MSN8C: A Promising Candidate for Antitumor Applications as a Novel Catalytic Inhibitor of Topoisomerase II.

MSN8C, an analog of mansonone E, has been identified as a novel catalytic inhibitor of human DNA topoisomerase II that induces tumor regression and differs from VP-16(etoposide). Treatment with MSN8C showed significant antiproliferative activity against eleven human tumor cell lines in vitro. It was particularly effective against the HL-60/MX2 cell line, which is resistant to Topo II poisons. The resistance factor (RF) of MSN8C for Topo II in HL-60/MX2 versus HL-60 was 1.7, much lower than that of traditional Topo II poisons. Furthermore, in light of its potent antitumor efficacy and low toxicity, as demonstrated in the A549 tumor xenograft model, MSN8C has been identified as a promising candidate for antitumor applications.

Discovery of Quinacrine as a Potent Topo II and Hsp90 Dual-Target Inhibitor, Repurposing for Cancer Therapy.

Topo II and Hsp90 are promising targets. In this study, we first verified the structural similarities between Topo IIα ATPase and Hsp90α N-ATPase. Subsequently, 720 compounds from the Food and Drug Administration (FDA) drug library and kinase library were screened using the malachite green phosphate combination with the Topo II-mediated DNA relaxation and MTT assays. Subsequently, the antimalarial drug quinacrine was found to be a potential dual-target inhibitor of Topo II and Hsp90. Mechanistic studies showed that quinacrine could specifically bind to the Topo IIα ATPase domain and inhibit the activity of Topo IIα ATPase without impacting DNA cleavage. Furthermore, our study revealed that quinacrine could bind Hsp90 N-ATPase and inhibit Hsp90 activity. Significantly, quinacrine has broad antiproliferation activity and remains sensitive to the multidrug-resistant cell line MCF-7/ADR and the atypical drug-resistant tumor cell line HL-60/MX2. Our study identified quinacrine as a potential dual-target inhibitor of Topo II and Hsp90, depending on the ATP-binding domain, positioning it as a hit compound for further structural modification.

An experimental and theoretical study on the growth of plate-like ß-HMX crystals in the hydroxylated interlayer space.

Plate-like ß-HMX crystals are grown in the hydroxylated interlayer space using a crystallization technique combining the cooling crystallization and solvent-antisolvent methods. The obtained crystals have been investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM), and atomic force microscopy (AFM). The experimental results indicate that the most morphologically important face of the plate-like ß-HMX crystals is the (011) face adopting a layer-by-layer growth mode. Meanwhile, molecular dynamics (MD) simulations were performed to study the crystal morphology in HMX crystal growth in the hydroxylated interlayer space based on a modified attachment energy (MAE) model. The calculated results show that the major face is the (011) face and the interaction energies between the crystal face and the hydroxylated interlayer are in the order of (011) > (110) > (020), which agree well with the experimental results above.

9-Bromo-2,3-diethylbenzo[de]chromene-7,8-dione (MSN54): A novel non-intercalative topoisomerase II catalytic inhibitor.

Novel mansonone F derivative MSN54 (9-bromo-2,3-diethylbenzo[de]chromene-7,8-dione) exhibited significant cytotoxicity against twelve human tumor cell lines in vitro, with particularly strong potency against HL-60/MX2 cell line resistant to Topo II poisons. MSN54 was found to have IC50 of 0.69 and 1.43 µM against HL-60 and HL-60/MX2 cells, respectively. The resistance index is 10 times lower than that of the positive control VP-16 (etoposide). Various biological assays confirmed that MSN54 acted as a Topo IIα specific non-intercalative catalytic inhibitor. Furthermore, MSN54 exhibited good antitumor efficacy and low toxicity at a dose of 5 mg/kg in A549 tumor xenograft models. Thus, compound MSN54 is a promising candidate for the development of novel antitumor agents.

New boron nitride monolith phases from high-pressure compression of double-walled boron nitride nanotubes.

