A classification of idiopathic epiretinal membrane based on foveal avascular zone area using optical coherence tomography angiography.

OBJECTIVE: To evaluate the characteristics and prognoses of idiopathic macular epiretinal membrane (iERM) using a classification based on the foveal avascular zone (FAZ) area. METHOD: IERMs were classified into four stages based on the FAZ area. Baseline FAZ-related parameters, pre-and postoperative central macular thickness (CMT), and best corrected visual acuity (BCVA) were observed and compared between different stages. The correlations of structural parameters with pre-and postoperative logMAR BCVA were analyzed. RESULTS: 162 iERM eyes were enrolled, including 105 eyes followed up for 12 months after surgery. The preoperative BCVA was better at the early stage. Postoperative BCVA at Stages 2 and 3 were better compared to Stage 4. The early stage was associated with thinner CMT pre-and postoperatively. However, there was no significant difference in CMT between postoperative Stages 1 and 2 or Stages 3 and 4. Preoperative logMAR BCVA was negatively correlated with FAZ area, perimeter, and FD-300 and was positively correlated with CMT and acircularity index (AI). CMT correlated positively with BCVA for each stage, except Stage 4; FAZ area, perimeter, and FD-300 had a negative correlation at Stage 1. Baseline BCVA and CMT positively correlated with BCVA at the last follow-up, while FAZ area and FD-300 were negatively correlated. Baseline BCVA had a positive correlation for each stage, except Stage 1; FD-300 had a negative correlation at Stages 2 and 3; CMT had a positive correlation at Stage 3. CONCLUSION: A classification based on the FAZ area was established innovatively. This classification can reflect the progression of iERM and is helpful to the postoperative prognosis.

(1) Classification based on FAZ area facilitate automation and consistency compared to the previous OCT-based qualitative grading.(2) With baseline FAZ stage advanced, thickened CMT and worsened BCVA was observed at baseline and 1-year post-operation. (3) Baseline FAZ area and FD-300 negatively correlated with logMAR BCVA at the last follow-up, reflecting the nonnegligible prognostic impact of macular vascular changes.

Characteristics of the Peripapillary Structure and Vasculature in Patients With Myopic Anisometropia.

Purpose: To evaluate the interocular differences of the peripapillary structural and vascular parameters and that of association with axial length (AL) in participants with myopic anisometropia using swept-source optical coherence tomography. Methods: This prospective cross-sectional study included 90 eyes of 45 participants. Each participant's eyes were divided into the more and less myopic eye respectively according to spherical equivalent. The ß- and γ-parapapillary atrophy (PPA) areas, Bruch's membrane opening distance, border length, and border tissue angle were measured manually. Peripapillary choroidal vascularity index and choroidal thickness (CT) values in superior, nasal, inferior, and temporal were calculated using a custom-built algorithm based on MATLAB. Results: The interocular difference in AL and spherical equivalent was 0.62 ± 0.26 mm and -1.50 (-2.13, -1.25) diopters (D), respectively. The interocular difference in spherical equivalent was highly correlated with that of the AL. The ß- and γ-PPA areas were significantly greater in more myopic eyes. The mean and inferior peripapillary choroidal vascularity index and all regions of peripapillary CT were significantly lower in the more myopic eyes. The interocular difference in AL was significantly positively correlated with the interocular differences in γ-PPA area and border length and negatively correlated with the interocular differences in temporal choroidal vascularity index and mean, inferior, and temporal peripapillary CT. There was an independent correlation between the interocular differences in AL and the interocular differences in γ-PPA area, inferior, and temporal peripapillary CT. Conclusions: Significant differences between both groups were detected in most peripapillary parameters, especially in peripapillary CT. The γ-PPA area, border length, and peripapillary CT were significantly correlated with the elongation of AL. Translational Relevance: The current study characterized and analyzed the peripapillary parameters in myopic anisometropia, which helped to monitor myopic progression.

Accelerated Capacity and Cycling Performance via Facile Instantaneous Precipitation Induced Amorphization for Lithium-Ion Batteries.

