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Aderamastat (FP-025) is a small molecule, selective matrix metalloproteinase (MMP)-12 inhibitor, under development for respiratory conditions which may include chronic inflammatory airway diseases and pulmonary fibrosis. To support evaluation of the pharmacokinetic parameters of Aderamastat in humans, we developed and validated a high-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) analytical method for the quantification of Aderamastat in human plasma. This assay was validated in compliance with the Food and Drug Administration (FDA) Good Laboratory Practice Regulations (GLP) and European Medicines Agency (EMA) guidelines. K 2 EDTA human plasma samples were spiked with internal standard, processed by liquid-liquid extraction, and analyzed using reversed-phase HPLC with Turbo Ion Spray® MS/MS detection. Separation was done using a chromatographic gradient on 5 µm C6-Phenyl 110 Å, 50*2 mm analytical column at a temperature of 35 °C. The LC-MS/MS bioanalytical method, developed by QPS Taiwan to determine the concentration of Aderamastat in K 2 EDTA human plasma, was successfully validated with respect to linearity, sensitivity, accuracy, precision, dilution, selectivity, hemolyzed plasma, lipemic plasma, batch size, recovery, matrix effect, and carry-over. These data indicate that the method for determination of Aderamastat concentrations in human K 2 EDTA plasma can be used in pharmacokinetics studies and subsequent clinical trials with Aderamastat. Authors declare that, this novel data is not published and not under consideration for publication by another journal than this journal. All data will be made available on request., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Toward repositioning the antitubercular clinical candidate SQ109 as an antimalarial, analogs were investigated for structure-activity relationships for activity against asexual blood stages of the human malaria parasite Plasmodium falciparum pathogenic forms, as well as transmissible, sexual stage gametocytes. We show that equipotent activity (IC 50 ) in the 100-300 nM range could be attained for both asexual and sexual stages, with the activity of most compounds retained against a multidrug-resistant strain. The multistage activity profile relies on high lipophilicity ascribed to the adamantane headgroup, and antiplasmodial activity is critically dependent on the diamine linker. Frontrunner compounds showed conserved activity against genetically diverse southern African clinical isolates. We additionally validated that this series could block transmission to mosquitoes, marking these compounds as novel chemotypes with multistage antiplasmodial activity.

Muramyl dipeptide (MDP) is the smallest essential peptidoglycan substructure capable of promoting both innate and adaptive immune responses. Herein, we report on the design, synthesis, and in vivo study of the adjuvant properties of two novel MDP analogs containing an achiral adamantyl moiety attached to the desmuramyl dipeptide (DMP) pharmacophore and additionally modified by one mannosyl subunit (derivative 7) or two mannosyl subunits (derivative 11). Mannose substructures were introduced in order to assess how the degree of mannosylation affects the immune response and nucleotide-binding oligomerization-domain-containing protein 2 (NOD2) binding affinity, compared to the reference compound ManAdDMP. Both mannosylated MDP analogs showed improved immunomodulating properties, while the di-mannosylated derivative 11 displayed the highest, statistically significant increase in anti-OVA IgG production. In this study, for the first time, the di-mannosylated DMP derivative was synthesized and immunologically evaluated. Derivative 11 stimulates a Th-2-polarized type of immune reaction, similar to the reference compound ManAdDMP and MDP. Molecular dynamics (MD) simulations demonstrate that 11 has a higher NOD2 binding affinity than 7, indicating that introducing the second mannose significantly contributes to the binding affinity. Mannose interacts with key amino acid residues from the LRR hydrophobic pocket of the NOD2 receptor and loop 2.

Osteoarthritis (OA) is a chronic disease that causes pain, morbidity, and disability. The main strategy for OA treatment focuses on inflammation suppression, inhibition of osteoclastogenesis, and protection of articular cartilage. These functions cannot be performed effectively by monotherapy. Therefore, an effective drug delivery system is required, capable of containing and controlling the efflux of various drugs to alleviate osteoclastogenesis, protect cartilage and subchondral bone, and suppress inflammation. In this work, an encapsulation system is constructed using a self-healing chitosan hydrogel and allocated compound drugs. The self-healing gel is composed of branched-functionalized chitosan, created by simultaneously using polycaprolactone polyethylene glycol azide as a block polymer and the host-guest assembly of β-cyclodextrin and adamantane. Inhibitors of the NFkB pathway are loaded into the cavities of β-cyclodextrin and the spring-like structure of the block polymer, which can be rapidly released upon joint friction (due to the reassembly of β-cyclodextrin and adamantane by shear stress and the stretch of the block polymer). In vitro experiments using BMMs and the ATDC5 cell line confirm that the developed hydrogel can simultaneously suppress osteoclastogenesis and induce chondrogenesis. Additionally, a model of knee arthritis in C57 mice was used to confirm that this double-crosslinked encapsulation system can lubricate the knee joint surface and provide adequate protection on demand through shear-responsive drug release.

The development of in situ tumor vaccines offers promising prospects for cancer treatment. Nonetheless, the generation of plenary autologous antigens in vivo and their codelivery to DC cells along with adjuvants remains a significant challenge. Herein, we developed an in situ tumor vaccine using a supramolecular nanoparticle/hydrogel composite (ANP MTO /ALCD) and a deformable nanoadjuvant (PPE R848 ). The ANP MTO /ALCD composite consisted of β-cyclodextrin-decorated alginate (Alg- g -CD) and MTO-encapsulated adamantane-decorated nanoparticles (ANP MTO ) through supramolecular interaction, facilitating the long-term and sustained production of plenary autologous antigens, particularly under a 660 nm laser. Simultaneously, the produced autologous antigens were effectively captured by nanoadjuvant PPE R848 and subsequently transported to lymph nodes and DC cells, benefiting from its optimized size and deformability. This in situ tumor vaccine can trigger a robust antitumor immune response and demonstrate significant therapeutic efficacy in inhibiting tumor growth, suppressing tumor metastasis, and preventing postoperative recurrence, offering a straightforward approach to programming in situ tumor vaccines.

Platensilin, platensimycin, and platencin are potent inhibitors of β-ketoacyl-acyl carrier protein synthase (FabF) in the bacterial and mammalian fatty acid synthesis system, presenting promising drug leads for both antibacterial and antidiabetic therapies. Herein, a bioinspired skeleton reconstruction approach is reported, which enables the unified synthesis of these three natural FabF inhibitors and their skeletally diverse analogs, all stemming from a common ent -pimarane core. The synthesis features a diastereoselective biocatalytic reduction and an intermolecular Diels-Alder reaction to prepare the common ent -pimarane core. From this intermediate, stereoselective Mn-catalyzed hydrogen atom-transfer hydrogenation and subsequent Cu-catalyzed carbenoid C-H insertion afford platensilin. Furthermore, the intramolecular Diels-Alder reaction succeeded by regioselective ring opening of the newly formed cyclopropane enables the construction of the bicyclo[3.2.1]-octane and bicyclo[2.2.2]-octane ring systems of platensimycin and platencin, respectively. This skeletal reconstruction approach of the ent -pimarane core facilitates the preparation of analogs bearing different polycyclic scaffolds. Among these analogs, the previously unexplored cyclopropyl analog 47 exhibits improved antibacterial activity (MIC 80 = 0.0625 μg/mL) against S. aureus compared to platensimycin.