Pressure-induced phase transition of boron nitride nanotubes (BNNTs) provides an effective approach to develop new boron nitride nanostructures with more desirable functions than those of carbon nanotubes, owing to the unique polar B-N bonds. However, the synthetic BNNTs usually comprise double- or multi-walls, whose structural evolution under pressure is complicated and remains largely elusive. Here, we unveil the complete phase transition behavior of hexagonal bundles of double-walled (DW) BNNTs of different chirality and diameters under hydrostatic pressures of up to 60 GPa. A series of new monolith phases are obtained from the compressed DW-BNNT bundles, whose structures can be well retained even after releasing the pressure. The bonding characters; electronic, optical, and mechanical properties; and Raman signature of these monolith phases are elucidated, which provide essential guidance for synthesis of new boron nitride materials with unprecedented properties for technological applications.

Organic Semiconducting Alloys with Tunable Energy Levels.

Continuous band structure tuning, e.g., doping with different atoms, is one of the most important features of inorganic semiconductors. However, this can hardly be realized in organic semicondutors. Here, we report the first example of fine-tuning organic semiconductor band structures by alloying structurally similar derivatives into one single phase. By incorporating halogen atoms on different positions of the backbone, BDOPV derivatives with complementary intramolecular or intermolecular charge distributions were obtained. To maximize the Coloumbic attractive interactions and minimize repulsive interactions, they form antiparallel cofacial stacking in monocomponent or in alloy single crystals, resulting in efficient π orbital overlap. Benefiting from self-assembly induced solid state "olefin metathesis" reaction, it was observed, for the first time, that three BDOPV derivatives cocrystallized in one single crystal. Molecules with different energy levels serve like the dopants in inorganic semiconductors. Consequently, as the total number of halogen atoms increased, highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) levels of the alloy single crystals decreased monotonously in the range from -5.94 to -6.96 eV and -4.19 to -4.48 eV, respectively.

An Interrupted Zeolite PKU-26 and Its Transformation to a Fully Four-Connected Zeolite PKU-27 upon Calcination.

The thermal stability and structural transformation mechanism are critical for the industrial applications of zeolites and the design of new framework types. Herein, a new zeolite PKU-26 has been hydrothermally synthesized under fluoride conditions using a tetraethylammonium (TEA+ ) cation as the structure-directing agent (SDA) and its framework contains partial Q3 T atoms [Q3 for T(-O-T)3 OH]. Upon calcination, PKU-26 processed a single-crystal to single-crystal transformation to another novel zeolite PKU-27 with the elimination of terminal -OH groups and enhanced thermal stability up to 650 °C, exhibiting the first Q3 →Q4 transformation [Q4 for T(-O-T)4 ] in 3D zeolite frameworks. The mechanism of the structural transformation, involving proton transfer, framework dehydration, and TO4 reconstruction, is proposed and supported by theoretical calculations.

Design, synthesis and biological evaluation of novel perimidine o-quinone derivatives as non-intercalative topoisomerase II catalytic inhibitors.

For the development of novel anticancer agents, we designed and synthesized a total of 37 perimidine o-quinone derivatives containing the o-quinone group at the A or B ring and different substituents (alkyl groups, aryl groups or heterocycles) at the C ring of the compounds. The structure-activity relationships (SARs) were established based on the cytotoxicity data of compounds from the HL-60, Huh7, Hct116, and Hela cell lines. The cytotoxicity results showed that most compounds exhibited potent cytotoxicity. In particular, compound b-12 showed the best anti-proliferative activity (IC50 ≤ 1 µM) against four cancer cell lines and strong potency against the HL-60/MX2 (0.47 µM) cell line, which is resistant to Topo II poisons. Further studies showed that b-12 exhibited potent Topo IIα inhibitory activity (IC50 = 7.54 µM) compared with Topo I, which acted as a class of non-intercalative Topo IIα catalytic inhibitor by inhibiting the ATP binding site of Topo II. Cell apoptosis and cell cycle assays confirmed that b-12 could induce the apoptosis of Huh7 cells in a dose-dependent manner.

Synthesis and evaluation of 1,2,3,4-tetrahydro-1-acridone analogues as potential dual inhibitors for amyloid-beta and tau aggregation.