Conversion-alloying anodes have garnered escalating attention with high theoretical capacity, however, they are seriously hindered by large volume distortion and capacity fading. To counter, structural modification needs more exploration. Herein, advantageous structure and high-performance are realized in new amorphous PbSb2 O6 (PSO-a) nanosphere via facile instantaneous precipitation induced amorphization; conversion-alloying mechanism endows it with prominent lithium-storage capability; nanostructure can shorten ion-transfer distance and accommodate volume change outside the bulk of PSO-a; and loosely-stacked isotropic amorphous structure can enhance kinetics both at electrode/electrolyte interfaces and in the bulk. Volume change is synergistically stabilized from within to outside the bulk, leading to accelerated capacity and cycling. As expected, when employed in half-cells with 1 m LiPF6 in ethylene carbonate/diethyl carbonate/dimethyl carbonate/fluoroethylene carbonate (3:3:3:1 by mass) as electrolyte, glass microfiber filter as separator, and pure lithium foil as counter electrode, it realizes eminent performance with high specific capacity of 1512.6 mA h g-1 at 0.1 A g-1 and 755.1 mA h g-1 after 1000 cycles at 3 A g-1 . To the best of the authors' knowledge, this is the first time PbSb2 O6 is utilized as high-performance anode for lithium-ion batteries. Furthermore, this facile strategy provides a promising direction for high-performance amorphous anode material.

Analysis of Cytokine Levels Based on Optical Coherence Tomography Findings in Acute and Chronic Central Serous Chorioretinopathy.

Purpose: To investigate the characteristics of optical coherence tomography (OCT) and aqueous humor cytokine differences between acute and chronic central serous chorioretinopathy (CSC) and to evaluate the relevance of these findings.Methods: This was a cross-sectional, observational study. Patients with CSC were divided into acute and chronic groups based on the symptom duration and were compared with normal controls. Best-corrected visual acuity (BCVA), central macular thickness (CMT), subfoveal choroidal thickness (CT), hyperreflective foci (HF), and cytokines including vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, IL-10, interferon-inducible protein-10 (IP-10), and monocyte chemoattractant protein-1 (MCP-1) were used as comparison metrics.Results: A total of 62 patients (62 eyes) with CSC (22 with acute CSC and 40 with chronic CSC) and 35 patients as controls were included in this study. The chronic CSC group had significantly older average ages and worse BCVA than the acute CSC group (both p < 0.05). Both CSC groups showed significant increases in CMT and CT (both p < 0.05). In chronic CSC, the CMT was thinner, with more HF in the neuroretina (p = 0.034). VEGF levels were significantly higher in patients with chronic CSC than in those with acute CSC and controls (p < 0.05). The levels of inflammatory cytokines showed no significant difference between the CSC and control groups. Spearman's correlation analysis showed that the number of HF was positively correlated with disease duration (r = 0.311, p = 0.014), logMAR BCVA (r = 0.487, P < 0.001) and MCP-1 levels (r = 0.256, p = 0.045).Conclusions: Chronicity of CSC could lead to upregulation of VEGF. HF was associated with a more severe visual impairment in CSC patients and had relations with the levels of MCP-1.

The Characteristic of Optical Coherence Tomography Angiography and Retinal Arteries Angle in Familial Exudative Vitreoretinopathy with Inner Retinal Layer Persistence.