Using a multigram-scalable synthesis, we obtained nine dinuclear complexes based on nonendogenous iron(I) centers and featuring variable aminocarbyne and P-ligands. One compound from the series ( FEACYP ) emerged for its strong cytotoxicity in vitro against four human cancer cell lines, surpassing the activity of cisplatin by 3-6 times in three cell lines, with an average selectivity index of 6.2 compared to noncancerous HEK293 cells. FEACYP demonstrated outstanding water solubility (15 g/L) and stability in physiological-like solutions. It confirmed its superior antiproliferative activity when tested in 3D spheroids of human pancreatic cancer cells and showed a capacity to inhibit thioredoxin reductase (TrxR) similar to auranofin. In vivo treatment of murine LLC carcinoma with FEACYP (8 mg kg -1 dose) led to excellent tumor growth suppression (88%) on day 15, with no signs of systemic toxicity and only limited body weight loss.

Cannabinoid receptor subtype 2 (CB2R) is emerging as a pivotal biomarker to identify the first steps of inflammation-based diseases such as cancer and neurodegeneration. There is an urgent need to find specific probes that may result in green and safe alternatives to the commonly used radiative technologies, to deepen the knowledge of the CB2R pathways impacting the onset of the above-mentioned pathologies. Therefore, based on one of the CB2R pharmacophores, we developed a class of fluorescent N -adamantyl-1-alkyl-4-oxo-1,4-dihydroquinoline-3-carboxamide derivatives spanning from the green to the near-infrared (NIR) regions of the light spectrum. Among the synthesized fluorescent ligands, the green-emitting compound 55 exhibited a favorable binding profile (strong CB2R affinity and high selectivity). Notably, this ligand demonstrated versatility as its use was validated in different experimental settings such as flow cytometry saturation, competitive fluorescence assays, and in vitro microglia cells mimicking inflammation states where CB2R are overexpressed.

Purpose: NPB-22 (quinolin-8-yl 1-pentyl-1H-indazole-3-carboxylate), Adamantyl-THPINACA (N-(1-adamantantyl)-1-[(tetrahydro-2H-pyran-4-yl)methyl]-1H-indazole-3-carboxamide), and CUMYL-4CN-B7AICA (1-(4-cyanobutyl)-N-(2-phenylpropan-2-yl)-1H- pyrrolo[2,3-b]pyridine-3-carboxamide), synthetic cannabinoids were evaluated in terms of CB 1 (cannabinoid receptor type 1) and CB 2 (cannabinoid receptor type 2) activities, and their biological effects when inhaled similar to cigarettes were examined., Methods: The half maximal effective concentration values of the aforementioned synthetic cannabinoids at the CB 1 and CB 2 were investigated using [ 35 S]guanosine-5'-O-(3-thio)-triphosphate binding assays. In addition, their biological effects were evaluated using the inhalation exposure test with mice. The smoke generated was recovered by organic solvents in the midget impingers, and the thermal degradation compounds of the smoke components were identified and quantified using a liquid chromatography-photo diode array detector., Results: NPB-22 and Adamantyl-THPINACA had equivalent CB 1 activity in in vitro assays. Meanwhile, NPB-22 had a weaker biological effect on some items on the inhalation exposure test than Adamantyl-THPINACA. When analyzing organic solvents in the midget impingers, it was revealed that NPB-22 was degraded to 8-quinolinol and pentyl indazole 3-carboxylic acid by combustion. In addition, these degradation compounds did not have CB 1 activity., Conclusion: It was estimated that the biological effects of NPB-22 on the inhalation exposure test weakened because it underwent thermal degradation by combustion, and the resultant degradation compounds did not have any CB 1 activity in vitro., (© 2024. The Author(s).)

The new ligand L 2Ad , obtained by conjugating the bifunctional species bis(3,5-dimethylpyrazol-1-yl)-acetate and the drug amantadine, was used as a chelator for the synthesis of new Cu complexes 1 - 5 . Their structures were investigated by synchrotron radiation-induced X-ray photoelectron spectroscopy (SR-XPS), near-edge X-ray absorption fine structure (NEXAFS) spectroscopy, and by combining X-ray absorption fine structure (XAFS) spectroscopy techniques and DFT modeling. The structure of complex 3 was determined by single-crystal X-ray diffraction analysis. Tested on U87, T98, and U251 glioma cells, Cu(II) complex 3 and Cu(I) complex 5 decreased cell viability with IC 50 values significantly lower than cisplatin, affecting cell growth, proliferation, and death. Their effects were prevented by treatment with the Cu chelator tetrathiomolybdate, suggesting the involvement of copper in their cytotoxic activity. Both complexes were able to increase ROS production, leading to DNA damage and death. Interestingly, nontoxic doses of 3 or 5 enhanced the chemosensitivity to Temozolomide.

Synthetic cannabinoid receptor agonists (SCRAs) are a growing class of new psychoactive substances (NPS) commonly derived from an N -alkylated indole, indazole, or 7-azaindole scaffold. Diversification of this core (at the 3-position) with amide-linked pendant amino acid groups and modular N -alkylation (of the indole/indazole/7-azaindole core) ensures that novel SCRAs continue to enter the illicit drug market rapidly. In response to the large number of SCRAs that have been detected, pharmacological evaluation of this NPS class has become increasingly common. Adamantane-derived SCRAs have consistently appeared throughout the market since 2011, and as such, a systematic set of these derivatives was synthesized and pharmacologically evaluated. Deuterated and fluorinated adamantane derivatives were prepared to evaluate typical hydrogen bioisosteres, as well as evaluation of the newly detected AFUBIATA.

Oral dispersible films have received broad interest due to fast drug absorption and no first-path metabolism, leading to high bioavailability and better patient compliance. Saxagliptin (SXG) is an antidiabetic drug that undergoes first-path metabolism, resulting in a less active metabolite, so the development of SXG oral dispersible films (SXG-ODFs) improves SXG bioavailability. The formula optimisation included a response surface experimental design and the impact of three formulation factors, the type and concentration of polymer and plasticiser concentration on in-vitro disintegration time and folding endurance. Two optimised SXG-ODFs prepared using either polyvinyl alcohol (PVA) or hydroxypropyl methylcellulose were investigated. SXG-ODFs prepared with PVA demonstrated a superior rapid disintegration time, ranging from 17 to 890 s, with the fastest disintegration time recorded at 17 s. These short durations can be attributed to the hydrophilic nature of PVA, facilitating rapid hydration and disintegration upon contact with saliva. Additionally, PVA-based films displayed remarkable folding endurance, surpassing 200 folds without rupture, indicating flexibility and stability. The high tensile strength of PVA-based films further underscores their robust mechanical properties, with tensile strength values reaching up to 4.53 MPa. SXG exhibits a UV absorption wavelength of around 212 nm, posing challenges for traditional quantitative spectrophotometric analysis, so a polyaniline nanoparticles-based solid-contact screen-printed ion-selective electrode (SP-ISE) was employed for the determination of SXG release profile effectively in comparison to HPLC. SP-ISE showed a better real-time release profile of SXG-ODFs, and the optimised formula showed lower blood glucose levels than commercial tablets., (© 2024. The Author(s).)

