Monascus pigment rubropunctatin derivative FZU-H reduces Aβ(1-42)-induced neurotoxicity in Neuro-2A cells

Alzheimer''s disease (AD) is an extremely complex disease, characterized by several pathological features including oxidative stress and amyloid-β (Aβ) aggregation. Blockage of Aβ-induced injury has emerged as a potential therapeutic approach for AD. Our previous efforts resulted in the discovery of Monascus pigment rubropunctatin derivative FZU-H with potential neuroprotective effects. This novel lead compound significantly diminishes toxicity induced by Aβ(1-42) in Neuro-2A cells. Our further mechanism investigation revealed that FZU-H inhibited Aβ(1-42)-induced caspase-3 protein activation and the loss of mitochondrial membrane potential. In addition, treatment of FZU-H was proven to attenuate Aβ(1-42)-induced cell redox imbalance and Tau hyperphosphorylation which caused by okadaic acid in Neuro-2A cells. These results indicated that FZU-H shows promising neuroprotective effects for AD.

Monascus pigment rubropunctatin derivative FZU-H shows promising neuroprotective effects for AD.     

N-Amino peptide scanning reveals inhibitors of Aβ42 aggregation

The aggregation of amyloids into toxic oligomers is believed to be a key pathogenic event in the onset of Alzheimer''s disease. Peptidomimetic modulators capable of destabilizing the propagation of an extended network of β-sheet fibrils represent a potential intervention strategy. Modifications to amyloid-beta (Aβ) peptides derived from the core domain have afforded inhibitors capable of both antagonizing aggregation and reducing amyloid toxicity. Previous work from our laboratory has shown that peptide backbone amination stabilizes β-sheet-like conformations and precludes β-strand aggregation. Here, we report the synthesis of N-aminated hexapeptides capable of inhibiting the fibrillization of full-length Aβ₄₂. A key feature of our design is N-amino substituents at alternating backbone amides within the aggregation-prone Aβ_16–21 sequence. This strategy allows for maintenance of an intact hydrogen-bonding backbone edge as well as side chain moieties important for favorable hydrophobic interactions. An N-amino scan of Aβ_16–21 resulted in the identification of peptidomimetics that block Aβ₄₂ fibrilization in several biophysical assays.

Structure-based design of backbone-aminated peptides affords novel β-strand mimics that inhibit amyloid-beta fibrillogenesis.     

Aryldiazoquinoline based multifunctional small molecules for modulating Aβ42 aggregation and cholinesterase activity related to Alzheimer's disease

Research continues to find a breakthrough for the treatment of Alzheimer''s Disease (AD) due to its complicated pathology. Presented herein is a novel series of arydiazoquinoline molecules investigated for their multifunctional properties against the factors contributing to Alzheimer''s disease (AD). The inhibitory properties of fourteen closely related aryldiazoquinoline derivatives have been evaluated for their inhibitory effect on Aβ₄₂ peptide aggregation. Most of these molecules inhibited Aβ₄₂ fibrillation by 50–80%. Selected molecules were also investigated for their binding behaviour to preformed Aβ₄₀ aggregates indicating a nanomolar affinity. In addition, these compounds were further investigated as cholinesterase inhibitors. Interestingly, some of the compounds turned out to be moderate in vitro inhibitors for AChE activity with IC₅₀ values in low micro molar range. The highest anti-AChE activity was shown by compound labelled as 2a with an IC₅₀ value of 6.2 μM followed by 2b with IC₅₀ value of 7.0 μM. In order to understand the inhibitory effect, binding of selected molecules to AChE enzyme was studied using molecular docking. In addition, cell toxicity studies using Neuro2a cells were performed to assess their effect on neuronal cell viability which suggests that these molecules possess a non-toxic molecular framework. Overall, the study identifies a family of molecules that show good in vitro anti-Aβ-aggregation properties and moderately inhibit cholinesterase activity.