Amyloid-ß (Aß) and tau protein are two crucial hallmarks in Alzheimer's disease (AD). Their aggregation forms are thought to be toxic to the neurons in the brain. A series of new 1,2,3,4-tetrahydro-1-acridone analogues were designed, synthesized, and evaluated as potential dual inhibitors for Aß and tau aggregation. In vitro studies showed that compounds 25-30 (20 µM) with N-methylation of the quinolone ring effectively inhibited Aß1-42 aggregation by 84.7%-99.5% and tau aggregation by 71.2%-101.8%. Their structure-activity relationships are discussed. In particular, 30 could permeate the blood-brain barrier, bind to Aß1-42 and tau, inhibit Aß1-42 ß-sheets formation, and prevent tau aggregation in living cells.

Stabilization of the Pentazolate Anion in a Zeolitic Architecture with Na20 N60 and Na24 N60 Nanocages.

The experimental detection and synthesis of pentazole (HN5 ) and its anion (cyclo-N5- ) have been actively pursued for the past hundred years. The synthesis of an aesthetic three-dimensional metal-pentazolate framework (denoted as MPF-1) is presented. It consists of sodium ions and cyclo-N5- anions in which the isolated cyclo-N5- anions are preternaturally stabilized in this inorganic open framework featuring two types of nanocages (Na20 N60 and Na24 N60 ) through strong metal coordination bonds. The compound MPF-1 is indefinitely stable at room temperature and exhibits high thermal stability relative to the reported cyclo-N5- salts. This finding offers a new approach to create metal-pentazolate frameworks (MPFs) and enables the future exploration of interesting pentazole chemistry and also related functional materials.

Synthesis and characterization of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for treatment of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative brain disorder that is characterized by dementia, cognitive impairment, and memory loss. Diverse factors are related to the development of AD, such as increased level of ß-amyloid (Aß), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress. METHODS: The following methods were used: organic syntheses of 1H-phenanthro[9,10-d]imidazole derivatives, inhibition of self-mediated and metal-induced Aß1-42 aggregation, inhibition studies for acetylcholinesterase and butyrylcholinesterase, anti-oxidation activity studies, CD, MTT assay, transmission electron microscopy, dot plot assay, gel electrophoresis, Western blot, and molecular docking studies. RESULTS: We synthesized and characterized a new type of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for AD treatment. Our results showed that most of these derivatives exhibited strong Aß aggregation inhibitory activity. Compound 9g had 74% Aß1-42 aggregation inhibitory effect at 10µM concentration with its IC50 value of 6.5µM for self-induced Aß1-42 aggregation. This compound also showed good inhibition of metal-mediated (Cu(2+) and Fe(2+)) and acetylcholinesterase-induced Aß1-42 aggregation, as indicated by using thioflavin T assay, transmission electron microscopy, gel electrophoresis, and Western blot. Besides, compound 9g exhibited cholinesterase inhibitory activity, with its IC50 values of 0.86µM and 0.51µM for acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound 9g showed good anti-oxidation effect with oxygen radical absorbance capacity (ORAC) value of 2.29. CONCLUSIONS: Compound 9g was found to be a potent multi-target-directed agent for Alzheimer's disease. GENERAL SIGNIFICANCE: Compound 9g could become a lead compound for further development as a multi-target-directed agent for AD treatment.

Cerebral angiography, blood flow and vascular reactivity in progressive hypertension.

Chronic hypertension alters cerebral vascular morphology, cerebral blood flow (CBF), cerebrovascular reactivity, and increses susceptibility to neurological disorders. This study evaluated: i) the lumen diameters of major cerebral and downstream arteries using magnetic resonance angiography, ii) basal CBF, and iii) cerebrovascular reactivity to hypercapnia of multiple brain regions using arterial-spin-labeling technique in spontaneously hypertensive rats (SHR) at different stages. Comparisons were made with age-matched normotensive Wistar Kyoto (WKY) rats. In 10-week SHR, lumen diameter started to reduce, basal CBF, and hypercapnic CBF response were higher from elevated arterial blood pressure, but there was no evidence of stenosis, compared to age-matched WKY. In 20-week SHR, lumen diameter remained reduced, CBF returned toward normal from vasoconstriction, hypercapnic CBF response reversed and became smaller, but without apparent stenosis. In 40-week SHR, lumen diameter remained reduced and basal CBF further decreased, resulting in larger differences compared to WKY. There was significant stenosis in main supplying cerebral vessels. Hypercapnic CBF response further decreased, with some animals showing negative hypercapnic CBF responses in some brain regions, indicative of compromised cerebrovascular reserve. The territory with negative hypercapnia CBF responses corresponded with the severity of stenosis in arteries that supplied those territories. We also found enlargement of downstream vessels and formation of collateral vessels as compensatory responses to stenosis of upstream vessels. The middle cerebral and azygos arteries were amongst the most susceptible to hypertension-induced changes. Multimodal MRI provides clinically relevant data that might be useful to characterize disease pathogenesis, stage disease progression, and monitor treatment effects in hypertension.