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

The non-canonical amino acid adamantylglycine (Ada) is introduced into peptides to allow high-affinity binding to cucurbit[7]uril (CB7). Introduction of Ada into a cell-penetrating peptide (CPP) sequence had minimal influence on the membrane transport, yet enabled up- and down-regulation of the membrane transport activity.

Hyperadamans A-G (1-7), seven new adamantane type polycyclic polyprenylated acylphloroglucinols (PPAPs), were isolated from Hypericum wilsonii N. Robson. Structurally, 1-4 were the first adamantanes bearing an unusual 2,7-dioxabicyclo-[2.2.1]-heptane fragment, and compound 5 was the first adamantane with a rare 1,6-dioxaspiro[4.4]nonane section. Importantly, 1-7 exhibited significant immunosuppressive activity on Con A-induced T-lymphocyte proliferation in vitro, with IC 50 values ranging from 3.97 ± 0.10 to 18.12 ± 1.07 μM. Pretreatment with 1 in Con A-challenged autoimmune hepatitis mice could dramatically ameliorate the levels of hepatic injury indexes (ALT and AST) and reduce the product of proinflammatory cytokines (COX-2, IL-6, IL-1β, IL-18, IL-23A and TNF-α). Furthermore, the protective effect of 1 on the Con A-induced liver injury was corroborated by the histological analysis and the immunohistochemistry., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The fluorescence of functional dyes was generally quenched in aqueous solution, which hindered their application in water-bearing detections. In this work, a novel strategy based on host-guest interaction was provided for the purpose of fluorescence enhancement in aqueous solution and cell imaging. Three adamantane-modified fluorescent dyes (Coum-Ad, NP-Ad, NR-Ad) with coumarin, 1,8-naphthalimide and Nile Red as fluorophores were initially designed and prepared. The ((adamantan-1-yl)methyl)amino group, as the auxochrome of those dyes, complexed with methylated β-cyclodextrin (M-β-CD) via supramolecular interaction, and then fluorescent supramolecular nanoparticles (FSNPs) were formed by self-assembly in water. The inclusion equilibrium constant (K) could be as high as 3.94×10 4  M -1 . With the addition of M-β-CD, fluorescence quantum yields of these dyes were separately improved to 69.8 %, 32.9 % and 41.3 %. Inspired by the above satisfactory results, six adamantane-modified probes organelle-NPAds with organelle-targeting capability were further obtained. As the formation of hydrogen bonds between organelle-NPAd2 and M-β-CD verified by theoretical calculation, K of organelle-NPAd2 (5.13×10 4  M -1 ~4.53×10 5  M -1 ) with M-β-CD was higher than that of organelle-NPAd1 (1.15×10 4  M -1 ~3.66×10 4  M -1 ) and their fluorescence quantum yields increased to 32.8 %~83.6 % in aqueous solution. In addition, fluorescence enhancement was realized in cell imaging with the addition of M-β-CD., (© 2023 Wiley-VCH GmbH.)

The integration of microscopic hydrogels with high specific surface area and physically reactive groups into microfluidic systems for selective molecular interactions is attracting increasing attention. Herein, the reversible capture and release of molecules through host-guest interactions of hydrogel dots in a microfluidic device is reported, which translates the supramolecular chemistry to the microscale conditions under continuous flow. Polyacrylamide (PAAm) hydrogel arrays with grafted β-cyclodextrin (β-CD)  modified poly(2-methyl-2-oxazoline) (CD-PMOXA) chains are fabricated by photopolymerization and integrated into a polydimethylsiloxane (PDMS)-on-glass chip. The β-CD/adamantane (β-CD/Ada) host-guest complex is confirmed by two dimensional Nuclear Overhauser Effect Spectroscopy NMR (2D NOESY NMR) prior to transfer to microfluidics. Ada-modified molecules are successfully captured by host-guest interaction formed between the CD-PMOXA grafted chains in the hydrogel network and the guest molecule in the solution. Furthermore, the captured molecules are released by perfusing free β-CD with higher binding affinity than those grafted in the hydrogel array. A small guest molecule adamantane-fluorescein-isothiocyanate (Ada-FITC) and a macromolecular guest molecule (Ada-PMOXA-Cyanine 5 (Cy5)) are separately captured and released for three times with a release ratio up to 46% and 92%, respectively. The reproducible capture and release of functional molecules with different sizes demonstrates the stability of this hydrogel system in microfluidics and will provide an opportunity for future applications., (© 2023 The Authors. Macromolecular Rapid Communications published by Wiley-VCH GmbH.)

The goal of reducing the total-body radiation dose of macromolecule-based nuclear medicine with a 2-step pretargeting strategy has been achieved with several pretargeting methodologies in preclinical and clinical settings. However, the lack of modularity, biocompatibility, and in vivo stability in existing pretargeting agents obstructs their respective platforms' wide clinical use. We hypothesized that host-guest chemistry would provide an optimal pretargeting methodology. A cucurbit[7]uril host and an adamantane guest molecule form a high-affinity host-guest complex (association constant, ∼10 14 M -1 ), and in this work, we explored the use of this noncovalent interaction as the basis for antibody-based pretargeted PET. Along with the straightforward modularity of these agents, cucurbit[7]uril and adamantane are recognized to have high in vivo stability and suitability for human use, which is why we proposed this methodology as the ideal approach for pretargeted nuclear medicine. Methods: Three 64 Cu-labeled adamantane guest radioligands were developed, and their in vitro stability, lipophilicity, and in vivo blood half-lives were compared. The adamantane radioligands were analyzed for pretargeting using a cucurbit[7]uril-modified carcinoembryonic antigen-targeting full-length antibody, hT84.66-M5A, as the macromolecule pretargeting agent with 2 different dosing schedules. These molecules were evaluated for pretargeting in human pancreatic cancer BxPC3 and MIAPaCa-2 mouse xenografts using PET and in vivo biodistribution studies. The dosimetry of the cucurbit[7]uril-adamantane (CB7-Adma) pretargeting approach in men was calculated and compared with that of the directly 89 Zr-labeled hT84.66-M5A. Results: The adamantane radioligands possessed high in vitro stability up to 24 h (>90%). Pretargeted PET with CB7-Adma methodology resulted in specific tumor uptake ( P < 0.05) with low background signal. The in vivo formed CB7-Adma complex was demonstrated to be stable, with high tumor uptake up to 24 h after radioligand injection (12.0 ± 0.9 percentage injected dose/g). The total-body radiation dose of the pretargeting strategy was only 3.3% that of the directly 89 Zr-labeled hT84.66-M5A. Conclusion: The CB7-Adma strategy is highly suitable for pretargeted PET. The exceptional stability of the pretargeting agents and the specific and high tumor uptake of the pretargeted adamantane radioligands provide great potential for the platform., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N -Mannich bases ( 1 - 3 ) are presented. Compounds 1 , 2 and 3 crystallized in the monoclinic P 2 1 / c , P 2 1 and P 2 1 / n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π interactions. The energy frameworks for crystal structures of 1 - 3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1 - 3 were determined using in silico techniques. Molecular docking of the compounds into the 11β-HSD1 active site showed comparable binding affinity scores (-7.50 to -8.92 kcal/mol) to the 11β-HSD1 co-crystallized ligand 4YQ (-8.48 kcal/mol, 11β-HSD1 IC 50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.

