efficiency OLED luminous materials, and the development of achieving high quantum efficiency in solution-processed OLED is a great challenge. Here, we designed and synthesized three efficient emitters by combining isoquinoline, thiophene and pyridine groups with thianthrene 5,5,10,10-tetraoxide group. With the introduction of thianthrene 5,5,10,10-tetraoxide group, these Pt(II) complexes show improved electron injection/transport capabilities. A range of emission energies that can be tuned from green to red was realized by solution-processed OLEDs. Their electrochemical and photophysical properties were explored and analyzed. The structure of Pt-SOPy complex was also characterized by X-ray crystallography. Importantly, the green OLED using Pt-SOPy as an emitter shows excellent performance with a peak external quantum efficiency (EQE) of 24.7 %. As far as we known, the value sets a new record for solution-processed green OLEDs based on Pt(II) complexes.

Genome mining of nonenzymatic ortho-quinone methide-based pseudonatural products from ascidian-derived fungus Diaporthe sp.SYSU-MS4722.

Ortho-quinone methides (o-QMs), generated by oxidative dehydration of clavatol, are highly reactive intermediates in biosynthesis that give rise to a variety of clavatol-containing pseudonatural products (PNPs) in fungi through intra- and intermolecular nonenzymatic cyclization/addition reaction, and some compounds have significant biological activities. Here we report our genome mining efforts on a cryptic clavatol biosynthetic gene cluster (BGC) from an ascidian-derived fungus Diaporthe sp. SYSU-MS4722. The core genes NR-PKS (DiaG), Esterase (DiaF) derived from the fungus Diaporthe sp. SYSU-MS4722 clavatol BGC and the known α-ketoglutarate-dependent nonheme iron enzymes (ClaD) were heterologously expressed in the Aspergillus oryzae NSAR1 (A. oryzae NSAR1). Thirteen new monomeric, dimeric, and trimeric clavatol-based PNPs (7-19), together with three known compounds (20-22) were isolated from the above transformant. Their structures including absolute configurations were elucidated by spectroscopic analysis (UV, IR, HR-ESI-MS, 1D and 2D NMR data), complemented with the X-ray crystallography, the comparison of the experimental and calculated ECD spectra, and gauge-independent atomic orbital (GIAO) NMR calculations. Based on the structural characteristics, their plausible biosynthetic pathways were proposed. Notably, Compounds 8, 9, 14 and 16 exhibited potent anti-fibrotic activity with EC50 values of 28.9, 10.0, 3.5 and 30.1μM, respectively.

Artificial trimerization of β-glucosidase for enhanced thermostability and activity via computational redesign

The improvement of enzyme thermostability is of great significance in the biotechnology industry. Herein, we modified the C-terminus of β-glucosidase via the computer-aided rational design and successfully obtained six variants that exhibit improved optimal temperatures and thermal inactivation half-lives at 65 °C. Among these variants, the thermal inactivation half-life and hydrolytic activity of TrCel1b-H13 at 65 °C were increased by 416 and 3223 folds, respectively, compared to those of the wild type. The optimal catalytic temperature and melting temperature (Tm) of TrCel1b-H13 were elevated by 55 °C and 20 °C respectively, compared to those of the wild type. The Kcat/Km value of TrCel1b-H13 was improved by 13.3-fold, compared to that of the wild type. Furthermore, we found that the modified β-glucosidase, TrCel1b-H13, self-assembles into a trimeric structure, which was confirmed by X-ray crystallography and blue native polyacrylamide gel electrophoresis. The amino acid residues, including E28, H60, E99, K106, and K471, located at the trimeric interface of the adjacent subunits, were found to play an important role in maintaining the crystal structure of the protein trimer. Thus, protein multimerization via the computer-aided rational design method provides a cost-effective tool for simultaneously improving the thermostability and activity of enzymes.

The Iconic α-Helix: From Pauling to the Present.