Functional MRI during hyperbaric oxygen: Effects of oxygen on neurovascular coupling and BOLD fMRI signals.

Hyperbaric oxygen (HBO) therapy is used to treat a number of ailments. Improved understanding of how HBO affects neuronal activity, cerebral blood flow (CBF) and blood-oxygenation-level dependent (BOLD) changes could shed light on the role of oxygen in neurovascular coupling and help guide HBO treatments. The goal of this study was to test two hypotheses: i) activation-induced CBF fMRI response is not dependent on hemoglobin deoxygenation, and ii) activation-induced BOLD fMRI is markedly attenuated under HBO. CBF and BOLD fMRI of forepaw stimulation in anesthetized rats under HBO at 3 atmospheres absolute (ATA) were compared with normobaric air. Robust BOLD and CBF fMRI were detected under HBO. Inflow effects and spin-density changes did not contribute significantly to the BOLD fMRI signal under HBO. Analysis of the T2(⁎)-weighted signal at normobaric air and 1, 2 and 3ATA oxygen in the tissue and the superior sagittal sinus showed a strong dependence on increasing inhaled [O2]. Spontaneous electrophysiological activity and evoked local-field potentials were reduced under HBO. The differences between normobaric air and HBO in basal and evoked electrical activity could not fully account for the strong BOLD responses under HBO. We concluded that activation-induced CBF regulation in the brain does not operate through an oxygen-sensing mechanism and that stimulus-evoked BOLD responses and the venous T2(⁎)-weighted signals still have room to increase under 3ATA HBO. To our knowledge, this is the first fMRI study under HBO, providing insights into the effects of HBO on neural activity, neurovascular coupling, tissue oxygenation, and the BOLD signal.

Discovery of natural alkaloid bouchardatine as a novel inhibitor of adipogenesis/lipogenesis in 3T3-L1 adipocytes.

Bouchardatine (1), a naturally occurring ß-indoloquinazoline alkaloid, was synthesized. For the first time, the lipid-lowering effect and mechanism of 1 was investigated in 3T3-L1 adipocytes. Our study showed that 1 could significantly reduce lipid accumulation without cytotoxicity and mainly inhibited early differentiation of adipocyte through proliferation inhibition and cell cycle arrested in dose-dependent manner. Furthermore, the inhibition of early differentiation was reflected by down-regulation of key regulators of adipogenesis/lipogenesis, including CCAAT enhancer binding proteins (C/EBPß, C/EBPδ, C/EBPα), peroxisome proliferator-activated receptors γ (PPARγ) and sterol-regulatory element binding protein-1c (SREBP-1c), in both of mRNA and protein levels. Subsequently decreasing the protein levels of acetyl CoA carboxylase (ACC), fatty acid synthase (FAS), and stearyl coenzyme A desaturated enzyme 1 (SCD-1), the rate-limited metabolic enzymes of fatty acid synthesis, were also observed. Further studies revealed that 1 persistently activated adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) during differentiation, suggesting that the AMPK may be an upstream mechanism for the effect of 1 on adipogenesis and lipogenesis. Our data suggest that 1 can be a candidate for the development of new therapeutic drugs against obesity and related metabolic disorders.

MRI under hyperbaric air and oxygen: effects on local magnetic field and relaxation times.