Nanomedicine has developed as a potential technique for successful cancer therapy. A simple supramolecular self-assembly process is a helpful strategy for generating carrier-free nanodrugs. Mixing photodynamic treatment with chemotherapy has been sought to obtain a high therapeutic impact. In this study, we effectively construct a nanocarrier (CD-Por-PEG: Ada-CPT-Pt(IV)) combined with Carboplatin prodrug (Ada-CPT-Pt(IV)) and photosensitizer porphyrin (CD-Por-PEG) by host-guest interactions to accomplish stimuli-response combination treatment. Supported by greater spatial control of the binding ratio among host-guest molecules, Carboplatin and porphyrin were independently altered with β-cyclodextrin and adamantane to produce the amphiphilic host-guest combination for sequential self-assembly into therapeutic nanoparticles. The colloidal stability of the produced CD-Por-PEG: Ada-CPT-Pt(IV)-NPs was excellent, with an average hydrodynamic diameter of ∼170 nm. The microscopy images showed that CD-Por-PEG: Ada-CPT-Pt(IV) could aggregate cells and generate ROS after light irradiation (630 nm). Monotherapy had a cytotoxicity three times greater than the CD-Por-PEG: Ada-CPT-Pt(IV) nanoparticles. Studies in mice carrying SUNE1 nasopharyngeal tumours showed that nanoparticles effectively suppressed tumour development without causing systemic damage in this examination. The current self-assembly nanosystem makes precise control over the photosensitizer and drug loading possible ratio. It reduces the systemic adverse toxicity issues of drugs carrier, making this system ideal for nasopharyngeal cancer treatment.

Introduction of adamantane moieties on diamondoids such as adamantane, 2-azaadamantane or diamantane by amide formation and reduction to the corresponding amine was performed in a straightforward and easy way by amidation under Schotten-Baumann conditions and reduction with BH 3  ⋅ THF. The obtained amides and amines were studied in terms of structural properties towards the perspective of transformation into nanodiamonds. Crystal structure and dynamic NMR experiments of the most crowded amide obtained gave structural insights into the effect of bulkiness and steric strain on out-of-planarity of amide bonds (16.0°) and the kinetics and thermodynamics of amide bond rotation (ΔG ≠ 298K =11.5-13.3 kcal ⋅ mol -1 )., (© 2022 The Authors. Published by Wiley-VCH GmbH.)

Binding affinity prediction by means of computer simulation has been increasingly incorporated in drug discovery projects. Its wide application, however, is limited by the prediction accuracy of the free energy calculations. The main error sources are force fields used to describe molecular interactions and incomplete sampling of the configurational space. Organic host-guest systems have been used to address force field quality because they share similar interactions found in ligands and receptors, and their rigidity facilitates configurational sampling. Here, we test the binding free energy prediction accuracy for 14 guests with an aromatic or adamantane core and the CB7 host using molecular electron density derived nonbonded force field parameters. We developed a computational workflow written in Python to derive atomic charges and Lennard-Jones parameters with the Minimal Basis Iterative Stockholder method using the polarized electron density of several configurations of each guest in the bound and unbound states. The resulting nonbonded force field parameters improve binding affinity prediction, especially for guests with an adamantane core in which repulsive exchange and dispersion interactions to the host dominate.

The 13 C signals of adamantane are used as a chemical shift standard for solid-state NMR. Its chemical shifts are measured to greater accuracy than previously reported and over a temperature range from -2 to 70 °C. Combining the chemical shifts of adamantane's two NMR signals gives an accurate chemical shift over the whole temperature range without need for measuring the temperature directly. The difference between the chemical shifts gives the approximate temperature. The chemical shift of the adamantane CH signal at 25 °C is 37.777, σ = 0.003 ppm., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Roy Hoffman reports was provided by The Hebrew University of Jerusalem. Roy Hoffman reports a relationship with The Hebrew University of Jerusalem that includes., (Copyright © 2022 Elsevier Inc. All rights reserved.)

4,6,10-Trihydroxy-1,4,6,10-tetraazaadamantane (TAAD) has been shown to form a stable Fe(IV) complex having a diamantane cage structure, in which the metal center is coordinated by three oxygen atoms of the deprotonated ligand. The complex was characterized by X-ray diffraction analysis, HRMS, NMR, FT-IR, Mössbauer spectroscopy and DFT calculations, which supported the d 4 configuration of iron. The Fe(IV)-TAAD complex showed excellent performance in dioxygen activation under mild conditions serving as a mimetic of the thiol oxidase enzyme. The nucleophilicity of the bridgehead nitrogen atom in TAAD provides a straightforward way for the conjugation of Fe(IV)-TAAD complexes to various functional molecules. Using this approach, steroidal and peptide molecules having an iron(IV) label have been prepared for the first time. In addition, the Fe(IV)-TAAD complex was covalently bound to a polystyrene matrix and the resulting material was shown to serve as a heterogeneous catalyst for aerobic oxidation of thiols to disulfides.

Mycobacterial membrane protein large 3 (Mmpl3) as a trehalose monomycolate lipid transporter contributes to cell wall biosynthesis. Inhibition of Mmpl3 can suppress cell growth and lead to mycobacterial death. SQ109 is a hydrophobic inhibitor of Mmpl3. We have devised a detergent-free strategy to characterize the SQ109/Mmpl3 interaction using the Native Cell Membrane Nanoparticles (NCMN) system, a new method for extracting membrane proteins that better retains native lipids. The homogeneity of the Mmpl3 NCMN particles was confirmed with electron microscopy. The hydrophobic protein-ligand interaction analysis shown for Mmpl3 using the NCMN system may broadly apply to other membrane proteins., (Copyright © 2021. Published by Elsevier B.V.)

Supramolecular chemistry provides huge potentials and opportunities in agricultural pest management. In an attempt to develop highly bioactive, eco-friendly, and biocompatible supramolecular complexes for managing intractable plant bacterial diseases, herein, a type of interesting adamantane-functionalized 1,3,4-oxadiazole was rationally prepared to facilitate the formation of supramolecular complexes via β-cyclodextrin-adamantane host-guest interactions. Initial antibacterial screening revealed that most of these adamantane-decorated 1,3,4-oxadiazoles were obviously bioactive against three typically destructive phytopathogens. The lowest EC 50 values could reach 0.936 ( III 18 ), 0.889 ( III 18 ), and 2.10 ( III 19 ) μg/mL against the corresponding Xanthomonas oryzae pv. oryzae ( Xoo ), Xanthomonas axonopodis pv. citri ( Xac ), and Pseudomonas syringae pv. actinidiae ( Psa ). Next, the representative supramolecular binary complex III 18 @β-CD (binding mode 1:1) was successfully fabricated and characterized by 1 H nuclear magnetic resonance (NMR), isothermal titration calorimetry (ITC), high-resolution mass spectrometry (HRMS), dynamic light scattering (DLS), and transmission electron microscopy (TEM). Eventually, correlative water solubility and foliar surface wettability were significantly improved after the formation of host-guest assemblies. In vivo antibacterial evaluation found that the achieved supramolecular complex could distinctly alleviate the disease symptoms and promote the control efficiencies against rice bacterial blight (from 34.6-35.7% ( III 18 ) to 40.3-43.6% ( III 18 @β-CD)) and kiwi canker diseases (from 41.0-42.3% ( III 18 ) to 53.9-68.0% ( III 18 @β-CD)) at 200 μg/mL (active ingredient). The current study can provide a feasible platform and insight for constructing biocompatible supramolecular assemblies for managing destructive bacterial infections in agriculture.