The protein folding problem dates back to Pauling's insights almost a century ago, but the first venture into actual protein structure was the Pauling-Corey-Brandson α-helix in 1951, a proposed model that was confirmed almost immediately using X-ray crystallography. Many subsequent efforts to predict protein helices from the amino acid sequence met with only partial success, as discussed here. Surprisingly, in 2021, these efforts were superseded by deep-learning artificial intelligence, especially AlphaFold2, a machine learning program based on neural nets. This approach can predict most protein structures successfully at or near atomic resolution. Deservedly, deep-learning artificial intelligence was named Science magazine's 2021 "breakthrough of the year." Today, ~200 million predicted protein structures can be downloaded from the AlphaFold2 Protein Structure Database. Deep learning represents a deep conundrum because these successfully predicted macromolecular structures are based on methods that are completely devoid of a hypothesis or of any physical chemistry. Perhaps we are now poised to transcend five centuries of reductive science.

Synthesis, X-ray, antioxidant, in-vitro biological & in-silico docking studies of novel organoselenides: Promising colorectal cancer inhibitors.

A series of multi-target organoselenides 3a-h has been synthesized with the advantages of a simple operation, and good yields of 66-89% escorted by mechanistic enlightenment. The compounds 3b, 3c continued to exist as orthorhombic and trigonal, whereas 3d exist as monoclinic confirmed by the X-ray crystallography. Organoselenides 3c and 3f displayed the highest % radical scavenging potential with % inhibition of 98.16±2.1 and 97.63±2.1 respectively utilizing the DPPH assay. Moreover, compounds 3c and 3f unveiled potent antibacterial activity against Gram-positive and Gram-negative bacterial strains, with notable MIC values of 8μg/mL and 10μg/mL against S. aureus, comparable to the standard drug Tetracycline (MIC = 8μg/mL). Additionally, 3c and 3f demonstrated promising anticancer profiles against HCT-116 colorectal carcinoma cell lines, with IC50 values of 14.77±1.29μM and 20.3±0.66μM as compared to 5-Fluorouracil (5.25±0.43μM). Furthermore, in-silico macromolecular (PDB code: 2W9S and 3RUK) interactions arrayed incremental support for the observed in-vitro antibacterial and anticancer activities of compounds 3c & 3f and subsequently unveiled these as promising colorectal cancer inhibitors with elevated D scores of -5.78 & -5.72kcal/mol respectively. Additionally, against the antibacterial target Staphylococcus aureus dihydrofolate reductase (PDB: 2W9S), docking scores of -5.28 and -4.88kcal/mol were observed for 3c and 3f, respectively.

Design of an abiotic unimolecular three-helix bundle.

Starting from the solid state structure of C 3-symmetrical homochiral parallel trimolecular bundle of three aromatic helices held together by intermolecular hydrogen bonds, we have used simple rational principles and molecular modelling to design a similar heterochiral structure where one helix had an opposite orientation and handedness. A rigid and a flexible linker to connect these helices and transform the bundle into a unimolecular object were designed and synthesized. Model sequences with two helices and one linker were then prepared. Their conformations were investigated in solution by nuclear magnetic resonance and circular dichroism, in the solid state by X-ray crystallography, and by molecular dynamics simulations, overall supporting the initial design. A final 6.9 kDa unimolecular three-helix bundle was then prepared using a fragment condensation approach. Solution studies support the formation of the targetted tertiary fold in the case of the rigid linker, thereby validating the overall approach.

Replacement of a single residue changes the primary specificity of thrombin.