PURPOSE: Hyperbaric oxygen therapy has shown efficacies in the treatment of a number of diseases. The goal of this study was to develop a rodent hyperbaric chamber for MRI studies and to investigate the effects of hyperbaric air and hyperbaric oxygen on local magnetic field (B0 ) and MRI relaxation parameters in the rat brain. METHODS: A hyperbaric chamber, constructed to fit inside an animal MRI scanner, was pressurized with air to four atmospheres, while oxygen was delivered locally via nose cone. B0 , T2 , T2 *, and T1 maps in the rat brain were evaluated under normobaric air, hyperbaric air, and hyperbaric oxygen at 7T. RESULTS: Under hyperbaric oxygen, images exhibited artifacts and temporal instability, attributable to fluctuating oxygen concentration from air and oxygen mixing near the imaging region. Physically shielding the imaging region from fluctuating oxygen concentration resolved the problems. With increasing oxygen at hyperbaric pressure, B0 was shifted downfield with increased inhomogeneity near the ear canals and nose. Brain T2 and T2 * were lengthened, and T1 was shortened. CONCLUSION: This study establishes the means to perform MRI on rodents under hyperbaric conditions. Hyperbaric air and hyperbaric oxygen have significant effects on B0 and tissue relaxation parameters compared with normobaric air.

Comparison of retinal and cerebral blood flow between continuous arterial spin labeling MRI and fluorescent microsphere techniques.

PURPOSE: To compare basal retinal and cerebral blood flow (BF) values using continuous arterial spin labeling (CASL) MRI and fluorescent microspheres. MATERIALS AND METHODS: A total of 41 animals were used. BF was measured using an established microsphere technique (a mixture of 2.5 million 8 µm green and 0.5 million 10 µm blue fluorescent microspheres) and CASL MRI blood flow measurement in the rat retina and brain at 7 Tesla (T) and 11.7T, respectively. RESULTS: Retinal BF by MRI was 1.18 ± 0.57 mL/g/min and choroidal BF was 8.14 ± 1.8 mL/g/min (n = 6). Microsphere retinal BF was 9.12 ± 2.8 µL/min per tissue and choroidal BF was 73.38 ± 44 µL/min per tissue (n = 18), corresponding to a retinal BF value of 1.22 ± 0.36 mL/g/min by means of a wet weight conversion. The wet-weight of the choroid could not be determined. To corroborate our findings, cerebral BF (CBF) by MRI was also analyzed. In the cerebral cortices, CBF was 0.91 ± 0.29 mL/g/min (n = 14) by CASL MRI and 1.09 ± 0.37 mL/g/min (n = 6) by microspheres. There were no significant differences found between MRI and microsphere blood flow in the retina and brain. CONCLUSION: BF values in the rat retina and cerebral cortex by MRI are in agreement with those obtained by the microsphere technique.

Facilitating polymorphic crystallization of HMX through ultrasound and trace additive assistance.

Low sensitivity octahydro-1,3,4,7-tetranitro-1,3,5,7-tetrazocine (HMX) has garnered significant attention from researchers due to its reduced shock sensitivity. However, the crystallization process poses challenges due to the high solidity and viscosity of the metastable α phase. Despite efforts to address this with additional energy sources like ultrasonic irradiation, prolonged exposure duration often results in small particle sizes, hindering the production of HMX with a consistent particle size distribution, thus limiting its applicability. To overcome these challenges, a method combining ultrasonic irradiation and trace H+ additive was proposed and investigated for their impact on the polymorphic transformation of HMX. The H+ additive was found to modify barriers, thus there was a lack of competitive driving force for the nucleation or growth of the metastable α form, thereby shortening the transformation pathway and duration. Moreover, the H+ additive significantly accelerated the nucleation rate of the ß form (67.7 orders of magnitude faster with 0.10 wt ‰ H+) and the growth rate of ß form HMX (5.8 orders of magnitude faster with 0.10 wt ‰ H+). While H+ additive alone was insufficient to induce spontaneous nucleation of the ß form, combining it with short-duration ultrasonic irradiation further promoted ß nucleation and shortened the polymorphic transformation duration (almost 20 orders of magnitude shorter). This rational approach led to effective control of the transformation process. The resulting low sensitivity HMX crystals exhibited varying mean sizes ranging from 20 to 340 µm, with purity exceeding 99.6 %, an apparent density greater than 1.8994 g/cm3, and few internal defects, fully meeting the requirements of low-sensitivity HMX, thus significantly expanding its potential applications. Our study sheds light on the mechanisms governing HMX polymorphic transformation in the presence of additives and ultrasonic irradiation, offering guidance for the rational control of this complex transformation.