PURPOSE: To compare the angle of retinal arteries and macular vessel density and foveal avascular zone (FAZ) in early stage familial exudative vitreoretinopathy (FEVR) patients with inner retinal layer (IRL) persistence with FEVR patients without IRL persistence and normal people. METHODS: This study enrolled 113 early stage FEVR patients and 55 age-matched normal subjects. FEVR patients were divided into IRL group and non-IRL group based on the presence or absence of IRL in fovea. The angle of superior temporal and inferior temporal branch retinal arteries on ultra-wide-field fundus images were measured. Superficial and deep vessel density of whole image, fovea and parafovea, the area and perimeter of FAZ, A-circularity index (AI, perimeter/standard circle perimeter with equal area) and vessel density around the 300-µm width of the FAZ (FD), central macular thickness (CMT) on 3 mm × 3mm OCTA were measured. RESULTS: 30 FEVR patients in IRL group, 83 FEVR patients in non-IRL group, 55 normal people in control group were evaluated. BCVA were worst in IRL group (p < .001). The angle of retinal arteries was smaller in FEVR groups (p < .001) and were smallest in IRL group (p < .001). Superficial and deep vessel density of whole and parafovea area in FEVR patients were significantly lower than that in normal people (p < .05), AI were biggest (p = .01) and FD were smallest in IRL group (p < .001). CMT in IRL group were thicker than non-IRL group and control group (p < .05). CONCLUSION: Worse BCVA, smaller angle of retinal arteries (more vessels traction), lower macular vessel density, smaller and more irregular FAZ and thicker CMT were observed in FEVR patients with IRL persistence even in early stage.

Formation of the Fungal Indole Alkaloid Speradine F Implies Multiple Nonenzymatic Oxidation Steps.

The highly oxygenated indole alkaloid speradine F (4) with a 6/5/6/5/5/5 hexacyclic skeleton was isolated from a culture of Penicillium palitans, together with its precursors ß-cyclopiazonic acid (ß-CPA, 5) and cyclopiazonic acid (CPA, 1). Gene deletion and heterologous expression led to the identification of the responsible five-gene spe cluster for the speradine skeleton formation. Precursor supply experiments proved that 1 was enzymatically converted, via 2-oxoCPA (2), to speradine A (3), which subsequently undergoes multistep nonenzymatic hydroxylations to 4.

Total and horizontal distances of the foveal stereotaxic displacement can be prognostic indicators for patients with idiopathic epiretinal membrane.

Introduction: This study aimed to examine the foveal stereo deviations in the different ectopic inner foveal layer (EIFL) stages of idiopathic epiretinal membrane (iERM) and assess its predictive utility for the baseline and postoperative best-corrected visual acuity (BCVA). Methods: Based on the calculational combination of foveal displacements in the horizontal and vertical axial optical coherence tomography (OCT) images, the foveal stereotaxic displacement was estimated through the total distance (TD, the distance from the foveal bottom to the inner edge of displaced central foveal) and horizontal distance (HD, projection of the TD in the retinal plane). The preoperative TD, HD, and other OCT- and OCT angiography (OCTA)-related indicators were obtained. The correlations between structural parameters and baseline and postoperative BCVA were evaluated through correlation and multiple linear regression analyses. Results: In patients with advanced EIFL stage, there was a significant increase in the HD, TD, baseline log of the minimum angle of resolution unit for BCVA, central macular thickness (CMT), acircularity index, and incidence of microcystic macular edema (MME; p < 0.05). Further, they showed a decreased foveal avascular zone (FAZ) area and perimeter (p < 0.001). HD, TD, CMT, MME, FAZ area, and FAZ perimeter were significantly correlated with the baseline and postoperative BCVA (p < 0.05). TD had the highest correlation indexic and was an individual predictor of the baseline and postoperative BCVA. Moreover, FD-300 and MME were individual predictors of postoperative BCVA. Discussion: Stereoscopic foveal deviations significantly correlated with the baseline and postoperative visual acuity. TD may be used as an independent prognostic factor for BCVA.

The effect comparison of ILM flap and traditional ILM peeling in iMH.