The fluorescent organic 2,5,8-tris((adamantan-1-yl)-methoxy)-heptazine (HTZ-Ad) was solubilized in water by inclusion of adamantane groups into free β-cyclodextrins or a cyclodextrin shell of glyconanoparticles. These glyconanoparticles with average diameters between 40 and 60 nm result from the self-assembly of polystyrene- block -β-cyclodextrin copolymers. Under UV irradiation at 365 nm, the modified nanoparticles exhibit fluorescence emission in aqueous media as well as in their adsorbed state. This constitutes the first spectroscopic characterization of a trialkoxyheptazine in aqueous medium. The specific binding of the glyconanoparticles to a surface was achieved via host-guest interactions with an electrochemically generated poly(pyrrole-adamantane) film. An interdigitated microelectrode modified with poly(pyrrole-adamantane) film and glyconanoparticles was incubated in HTZ-Ad, resulting in a substrate with spatially controlled fluorescence. The same modified electrode was incubated with an aqueous suspension of glyconanoparticles previously functionalized by HTZ-Ad, resulting in a fluorescent 3D assembly.

The aqueous dissolution profile of the isomeric synthetic adamantane phenylalkylamine hydrochlorides I and II was probed. These adducts have shown significant antiproliferative/anticancer activity associated with an analgesic profile against neuropathic pain. They are both devoid of toxic effects and show appreciable enzymatic human plasma stability. The structures of these two compounds have been elucidated using 2D NMR experiments, which were used to study their predominant conformations. Compound II 's scaffold appeared more flexible, as shown by the NOE spatial interactions between the alkyl bridge chain, the aromatic rings, and the adamantane nucleus. Conversely, compound I appeared very rigid, as it did not share significant NOEs between the aforementioned structural segments. MD simulations confirmed the NOE results. The aqueous dissolution profile of both molecules fits well with their minimum energy conformers' features, which stem from the NOE data; this was nicely demonstrated, especially in the case of compound II .

PtmU3 is a newly identified nonheme diiron monooxygenase, which installs a C-5 β-hydroxyl group into the C-19 CoA-ester intermediate involved in the biosynthesis of unique diterpene-derived scaffolds of platensimycin and platencin. PtmU3 possesses a noncanonical diiron active site architecture of a saturated six-coordinate iron center and lacks the μ-oxo bridge. Although the hydroxylation process is a simple reaction for nonheme mononuclear iron-dependent enzymes, how PtmU3 employs the diiron center to catalyze the H-abstraction and OH-rebound is still unknown. In particular, the electronic characteristic of diiron is also unclear. To understand the catalytic mechanism of PtmU3, we constructed two reactant models in which both the Fe1 II -Fe2 III -superoxo and Fe1 II -Fe2 IV ═O are considered to trigger the H-abstraction and performed a series of quantum mechanics/molecular mechanics calculations. Our calculation results reveal that PtmU3 is a special monooxygenase, that is, both atoms of the dioxygen molecule can be incorporated into two molecules of the substrate by the successive reactions. In the first-round reaction, PtmU3 uses the Fe1 II -Fe2 III -superoxo to install a hydroxyl group into the substrate, generating the high-reactive Fe1 II -Fe2 IV ═O complex. In the second-round reaction, the Fe1 II -Fe2 IV ═O species is responsible for the hydroxylation of another molecule of the substrate. In the diiron center, Fe2 adopts the high spin state ( S = 5/2) during the catalysis, whereas for Fe1, in addition to its structural role, it may also play an assistant role for Fe1 catalysis. In the two successive OH-installing steps, the H-abstraction is always the rate-liming step. E241 and D308 not only act as bridging ligands to connect two Fe ions but also take part in the electron reorganization. Owing to the high reactivity of Fe1 II -Fe2 IV ═O compared to Fe1 II -Fe2 III -superoxo, besides the C5-hydroxylation, the C3- or C18-hydroxylation was also calculated to be feasible.

One way to enhance the poor mechanical properties of the self-healing hydrogels based on host-guest (HG) interaction is employing the dual cross-linking method. Here, the alginate-based hydrogels based on HG complexation were prepared through the modification of alginate (ALG) polysaccharide with beta-cyclodextrin (βCD) and adamantane (Ad) as host and guest groups with different grafting values, respectively. The porous structure was confirmed for all ALG-CD:ALG-Ad hydrogels. The average pore size of ALG-CD 1 :ALG-Ad 1 hydrogel cross-linked by HG interactions was 288 μm. Mechanical properties of the alginate-based HG hydrogels were improved by incorporating Ca 2+ ions in their structure through dual cross-linking methodology. The maximum modulus of the porous dual-crosslinked hydrogel was reached up to 6500 Pa. The healing time of less than 5 s was obtained for the alginate-based hydrogels. The fabricated hydrogels can be used in 3D printing, tissue engineering, and drug delivery systems due to their biocompatibility and shear-thinning behavior., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cyclin-dependent kinases (CDKs) play an important role in the cell-division cycle. Synthetic inhibitors of CDKs are based on 2,6,9-trisubstituted purines and are developed as potential anticancer drugs; however, they have low solubility in water. In this study, we proved that the pharmaco-chemical properties of purine-based inhibitors can be improved by appropriate substitution with the adamantane moiety. We prepared ten new purine derivatives with adamantane skeletons that were linked at position 6 using phenylene spacers of variable geometry and polarity. We demonstrated that the adamantane skeleton does not compromise the biological activity, and some of the new purines displayed even higher inhibition activity towards CDK2/cyclin E than the parental compounds. These findings were supported by a docking study, which showed an adamantane scaffold inside the binding pocket participating in the complex stabilisation with non-polar interactions. In addition, we demonstrated that β-cyclodextrin (CD) increases the drug's solubility in water, although this is at the cost of reducing the biochemical and cellular effect. Most likely, the drug concentration, which is necessary for target engagement, was decreased by competitive drug binding within the complex with β-CD.