Development of Novel N-Acylhydrazone Derivatives with High Anti-obesity Activity and Improved Safety by Exploring the Pharmaceutical Properties of Aldehyde Group.

The discovery of effective and safe antiobesity agents remains a challenging yet promising field. Our previous studies identified Bouchardatine derivatives as potential antiobesity agents. However, the 8a-aldehyde moiety rendered them unsuitable for drug development. In this study, we designed two series of novel derivatives to modify this structural feature. Through a structure-activity relationship study, we elucidated the role of the 8a-aldehyde group in toxicity induction. We identified compound 14d, featuring an 8a-N-acylhydrazone moiety, which exhibited significant lipid-lowering activity and reduced toxicity. Compound 14d shares a similar lipid-lowering mechanism with our lead compound 3, but demonstrates improved pharmacokinetic properties and safety profile. Both oral and injectable administration of 14d significantly reduced body weight gain and ameliorated metabolic syndrome in diet-induced obese mice. Our findings identify 14d as a promising antiobesity agent and highlight the potential of substituting the aldehyde group with an N-acylhydrazone to enhance drug-like properties.

Methylene blue potentiates stimulus-evoked fMRI responses and cerebral oxygen consumption during normoxia and hypoxia.

Methylene blue USP (MB) at low doses has metabolic-enhancing and antioxidant properties and exhibits experimental neurotherapeutic benefits, but little is known about its in vivo effects on cerebral blood flow (CBF), functional evoked responses, and the associated changes in cerebral metabolic rate of oxygen (CMRO2). This study used magnetic resonance imaging (MRI) to evaluate the in vivo effects of a single intravenous MB therapeutic dose (0.5mg/kg) on basal CBF, blood oxygenation level-dependent (BOLD) and CBF responses to hypercapnic (5% CO2 in air) inhalation, as well as changes in BOLD, CBF, and CMRO2 during forepaw stimulation in the rat brain. MB did not have significant effects on arterial oxygen saturation, heart rate and fMRI responses to hypercapnia. However, MB significantly potentiated forepaw-evoked BOLD and CBF changes under normoxia. To further evaluate in vivo effects of MB under metabolic stress conditions, MRI measurements were also made under mild hypoxia (15% O2). Hypoxia per se increased evoked functional MRI responses. MB under hypoxia further potentiated forepaw-evoked BOLD, CBF and oxygen consumption responses relative to normoxia. These findings provide insights into MB's effects on cerebral hemodynamics in vivo and could help to optimize treatments in neurological diseases with mitochondrial dysfunction and oxidative stress.

Synthesis and biological evaluation of benzo[a]phenazine derivatives as a dual inhibitor of topoisomerase I and II.

Topoisomerases (Topo I and Topo II) are very important players in DNA replication, repair, and transcription, and are a promising class of antitumor target. In present study, a series of benzo[a]phenazine derivatives with alkylamino side chains at C-5 were designed, synthesized, and their biological activities were evaluated. Most of derivatives showed good antiproliferative activity with a range of IC50 values of 1-10 µM on the four cancer cell lines HeLa, A549, MCF-7, and HL-60. Topoisomerase-mediated DNA relaxation assay results showed that derivatives could effectively inhibit the activity of both Topo I and Topo II, and the structure-activity relationship studies indicated the importance of introducing an alkylamino side chain. Further mechanism studies revealed that the compounds could stabilize the Topo I-DNA cleavage complexes and inhibit the ATPase activity of hTopo II, indicating that they are a rare class of dual topoisomerase inhibitors by acting as Topo I poisons and Topo II catalytic inhibitors. Moreover, flow cytometric analysis and caspase-3/7 activation assay showed that this class of compounds could induce apoptosis of HL-60 cells.