Novel series of aryldiazoquinoline multifunctional molecules controls amyloid formation and neuro-protective role by inhibiting esterase enzymes.     

Development of novel N-(6-methanesulfonyl-benzothiazol-2-yl)-3-(4-substituted-piperazin-1-yl)-propionamides with cholinesterase inhibition,anti-β-amyloid aggregation,neuroprotection and cognition enhancing properties for the therapy of Alzheimer's disease

A novel series of benzothiazole–piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer''s disease (AD). The synthesized hybrid molecules illustrated modest to strong inhibition of acetylcholinesterase (AChE) and Aβ_1-42 aggregation. Compound 12 emerged as the most potent hybrid molecule exhibiting balanced functions with effective, uncompetitive and selective inhibition against AChE (IC₅₀ = 2.31 μM), good copper chelation, Aβ_1-42 aggregation inhibition (53.30%) and disaggregation activities. Confocal laser scanning microscopy and TEM analysis also validate the Aβ fibril inhibition ability of this compound. Furthermore, this compound has also shown low toxicity and is capable of impeding loss of cell viability elicited by H₂O₂ neurotoxicity in SHSY-5Y cells. Notably, compound 12 significantly improved cognition and spatial memory against scopolamine-induced memory deficit in a mouse model. Hence, our results corroborate the multifunctional nature of novel hybrid molecule 12 against AD and it may be a suitable lead for further development as an effective therapeutic agent for therapy in the future.

A novel series of benzothiazole–piperazine hybrids were rationally designed, synthesized, and evaluated as multifunctional ligands against Alzheimer''s disease (AD).     

Inhibition of metal-induced amyloid β-peptide aggregation by a blood–brain barrier permeable silica–cyclen nanochelator

Alzheimer''s disease (AD) is a neurodegenerative malady associated with amyloid β-peptide (Aβ) aggregation in the brain. Metal ions play important roles in Aβ aggregation and neurotoxicity. Metal chelators are potential therapeutic agents for AD because they could sequester metal ions from the Aβ aggregates and reverse the aggregation. The blood–brain barrier (BBB) is a major obstacle for drug delivery to AD patients. Herein, a nanoscale silica–cyclen composite combining cyclen as the metal chelator and silica nanoparticles as a carrier was reported. Silica–cyclen was characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR) and dynamic light scattering (DLS). The inhibitory effect of the silica–cyclen nanochelator on Zn²⁺- or Cu²⁺-induced Aβ aggregation was investigated by using a BCA protein assay and TEM. Similar to cyclen, silica–cyclen can effectively inhibit the Aβ aggregation and reduce the generation of reactive oxygen species induced by the Cu–Aβ₄₀ complex, thereby lessening the metal-induced Aβ toxicity against PC12 cells. In vivo studies indicate that the silica–cyclen nanochelator can cross the BBB, which may provide inspiration for the construction of novel Aβ inhibitors.

A BBB-passable nanoscale silica–cyclen chelator effectively reduces the metal-induced Aβ aggregates and related ROS, thereby decreasing the neurotoxicity of Aβ.     

Bleomycin modulates amyloid aggregation in β-amyloid and hIAPP

Aberrant misfolding and amyloid aggregation, which result in amyloid fibrils, are frequent and critical pathological incidents in various neurodegenerative disorders. Multiple drugs or inhibitors have been investigated to avert amyloid aggregation in individual peptides, exhibiting sequence-dependent inhibition mechanisms. Establishing or inventing inhibitors capable of preventing amyloid aggregation in a wide variety of amyloid peptides is quite a daunting task. Bleomycin (BLM), a complex glycopeptide, has been widely used as an antibiotic and antitumor drug due to its ability to inhibit DNA metabolism, and as an antineoplastic, especially for solid tumors. In this study, we investigated the dual inhibitory effects of BLM on Aβ aggregation, associated with Alzheimer''s disease and hIAPP, which is linked to type 2 diabetes, using both computational and experimental techniques. Combined results from drug repurposing and replica exchange molecular dynamics simulations demonstrate that BLM binds to the β-sheet region considered a hotspot for amyloid fibrils of Aβ and hIAPP. BLM was also found to be involved in β-sheet destabilization and, ultimately, in its reduction. Further, experimental validation through in vitro amyloid aggregation assays was obtained wherein the fibrillar load was decreased for the BLM-treated Aβ and hIAPP peptides in comparison to controls. For the first time, this study shows that BLM is a dual inhibitor of Aβ and hIAPP amyloid aggregation. In the future, the conformational optimization and processing of BLM may help develop various efficient sequence-dependent inhibitors against amyloid aggregation in various amyloid peptides.