Purpose: To compare the changes in anatomical structure and visual function after idiopathic macular hole (iMH) treatment with internal limiting membrane (ILM) peeling and inverted ILM flap and determine the value of the inverted ILM flap for the treatment of iMH. Methods: Forty-nine patients with iMH (49 eyes) were included in this study and followed up for 1 year (12 months) after treatment with inverted ILM flap and ILM peeling respectively. The main foveal parameters assessed included the preoperative minimum diameter (MD), intraoperative residual fragments, and postoperative ELM reconstruction. Visual function was assessed using best-corrected visual acuity. Results: The hole closure rate was 100% for 49 patients; 15 patients were treated with the inverted ILM flap, and 34 patients underwent ILM peeling. There were no differences between the postoperative best-corrected visual acuities and the rates of ELM reconstruction for the flap and peeling groups with different MDs. In the flap group, ELM reconstruction was associated with the preoperative MD, presence of an ILM flap, and hyperreflective changes in the inner retina 1 month after surgery. In the peeling group, ELM reconstruction was associated with the preoperative MD, intraoperative residual fragments at the hole edge, and hyperreflective changes in the inner retina. Conclusion: The inverted ILM flap and the ILM Peeling were both able to obtain high closure rate. However, the inverted ILM flap showed no obvious advantages related to anatomical morphology and visual function over ILM peeling.

Morphological characteristics of retinal vessels in eyes with high myopia: Ultra-wide field images analyzed by artificial intelligence using a transfer learning system.

Purpose: The purpose of this study is to investigate the retinal vascular morphological characteristics in high myopia patients of different severity. Methods: 317 eyes of high myopia patients and 104 eyes of healthy control subjects were included in this study. The severity of high myopia patients is classified into C0-C4 according to the Meta Analysis of the Pathologic Myopia (META-PM) classification and their vascular morphological characteristics in ultra-wide field imaging were analyzed using transfer learning methods and RU-net. Correlation with axial length (AL), best corrected visual acuity (BCVA) and age was analyzed. In addition, the vascular morphological characteristics of myopic choroidal neovascularization (mCNV) patients and their matched high myopia patients were compared. Results: The RU-net and transfer learning system of blood vessel segmentation had an accuracy of 98.24%, a sensitivity of 71.42%, a specificity of 99.37%, a precision of 73.68% and a F1 score of 72.29. Compared with healthy control group, high myopia group had smaller vessel angle (31.12 ± 2.27 vs. 32.33 ± 2.14), smaller fractal dimension (Df) (1.383 ± 0.060 vs. 1.424 ± 0.038), smaller vessel density (2.57 ± 0.96 vs. 3.92 ± 0.93) and fewer vascular branches (201.87 ± 75.92 vs. 271.31 ± 67.37), all P < 0.001. With the increase of myopia maculopathy severity, vessel angle, Df, vessel density and vascular branches significantly decreased (all P < 0.001). There were significant correlations of these characteristics with AL, BCVA and age. Patients with mCNV tended to have larger vessel density (P < 0.001) and more vascular branches (P = 0.045). Conclusion: The RU-net and transfer learning technology used in this study has an accuracy of 98.24%, thus has good performance in quantitative analysis of vascular morphological characteristics in Ultra-wide field images. Along with the increase of myopic maculopathy severity and the elongation of eyeball, vessel angle, Df, vessel density and vascular branches decreased. Myopic CNV patients have larger vessel density and more vascular branches.

Retinal microvasculature observations of fellow eyes after intra-arterial chemotherapy for unilateral retinoblastoma using optical coherence tomography angiography.

Purpose: To investigate the characteristics of the retinal microvasculature of the fellow eyes in patients with unilateral retinoblastoma (RB) after intra-arterial chemotherapy (IAC) through optical coherence tomography angiography. Methods: This retrospective study enrolled 11 fellow eyes of patients with unilateral RB receiving IAC (group I), nine fellow eyes of patients with unilateral RB receiving IAC and intravenous chemotherapy (IVC) (group II), and 14 age-matched normal eyes (control group). Optical coherence tomography angiography was performed on all individuals. Vascular density of superficial capillary plexus and deep capillary plexus (DCP), foveal avascular zone related parameters, and retinal thickness were measured and compared among the three groups. Results: There was no statistical difference in age and logMAR visual acuity among the three groups. Compared with the control group, the vascular density of the DCP was lower in group I and II. Decreased vascular density of FD-300 and thinner thickness of outer plexus layer to Bruch's membrane were detected in group II compared with the control group. The vascular density and retinal thickness showed no differences between group I and II. Conclusion: The decreased vascular density in the DCP without measurable visual impairment was observed in fellow eyes after IAC or IAC + IVC for unilateral RB. Further studies with a larger sample would be necessary to determine the clinical significance of these findings.