Thrombin prefers substrates carrying Arg at the site of cleavage (P1) because of the presence of D189 in the primary specificity (S1) pocket but can also cleave substrates carrying Phe at P1. The structural basis of this property is unknown. Solve the X-ray structure of thrombin bound to a ligand carrying Phe at P1 and investigate the effects of replacing D189. X-ray crystallography is used to solve the structure of thrombin bound to the irreversible inhibitor H-D-Phe-Pro-Phe-CH2Cl (PPPCK). Residue D189 is mutated to Ala, Lys, Phe and Ser. The X-ray structure of the thrombin-PPPCK complex is solved at 2.5 Å resolution and compared to the structure of thrombin bound to H-D-Phe-Pro-Arg-CH2Cl (PPACK). PPPCK binds to thrombin in a conformation similar to that of PPACK, but Phe at P1 makes no contacts with D189. Replacement of D189 with Ala, Lys, Phe or Ser reverses both substrate preference and stability enhancement from Arg to Phe. D189 in the S1 pocket confers thrombin "trypsin-like" specificity for Arg at P1. However, the S1 pocket is wide enough to also enable "chymotrypsin-like" specificity for Phe at P1. Consistent with these structural features, a single amino acid replacement (D189A) switches thrombin specificity from trypsin-like to chymotrypsin-like, converting the substrate preference from H-D-Phe-Pro-Arg-p-nitroanilide to H-D-Phe-Pro-Phe-p-nitroanilide and preferential stability enhancement from PPACK to PPPCK. The observation that thrombin specificity is controlled mainly by a single residue establishes a new paradigm in the field of trypsin-like proteases.

A Simple Protocol for Visualization of RNA-Protein Complexes by Atomic Force Microscopy.

Atomic force microscopy (AFM) has recently received increasing interest in molecular biology. This technique allows quick and reliable detection of biomolecules. However, studying RNA-protein complexes using AFM poses significant challenges. Here, we describe a simple and reliable method to visualize positively charged proteins bound to RNA that does not require metallic cations. This method allowed us to effectively detect and visualize Staufen-RNA complexes by height or logarithmic stiffness. The study of the mechanical properties is particularly important in the case of protein-coated RNA complexes, where RNA cannot be detected by height channel. In any case, it is necessary to compare AFM data with the data derived from other techniques like nuclear magnetic resonance, X-ray crystallography, cryogenic electron microscopy, and small-angle X-ray scattering. © 2025 The Author(s). Current Protocols published by Wiley Periodicals LLC. Basic Protocol: Preparation and visualization of RNA-protein complex.

Synthesis, structure and π-expansion of tris(4,5-dehydro-2,3:6,7-dibenzotropone).

The polycyclic skeleton of tris(4,5-dehydro-2,3:6,7-dibenzotropone) is a key structural fragment in carbon schwarzites, a theoretical form of negatively curved carbon allotrope. This report presents a new synthesis of this compound using a Ni-mediated Yamamoto coupling reaction and structural analysis of it with X-ray crystallography. Interestingly, it is observed that tris(4,5-dehydro-2,3:6,7-dibenzotropone) crystallized from its solution in hexane resulting in colorless and yellow crystal polymorphs, where it adopts conformations of approximate C s and C 2 symmetry, respectively. Furthermore, expanding its π-skeleton through the Barton-Kellogg and Scholl reactions led to the successful synthesis of a curved polycyclic arene containing three heptagons and two pentagons.

FT-4202, a selective pyruvate kinase R activator for sickle cell disease

Anemia in patients with sickle cell disease (SCD) increases 2,3-diphosphoglycerate (2,3-DPG), decreasing hemoglobin–oxygen (Hb-O2) affinity to improve oxygen offloading and promote hemoglobin polymerization (sickling) of red blood cells (RBCs). We report the discovery of FT-4202, an investigational, selective pyruvate kinase type-R (PKR) activator with a multimodal mechanism of action and potential to increase ATP and decrease 2,3-DPG, resulting in increased Hb-O2 affinity, decreased Hb polymerization, and improved RBC health. FT-4202 was identified via structure-enabled lead optimization medicinal chemistry using X-ray crystallography, molecular modeling, and thermal shift assays. FT-4202, an allosteric PKR activator, stabilizes the tetrameric enzyme and increases PKR activity in human and mouse RBCs in vitro. Seven-day oral administration of FT-4202 in Berkeley SCD mice reduced 2,3-DPG, increased Hb-O2 affinity, and reduced RBC sickling versus control. There were no adverse in vitro safety findings. FT-4202 offers a therapeutic opportunity to modify the course of SCD.