Currently, smallpox, caused by the variola virus belonging to the poxvirus family, has been completely eradicated according to the WHO. However, other representatives of poxviruses, such as vaccinia virus, cowpox virus, ectromelia virus, monkeypox virus, mousepox virus and others, remain in the natural environment and can infect both animals and humans. The pathogens of animal diseases, belonging to the category with a high epidemic risk, have already caused several outbreaks among humans, and can, in an unfavorable combination of circumstances, cause not only an epidemic, but also a pandemic. Despite the fact that there are protocols for the treatment of poxvirus infections, the targeted design of new drugs will increase their availability and expand the arsenal of antiviral chemotherapeutic agents. One of the potential targets of poxviruses is the p37 protein, which is a tecovirimat target. This protein is relatively small, has no homologs among proteins of humans and other mammals and is necessary for the replication of viral particles, which makes it attractive target for virtual screening. Using the I-TASSER modelling and molecular dynamics refinement the p37 orthopox virus protein model was obtained and its was confirmed by ramachandran plot analysis and superimposition of the model with the template protein with similar function. A virtual library of adamantane containing compounds was generated and a number of potential inhibitors were chosen from virtual library using molecular docking. Several compounds bearing adamantane moiety were synthesized and their biological activity was tested in vitro on vaccinia, cowpox and mousepox viruses. The new compounds inhibiting vaccinia virus replication with IC 50 concentrations between 0.133 and 0.515 μM were found as a result of the research. The applied approach can be useful in the search of new inhibitors of orthopox reproduction. The proposed approach may be suitable for the design of new poxvirus inhibitors containing cage structural moiety., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Biodegradable supramolecular micelles were prepared exploiting the host-guest interaction of cyclodextrin and adamantane. Cyclodextrin-initiated polypeptides acted as the hydrophilic corona, whereas adamantane-terminated polycaprolactones served as the hydrophobic core.

Adamantane has been widely used as a "lipophilic bullet" in drug discovery and development, due to its unique diamond-like architecture with benign pharmacological/ pharmaceutical properties. Platensimycin is a natural product isolated from a soil streptomycete, which contains an adamantane-like moiety extensively modified from a diterpenoid precursor. In the current study, platensic alcohol was semisynthesized from platensimycin and used as an adamantane surrogate in anticancer drug lead adaphostin. The resulting hybrid platensic alcohol/adaphostin compounds, eg. 4a and 4b, exhibited similar cytotoxic activity with adaphostin against the tested cancer cell lines. In particular, 4b generates significantly more reactive oxygen species (ROS) and shows stronger synergy with the clinically used histone deacetylase inhibitor vorinostat than adaphostin, probably due to the presence of two hydroquinone groups. Density functional theory calculation supports that there could be certain π-π stacking interaction in 4b in aqueous solution, which might explain that 4b has similar serum stability with adaphostin. Our study not only leads to the identification of 4b as a potent ROS generating agent, but showcases a simple scaffold hopping strategy to harvest lipophilic scaffolds from natural products., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P -1 space group, while compounds 1 and 3 crystallize in the same monoclinic P 2 1 / c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO 2 and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO 2 /Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO 2 group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11β-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11β-HSD1 inhibitors were able to accurately dock within the 11β-HSD1 X-ray structure 4C7J . The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11β-HSD1 binding affinity scores as well as interactions to a known potent 11β-HSD1 inhibitor.

Nucleotide-binding oligomerization domain 2 (NOD2) is an intracellular receptor that recognizes the bacterial peptidoglycan fragment muramyl dipeptide (MDP). Our group has synthesized and biologically evaluated desmuramyl peptides containing adamantane and its mannose derivatives. The most active mannosylated derivative, ManAdDMP (Man-OCH 2 -d-(1-Ad)Gly-l-Ala-d-isoGln), is further characterized in silico in this study. We built intact model structures of the rabbit NOD2 protein, whose crystal structure lacks seven loops, and explored the binding of ManAdDMP. Two main binding sites for ManAdDMP are located within the nucleotide-binding oligomerization domain (NOD) and C-terminal leucine-rich repeat (LRR) domains. Our analysis shows that the dipeptide isoGln moiety of ManAdDMP significantly contributes to the binding, whereas the mannose moiety interacts with modelled loop 7, which is a part of the NOD helical domain 2. The presented results point to the importance of loops 2 and 7 in ligand recognition that could be useful for further investigation of NOD2 activation/inhibition.

A common mechanism in which glucocorticoids participate is suggested in the pathogenesis of such metabolic diseases as obesity, metabolic syndrome, or Cushing's syndrome. The enzyme involved in the control of the availability of cortisol, the active form of the glucocorticoid for the glucocorticoid receptor, is 11β-HSD1. Inhibition of 11β-HSD1 activity may bring beneficial results for the alleviation of the course of metabolic diseases such as metabolic syndrome, Cushing's syndrome or type 2 diabetes. In this work, we obtained 10 novel 2-(adamantan-1-ylamino)thiazol-4(5 H )-one derivatives containing different substituents at C-5 of thiazole ring and tested their activity towards inhibition of two 11β-HSD isoforms. For most of them, over 50% inhibition of 11β-HSD1 and less than 45% inhibition of 11β-HSD2 activity at the concentration of 10 µM was observed. The binding energies found during docking simulations for 11β-HSD1 correctly reproduced the experimental IC 50 values for analyzed compounds. The most active compound 2-(adamantan-1-ylamino)-1-thia-3-azaspiro[4.5]dec-2-en-4-one ( 3i ) inhibits the activity of isoform 1 by 82.82%. This value is comparable to the known inhibitor-carbenoxolone. The IC 50 value is twice the value determined by us for carbenoxolone, however inhibition of the enzyme isoform 2 to a lesser extent makes it an excellent material for further tests.

To enhance drug utilization and reduce their side effects, the strategy of "tumor-triggered targeting" was introduced to fabricate dual-pH-sensitive chitosan (CHI)/mesoporous silica nanoparticle (MSN)-based anticancer drug delivery system (DDS) in this work. Model drug doxorubicin hydrochloride (DOX) was loaded in MSN, which was modified with benzimidazole (Bz) group. Then chitosan-graft-β-cyclodextrin (CHI-g-CD) was applied as the "gatekeeper" to cover MSN through host-guest interaction between β-CD and Bz. After being coated with targeting peptide adamantane-glycine-arginine-glycine-aspartic acid-serine (Ad-GRGDS), methoxy poly(ethylene glycol) benzaldehyde (mPEG-CHO) was finally grafted on CHI through the pH-sensitive benzoic imine bond. Due to the dynamic protection of PEG, the obtained carriers were "stealthy" at pH 7.4, but could reveal the shielded targeting peptide and the positive charge of CHI in the weakly acidic environment achieved a "tumor-triggered targeting". Inside cancer cells, the interaction between β-CD and Bz group could be destroyed due to the lower pH, resulted in DOX release. Both in vitro and in vivo studies proved the DDS could targeting induce cancer cell apoptosis, inhibit tumor growth, and reduce the cytotoxicity of DOX against normal cells. It is expected that the system named DOX@MSN-CHI-RGD-PEG could be a potential choice for cancer therapy., (Copyright © 2021 Elsevier B.V. All rights reserved.)