Biosynthesis of Viridicatol in Penicillium palitans Implies a Cytochrome P450-Mediated meta Hydroxylation at a Monoalkylated Benzene Ring.

Cyclopenol (1) and viridicatol (6) with m-hydroxyl groups were isolated from a culture of Penicillium palitans. Genome mining and heterologous expression in Aspergillus nidulans led to the identification of their biosynthetic gene cluster and the cytochrome P450 enzyme VdoD responsible for the meta hydroxylation. Precursor feeding experiments into vdoD transformant proved the conversion of cyclopenin (2) to 1, which then undergoes a spontaneous or VdoA-catalyzed rearrangement to 6. A direct conversion of viridicatin (5) to 6 by VdoD was not detected.

Natural Self-Confined Structure Effectively Suppressing Volume Expansion toward Advanced Lithium Storage.

Volume expansion hinders conversion-type transition-metal oxides (TMOs) as potential anode candidates for high-capacity lithium-ion batteries. While nanostructuring and nanosizing have been employed to improve the cycling stability of TMOs, we show here that both high initial Coulombic efficiency (ICE) and stable cycling reversibility are achieved in the layered compound Li0.9Nb0.9Mo1.1O6 (L0.9NMO) by inherent properties of the bulk crystal structure. In this model, MoO6 octahedra as active centers react with lithium ions and endow capacity, while a grid composed of NbO6 octahedra effectively suppresses the volume expansion, enhances the conductivity, and supports the structural skeleton from collapse. As a result, bulk L0.9NMO not only delivers a high discharge capacity of 1128 mA h g-1 at 100 mA g-1 with a considerable ICE of 87% but also exhibits long cycling stability and good rate performance (339 mA h g-1 after 500 cycles at 1 A g-1 with an average Coulombic efficiency approaching 100%). The self-confined structure provides a competitive strategy for stable conversion-type lithium storage.

Hierarchical microfibrillar gels from evaporation-induced anisotropic self-assembly of in situ-generated nanocrystals.

Whilst nanocrystal gels may be formed via destabilization of pre-functionalized nanocrystal dispersions, gelation via assembly of unfunctionalized nanocrystals into fibrillar networks remains a significant challenge. Here, we show that gels with hierarchical microfibrillar networks are formed from anisotropic self-assembly of in situ-generated mesolamellar nanocrystals upon evaporation of ZnO nanofluids. The obtained gels display the thermo-reversible behavior characteristic of a non-covalent physical gel. We elucidate a three-stage gelation mechanism. In the pre-nucleation stage, the cloudy ZnO nanofluid transforms into a transparent stable suspension, comprising multi-branched networks of aggregates self-assembled from in situ-generated layered zinc hydroxide (LZH) nanocrystals upon solvent evaporation. In the subsequent nucleation and anisotropic 1D fibre growth stage, further evaporation triggers nucleation and growth of 1D nanofibers through reorganization of the nanocrystal aggregates, before rapid nanofibre bundling leading to microfibrillar networks in the ultimate gelation stage. Our results provide mechanistic insights for hierarchical self-assembly of nanocrystals into fibrillar gels and open up facile fabrication routes using reactive transition metal-oxide nanofluids for new functional fibres and gels.

Long non-coding RNA slincRAD functions in methylation regulation during the early stage of mouse adipogenesis.