Oxidation of styrene by Mn (II)-pyridine-2,6-dicarboxylate complex: Synthesis, X-ray structure and DFT studies

Oxidation of styrene by Mn (II)-pyridine-2,6-dicarboxylate complex: Synthesis, X-ray structure and DFT studies

Syntheses, crystal structure, Hirshfeld Surface Analyzes of cocrystals and salt of a flexible imidazole tethered naphthalenediimide with some organic acids.

One salt and three cocrystals of 2,7-bis(3-(1H-imidazol-1-yl)propyl)benzo[lmn][3,8]phenanthroline-1,3,6,8(2H,7H)-tetraone (L) have been synthesized and reported. 3-Nitro benzoic acid (3NBA) forms salt with L and 4-Nitro benzoic acid (4NBA), 4-Hydroxy benzoic acid (4HBA) and 4-Amino benzoic acid (4ABA) forms cocrystals with L. L forms 1:1 salt with 3-NBA and 1:1 cocrystal with 4-NBA, 4-HBA and 4-ABA respectively. All the complexes were formed in a warm solvent condition. The solid-state structures were determined by single crystal X-ray diffraction method. Salt 1, exhibit zig zag tetrameric water cluster in the solid-state structure. Various types of supramolecular interactions such as OH…O, CH…O, π…π, and CH…π were observed in the x-ray structures and all these interactions guide the formation of 3D supramolecular architecture in the solid-state of all the complexes. Besides these, the 2D-fingerprint (2D-FP) and Hirshfeld surface analysis (HSA) computations were served to prove the 2D-network packed crystal lattice interactions.

Probing non-peptide agonists binding at the human nociceptin/orphanin FQ receptor: a molecular modelling study.

The N/OFQ-NOP receptor is a fascinating peptidergic system with the potential to be exploited for the development of analgesic drugs devoid of side effects associated with classical opioid signalling modulation. To date, up to four X-ray and cryo-EM structures of the NOP receptor in complex with the endogenous peptide agonist N/OFQ and three small molecule antagonists have been solved and released. Despite the available structural information, the details of selective small molecule agonist binding to the NOP receptor in the active state remain elusive. In this study, by leveraging the available structural information and using N/OFQ(1-13)-NH2 as a reference compound, we developed a computational protocol based on docking followed by short molecular dynamics (MD) simulations that can suggest small molecule agonist binding modes at the NOP receptor that are reproducible and stable over time in the solvated membrane-embedded receptor active state and in agreement with known structure-activity relationship (SAR) data.

Perchlorate supported Cu(II) based 1D polymeric chain containing 1,10-phenanthroline: Synthesis, characterization and adsorption of organic dyes and heavy metal ions

A one-dimensional (1D) copper(II) polymeric chain, [Cu(1,10-phen)(ClO4)(H2O)2]n (1), was synthesized by reacting Cu(ClO4)2·6H2O with 1,10-phenanthroline in the presence of triethylamine in methanol. X-ray crystallography revealed that 1,10-phenanthroline functions as a...

Low-temperature heat capacity, phase transitions and thermodynamic functions of 2-furfurylamine

Heat capacities of 2-furfurylamine were measured by low-temperature adiabatic calorimetry in the temperature range from 5.6 to 356.1 K. Two phase transitions, solid phase transition and melting, were revealed at temperatures of 180.6 K and 228.17 K. Thermodynamic characteristics determined from experimental data show that the mechanism of solid phase transition is intermediate between order-disorder and displacive type. This conclusion is in agreement with X-ray crystallography data (Seidel et al., 2019). The standard thermodynamic functions in the condensed state (molar heat capacity, enthalpy, entropy and Gibbs energy) were calculated in the temperature range 5 - 350 K. Using the determined value of entropy for liquid 2-furfurylamine and available value of ΔfHm∘(l), the properties of formation, ΔfSm∘(l) and ΔfGm∘(l), were obtained. The thermodynamic functions of gaseous 2-furfurylamine were calculated taking into account the internal rotation in this molecule. The required molecular constants were determined from quantum chemical calculations.