A study was carried out on the solvolysis of 1-adamantyl chlorothioformate (1-AdSCOCl, 1 ) in hydroxylic solvents. The rate constants of the solvolysis of 1 were well correlated using the Grunwald-Winstein equation in all of the 20 solvents (R = 0.985). The solvolyses of 1 were analyzed as the following two competing reactions: the solvolysis ionization pathway through the intermediate (1-AdSCO) + (carboxylium ion) stabilized by the loss of chloride ions due to nucleophilic solvation and the solvolysis-decomposition pathway through the intermediate 1-Ad + Cl - ion pairs (carbocation) with the loss of carbonyl sulfide. In addition, the rate constants ( k exp ) for the solvolysis of 1 were separated into k 1-Ad + Cl - and k 1-AdSCO + Cl - through a product study and applied to the Grunwald-Winstein equation to obtain the sensitivity ( m -value) to change in solvent ionizing power. For binary hydroxylic solvents, the selectivities ( S ) for the formation of solvolysis products were very similar to those of the 1-adamantyl derivatives discussed previously. The kinetic solvent isotope effects (KSIEs), salt effects and activation parameters for the solvolyses of 1 were also determined. These observations are compared with those previously reported for the solvolyses of 1-adamantyl chloroformate (1-AdOCOCl, 2 ). The reasons for change in reaction channels are discussed in terms of the gas-phase stabilities of acylium ions calculated using Gaussian 03.

Neurotensin receptor 1 (NTS 1 ) is involved in the development and progression of numerous cancers, which makes it an interesting target for the development of diagnostic and therapeutic agents. A small molecule NTS 1 antagonist, named [ 177 Lu]Lu-IPN01087, is currently evaluated in phase I/II clinical trials for the targeted therapy of neurotensin receptor-positive cancers. In this study, we synthesized seven compounds based on the structure of NTS 1 antagonists, bearing different chelating agents, and radiolabeled them with gallium-68 for PET imaging. These compounds were evaluated in vitro and in vivo in mice bearing a HT-29 xenograft. The compound [ 68 Ga]Ga-bisNODAGA- 16 showed a promising biodistribution profile with mainly signal in tumor (4.917 ± 0.776%ID/g, 2 h post-injection). Its rapid clearance from healthy tissues led to high tumor-to-organ ratios, resulting in highly contrasted PET images. These results were confirmed on subcutaneous xenografts of AsPC-1 tumor cells, a model of NTS 1 -positive human pancreatic adenocarcinoma.

3D culture of cells in designer biomaterial matrices provides a biomimetic cellular microenvironment and can yield critical insights into cellular behaviours not available from conventional 2D cultures. Hydrogels with dynamic properties, achieved by incorporating either degradable structural components or reversible dynamic crosslinks, enable efficient cell adaptation of the matrix and support associated cellular functions. Herein we demonstrate that given similar equilibrium binding constants, hydrogels containing dynamic crosslinks with a large dissociation rate constant enable cell force-induced network reorganization, which results in rapid stellate spreading, assembly, mechanosensing, and differentiation of encapsulated stem cells when compared to similar hydrogels containing dynamic crosslinks with a low dissociation rate constant. Furthermore, the static and precise conjugation of cell adhesive ligands to the hydrogel subnetwork connected by such fast-dissociating crosslinks is also required for ultra-rapid stellate spreading (within 18 h post-encapsulation) and enhanced mechanosensing of stem cells in 3D. This work reveals the correlation between microscopic cell behaviours and the molecular level binding kinetics in hydrogel networks. Our findings provide valuable guidance to the design and evaluation of supramolecular biomaterials with cell-adaptable properties for studying cells in 3D cultures.

Two protoporphyrin IX (PpIX) adamantane derivatives were synthesized and then metallated with zinc. The Zn-PpIX derivatives, exhibiting a high singlet oxygen quantum yield, were tested for their photodynamic activity against the HT-29 cell line. In order to enhance their water-solubility and their cellular bioavailability, these photosensitizers were encapsulated into the hydrophobic cavity of cyclodextrins (CD) previously attached to cellulose nanocrystals (CNCs) via electrostatic interactions. Under illumination, the encapsulated adamantanyl-porphyrins exerted an enhanced in vitro cytotoxicity, as compared with the corresponding free photosensitizers., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Mutant p53 rescue by small molecules is a promising therapeutic strategy. In this structure-activity relationship study, we examined a series of adamantyl isothiocyanates (Ad-ITCs) to discover novel agents as therapeutics by targeting mutant p53. We demonstrated that the alkyl chain connecting adamantane and ITC is a crucial determinant for Ad-ITC inhibitory potency. Ad-ITC 6 with the longest chain between ITC and adamantane displayed the maximum growth inhibition in p53 R280K , p53 R273H , or p53 R306Stop mutant cells. Ad-ITC 6 acted in a mutant p53-dependent manner. It rescued p53 R280K and p53 R273H mutants, thereby resulting in upregulating canonical wild-type (WT) p53 targets and phosphorylating ATM. Ad-ISeC 14 with selenium showed a significantly enhanced inhibitory potency, without affecting its ability to rescue mutant p53. Ad-ITCs selectively depleted mutant p53, but not the WT, and this activity correlates with their inhibitory potencies. These data suggest that Ad-ITCs may serve as novel promising leads for the p53-targeted drug development.

Tyrosyl-DNA phosphodiesterase 1 (Tdp1) is a promising target for anticancer therapy due to its ability to counter the effects topoisomerase 1 (Top1) poison, such as topotecan, thus, decreasing their efficacy. Compounds containing adamantane and monoterpenoid residues connected via 1,2,4-triazole or 1,3,4-thiadiazole linkers were synthesized and tested against Tdp1. All the derivatives exhibited inhibition at low micromolar or nanomolar concentrations with the most potent inhibitors having IC 50 values in the 0.35-0.57 µM range. The cytotoxicity was determined in the HeLa, HCT-116 and SW837 cancer cell lines; moderate CC 50 (µM) values were seen from the mid-teens to no effect at 100 µM. Furthermore, citral derivative 20c , α-pinene-derived compounds 20f , 20g and 25c, and the citronellic acid derivative 25b were found to have a sensitizing effect in conjunction with topotecan in the HeLa cervical cancer and colon adenocarcinoma HCT-116 cell lines. The ligands are predicted to bind in the catalytic pocket of Tdp1 and have favorable physicochemical properties for further development as a potential adjunct therapy with Top1 poisons.

The pharmacological inhibition of soluble epoxide hydrolase (sEH) is efficient for the treatment of inflammatory and pain-related diseases. Numerous potent sEH inhibitors (sEHIs) present adamantyl or phenyl moieties, such as the clinical candidates AR9281 or EC5026. Herein, in a new series of sEHIs, these hydrophobic moieties have been merged in a benzohomoadamantane scaffold. Most of the new sEHIs have excellent inhibitory activities against sEH. Molecular dynamics simulations suggested that the addition of an aromatic ring into the adamantane scaffold produced conformational rearrangements in the enzyme to stabilize the aromatic ring of the benzohomoadamantane core. A screening cascade permitted us to select a candidate for an in vivo efficacy study in a murine model of cerulein-induced acute pancreatitis. The administration of 22 improved the health status of the animals and reduced pancreatic damage, demonstrating that the benzohomoadamantane unit is a promising scaffold for the design of novel sEHIs.