Adipocyte differentiation is a coordinated cellular process, which involves a series of dynamic molecular events. Up-regulation of long noncoding RNA slincRAD expression was found to occur in the early differentiation stages of 3T3-L1 cell, prior to the regulation of major transcription factors. By interacting with DNMT1 in S phase, slincRAD guides this essentially epigenetic factor to mediate promoter methylation of a batch of cell cycle-related genes, including cyclin-dependent kinase inhibitor p21. The regulation promotes the growth-arrested cells to re-enter into cell cycle under hormone induction and thereby advances the process of differentiation to clonal expansion stage. The abolishment of the interaction between slincRAD and DNMT1 by slincRAD knockdown results in a defective epigenetic regulation and finally compromised adipogenesis. Collectively, our study characterizes the epigenetic regulation of lncRNA involved in the early stage of adipogenesis.

Enhancements of Cancer Cell Damage Efficiencies in Photothermal and Photodynamic Processes through Cell Perforation and Preheating with Surface Plasmon Resonance of Gold Nanoring.

The methods of cell perforation and preheating are used for increasing cell uptake efficiencies of gold nanorings (NRIs), which have the localized surface plasmon resonance wavelength around 1064 nm, and photosensitizer, AlPcS, and hence enhancing the cell damage efficiency through the photothermal (PT) and photodynamic (PD) effects. The perforation and preheating effects are generated by illuminating a defocused 1064-nm femtosecond (fs) laser and a defocused 1064-nm continuous (cw) laser, respectively. Cell damage is produced by illuminating cell samples with a focused 1064-nm cw laser through the PT effect, a focused 1064-nm fs laser through both PT and PD effects, and a focused 660-nm cw laser through the PD effect. Under various conditions with and without cell wash before laser illumination, through either perforation or preheating process, cell uptake and hence cell damage efficiencies can be enhanced. Under our experimental conditions, perforation can be more effective at enhancing cell uptake and damage when compared with preheating.

New triterpenoids from Staphylea bumalda flower buds and their neuroprotective activity against H2O2-induced injury in vitro.

Four new acylated triterpene glycosides with aliphatic chains (4-7) as well as five known triterpenoids were isolated from the flower buds of Staphylea bumalda with bioassay guidance. Their structures were determined on the basis of spectral techniques, including IR, 1D and 2D NMR, and HR-APCI-MS. Most compounds (except 8) were isolated from S. bumalda for the first time. Additionally, the neuroprotective effects of 1 and 4-9 on suckling rat primary cultured hippocampal neurons against H2O2-induced injury were evaluated in vitro. The four new triterpenoids (4-7) showed neuroprotective effects, which increased the cell viability to over 74% at different concentrations, which was higher than the negative control (59%), while compounds 1 and 8-9 exhibited cytotoxic activity.

Terpenoids from the barks of Magnolia maudiae (Dunn) Figlar.

A new germacrenolide (1) and fourteen known terpenoids (2-15) were isolated from the barks of Magnolia maudiae (Dunn) Figlar (Magnoliaceae). The structure of (7αH,11ßH)-2α,8α-dihydroxy-4α,5ß-epoxy-germacr-1(10)-en-6α,12-olide (1) was elucidated by physical and spectroscopic data analysis, including 1D, 2D NMR and HR-ESI-MS. Lyratol F (9) was isolated from Magnolia for the first time. The structures of known compounds were established by comparing their spectroscopic data with those in literatures.

Layered perovskite LiEuTiO4 as a 0.8 V lithium intercalation electrode.

∼1 V lithium intercalation materials are promising anodes for lithium-ion batteries, because such materials give consideration to both the tolerance of lithium plating (e.g., graphite with ∼0.1 V versus Li+/Li easily results in lithium plating due to a too low potential) and the energy density of the batteries (e.g., Li4Ti5O12 with ∼1.55 V decreases the battery voltage, and thus reduces the energy density). Herein, the layered perovskite compound LiEuTiO4 with a 0.8 V lithium intercalation/deintercalation potential plateau was successfully synthesized by the ion-exchange reaction with NaEuTiO4 prepared via a sol-gel method. LiEuTiO4 can deliver a high capacity of 219.2 mA h g-1 (2nd discharge) at a rate of 100 mA g-1. Even after 500 cycles, the discharge capacity remains at ∼217 mA h g-1 and the Coulombic efficiency is 99.2%. To our knowledge, the cycle stability of LiEuTiO4 exceeds all previous ∼1 V electrodes. Different from the common lithium intercalation Ti-based electrodes (such as Li4Ti5O12) based on the reduction of the Ti4+ to Ti3+, electrochemical lithium intercalation into LiEuTiO4 leads to the reduction of the Eu3+ to Eu2+.

Development of 3-phenyl-N-(2-(3-phenylureido)ethyl)-thiophene-2-sulfonamide compounds as inhibitors of antiapoptotic Bcl-2 family proteins.

Antiapoptotic Bcl-2 family proteins, such as Bcl-xL , Bcl-2, and Mcl-1, are often overexpressed in tumor cells, which contributes to tumor cell resistance to chemotherapies and radiotherapies. Inhibitors of these proteins thus have potential applications in cancer treatment. We discovered, through structure-based virtual screening, a lead compound with micromolar binding affinity to Mcl-1 (inhibition constant (Ki )=3 µM). It contains a phenyltetrazole and a hydrazinecarbothioamide moiety, and it represents a structural scaffold not observed among known Bcl-2 inhibitors. This work presents the structural optimization of this lead compound. By following the scaffold-hopping strategy, we have designed and synthesized a total of 82 compounds in three sets. All of the compounds were evaluated in a fluorescence-polarization binding assay to measure their binding affinities to Bcl-xL , Bcl-2, and Mcl-1. Some of the compounds with a 3-phenylthiophene-2-sulfonamide core moiety showed sub-micromolar binding affinities to Mcl-1 (Ki =0.3-0.4 µM) or Bcl-2 (Ki ≈1 µM). They also showed obvious cytotoxicity on tumor cells (IC50 <10 µM). Two-dimensional heteronuclear single quantum coherence NMR spectra of three selected compounds, that is, YCW-E5, YCW-E10, and YCW-E11, indicated that they bind to the BH3-binding groove on Bcl-xL in a similar mode to ABT-737. Several apoptotic assays conducted on HL-60 cells demonstrated that these compounds are able to induce cell apoptosis through the mitochondrial pathway. We propose that the compounds with the 3-phenylthiophene-2-sulfonamide core moiety are worth further optimization as effective apoptosis inducers with an interesting selectivity towards Mcl-1 and Bcl-2.

De novo design, synthesis and evaluation of benzylpiperazine derivatives as highly selective binders of Mcl-1.

Considerable efforts have been made to the development of small-molecule inhibitors of antiapoptotic B-cell lymphoma 2 (Bcl-2) family proteins (such as Bcl-2, Bcl-xL , and Mcl-1) as a new class of anticancer therapies. Unlike general inhibitors of the entire family, selective inhibitors of each member protein can hopefully reduce the adverse side effects in chemotherapy treatments of cancers overexpressing different Bcl-2 family proteins. In this study, we designed four series of benzylpiperazine derivatives as plausible Bcl-2 inhibitors based on the outcomes of a computational algorithm. A total of 81 compounds were synthesized, and their binding affinities to Bcl-2, Bcl-xL , and Mcl-1 measured. Encouragingly, 22 compounds exhibited binding affinities in the micromolar range (Ki <20 µM) to at least one target protein. Moreover, some compounds were observed to be highly selective binders to Mcl-1 with no detectable binding to Bcl-2 or Bcl-xL , among which the most potent one has a Ki value of 0.18 µM for Mcl-1. Binding modes of four selected compounds to Mcl-1 and Bcl-xL were derived through molecular docking and molecular dynamics simulations. It seems that the binding affinity and selectivity of these compounds can be reasonably interpreted with these models. Our study demonstrated the possibility for obtaining selective Mcl-1 inhibitors with relatively simple chemical scaffolds. The active compounds identified by us could be used as lead compounds for developing even more potent selective Mcl-1 inhibitors with potential pharmaceutical applications.