In a recent publication, Eleftheriou et al. proposed that inhibitors of dipeptidyl peptidase-4 (DPP-4) are functional inhibitors of the main protease (M pro ) of SARS-CoV-2. Their predictions prompted the authors to suggest linagliptin, a DPP-4 inhibitor and approved anti-diabetes drug, as a repurposed drug candidate against the ongoing COVID-19 pandemic. We used an enzymatic assay measuring the inhibition of M pro catalytic activity in the presence of four different commercially available gliptins (linagliptin, sitagliptin, alogliptin and saxagliptin) and several structural analogues of linagliptin to study the binding of DPP-4 inhibitors to M pro and their functional activity. We show here that DPP-4 inhibitors like linagliptin, other gliptins and structural analogues are inactive against M pro ., (© 2020 The Authors. Published by Wiley-VCH GmbH.)

[4-(Adamantane-1-carboxamido)-3-oxo-1-thia-4-azaspiro[4.4]nonan-2-yl]acetic acid (4a) and [4-(adamantane-1-carboxamido)-8-nonsubstituted/substituted-3-oxo-1-thia-4-azas-piro[4.5]decane-2-yl]acetic acid (4b-g) derivatives were synthesized; their structures were verified by elemental analysis, infrared spectroscopy, 1 H nuclear magnetic resonance (NMR), 13 C NMR, and mass spectroscopy data; and their in vitro cytotoxicity activities were investigated against human hepatocellular carcinoma, human prostate adenocarcinoma, and human lung carcinoma cell lines (HepG2, PC-3, and A549, respectively), and a mouse fibroblast cell line (NIH/3T3). All compounds, except compound 4e, were found as cytotoxic, especially on A549 cells as compared with the other cells (selectivity index = 2.01-11.6). As a further step, the effects of compounds 4a-c on apoptosis induction were tested and the expression of selected apoptosis genes was analyzed. Among the selected compounds, compound 4a induced apoptosis remarkably. Moreover, computational calculations of the binding of compounds 4a-c to the BIR3 domain of the human inhibitor of apoptosis protein revealed ligand-protein interactions at the atomistic level and emphasized the importance of a hydrophobic moiety on the ligands for better binding., (© 2021 Deutsche Pharmazeutische Gesellschaft.)

Background: Despite introduction of modern antiepileptic drugs, 30% of epileptic patients are still drug resistant. Remarkable three-dimensional spatial structure of 1-Adamantane carboxylic acid (AdCA), yet the simplicity of the molecule, makes AdCA a promising lead compound., Methods: Sedative/motor impairment and 24-h mortality rate of AdCA were determined in mice. Impact of AdCA on (1) threshold and occurrence of clonic seizures induced by pentylenetetrazole (PTZ) in mice, (2) incidence of tonic seizures induced by maximal electroshock (MES) in mice, and (3) incidence of generalized seizures and duration of evoked afterdischarges in amygdala-kindled rats, were determined. The role of benzodiazepine receptors in the AdCA effect on clonic seizure threshold was also assessed., Results: AdCA showed sedative effect (median toxic dose [TD50] = 224.5 [190.2-289.9] mg/kg). Median lethal dose (LD50) = 805.5 (715.2–988.1) mg/kg was obtained for AdCA. The compound increased PTZ seizure threshold from 180 mg/kg (p < 0.05) and also inhibited the incidence of clonic seizures (ED50 = 256.3 [107.4-417.3] mg/kg). AdCA also decreased afterdischarge duration (p < 0.01) and the incidence of generalized seizures (ED50 < 50 mg/kg) in the kindled rats. However, AdCA did not protect mice against tonic seizures induced by MES. The benzodiazepine receptor antagonist flumazenil prevented the increase of seizure threshold by AdCA., Conclusion: AdCA possesses anticonvulsant activity in kindling and PTZ models through the activation of benzodiazepine/GABAA receptors with acceptable therapeutic index.

A new series of 1,3,4-thiadiazolo-adamantane derivatives were synthesized through molecular hybridization approach, then used as starting material to synthesize chloro and cyano acetamide-thiadiazole derivatives 2, 3. The newly designed compounds 1-3 were treated with different reagents to design 5-adamantyl thiadiazole derivatives 4-17 and evaluate their in vitro anti-proliferative activity against three cancer cell lines (MCF-7, HepG-2 and A549). Doxorubicin was used as a positive control. The most promising compounds 5, 6, 10a, 10b, 14b, 14c, and 17 showed up-regulation for BAX and down-regulation of Bcl-2, these findings proved their role as hopeful apoptotic inducers. In addition, the inhibitory activity against both wild EGFR WT and mutant EGFR L858R-TK for these derivatives revealed that compounds 5, 14c, and 17 have IC 50 value ranging from 85 nM to 71.5 nM against wild EGFR WT and 37.85-41.19 nM against the mutant type, Lapatinib was used as a reference standard with IC 50 values of 31.8 nM and 39.53 nM, respectively. The most potent derivatives were subjected to further evaluation against double mutant EGFR L858R/T790M and showed good IC 50 values between (0.27-0.78 nM) compared to Lapatinib (0.18 nM) and Erlotinib (0.21 nM). Among them, thiazolo-thiadiazole adamantane derivative 17 exhibited the strongest inhibitory activity to the EGFR. Molecular docking studies were performed inside the active site of EGFR (1M17), and binding energy scores ranged between (-19.19 to -22.07 Kcal/mol) compared to Erlotinib (-19.10 Kcal/mol). Furthermore, oral bioavailability beside some pharmacokinetics properties of these derivatives were also investigated in this research work., (Copyright © 2021. Published by Elsevier Inc.)

Understanding the host-guest chemistry of α-/β-/γ- cyclodextrins (CDs) and a wide range of organic species are fundamentally attractive, and are finding broad contemporary applications toward developing efficient drug delivery systems. With the widely used β-CD as the host, we herein demonstrate that its inclusion behaviors toward an array of six simple and bio-conjugatable adamantane derivatives, namely, 1-adamantanol (adm-1-OH), 2-adamantanol (adm-2-OH), adamantan-1-amine (adm-1-NH 2 ), 1-adamantanecarboxylic acid (adm-1-COOH), 1,3-adamantanedicarboxylic acid (adm-1,3-diCOOH), and 2-[3-(carboxymethyl)-1-adamantyl]acetic acid (adm-1,3-diCH 2 COOH), offer inclusion adducts with diverse adamantane-to-CD ratios and spatial guest locations. In all six cases, β-CD crystallizes as a pair supported by face-to-face hydrogen bonding between hydroxyl groups on C2 and C3 and their adjacent equivalents, giving rise to a truncated-cone-shaped cavity to accommodate one, two, or three adamantane derivatives. These inclusion complexes can be terminated as (adm-1-OH) 2 ⊂CD 2 ( 1 , 2:2), (adm-2-OH) 3 ⊂CD 2 ( 2 , 3:2), (adm-1-NH 2 ) 3 ⊂CD 2 ( 3 , 3:2), (adm-1-COOH) 2 ⊂CD 2 ( 4 , 2:2), (adm-1,3-diCOOH)⊂CD 2 ( 5 , 1:2), and (adm-1,3-diCH 2 COOH)⊂CD 2 ( 6 , 1:2). This work may shed light on the design of nanomedicine with hierarchical structures, mediated by delicate cyclodextrin-based hosts and adamantane-appended drugs as the guests.