Bleomycin acts as a dual inhibitor against both amyloid β and human islet amyloid polypeptide by binding to the β-sheet grooves considered as the amyloids hotspot.     

Preparation and photo-induced activities of water-soluble amyloid β-C60 complexes

We have shown that fullerene (C₆₀) becomes soluble in water by mixing fullerene and amyloid β peptide (Aβ40) whose fibril structures are considered to be associated with Alzheimer''s disease. The water-solubility of fullerene arises from the generation of a nanosized complex between fullerene and the monomer species of Aβ40 (Aβ40-C₆₀). The prepared Aβ40-C₆₀ exhibits photo-induced activity with visible light to induce the inhibition of Aβ40 fibrillation and the cytotoxicity for cultured HeLa cells. The observed photo-induced phenomena result from the generation of singlet oxygen via photoexcitation, inducing oxidative damage to Aβ40 and HeLa cells. The oxidized Aβ40 following photoexcitation of Aβ40-C₆₀ was confirmed by mass spectrometry.

We have shown that fullerene (C₆₀) becomes soluble in water by mixing fullerene and amyloid β peptide (Aβ40) whose fibril structures are considered to be associated with Alzheimer''s disease.     

Effect of C-terminus amidation of Aβ39–42 fragment derived peptides as potential inhibitors of Aβ aggregation

The C-terminus fragment (Val-Val-Ile-Ala) of amyloid-β is reported to inhibit the aggregation of the parent peptide. In an attempt to investigate the effect of sequential amino-acid scan and C-terminus amidation on the biological profile of the lead sequence, a series of tetrapeptides were synthesized using MW-SPPS. Peptide D-Phe-Val-Ile-Ala-NH₂ (12c) exhibited high protection against β-amyloid-mediated-neurotoxicity by inhibiting Aβ aggregation in the MTT cell viability and ThT-fluorescence assay. Circular dichroism studies illustrate the inability of Aβ₄₂ to form β-sheet in the presence of 12c, further confirmed by the absence of Aβ₄₂ fibrils in electron microscopy experiments. The peptide exhibits enhanced BBB permeation, no cytotoxicity along with prolonged proteolytic stability. In silico studies show that the peptide interacts with the key amino acids in Aβ, which potentiate its fibrillation, thereby arresting aggregation propensity. This structural class of designed scaffolds provides impetus towards the rational development of peptide-based-therapeutics for Alzheimer''s disease (AD).

Amidated C-terminal fragment, Aβ_39–42 derived non-cytotoxic β-sheet breaker peptides exhibit excellent potency, enhanced bioavailability and improved proteolytic stability.

First reported by Alois Alzheimer in 1906, Alzheimer''s Disease (AD) is a progressive, neurodegenerative disorder with an irreversible decline in memory and cognition.¹ It is commonly seen in elderly populations and is marked by two major histopathological hallmarks, amyloid-β (Aβ) plaques and neurofibrillary tangles (NFT).² The number of patients suffering from AD has been increasing at an alarming rate. It is estimated that around 60 million patients will be suffering from AD by the end of 2020 and half of this patient population would require the care equivalent to that of a nursing home.³ Even after a century of its discovery, there has been no treatment that targets the pathophysiology of AD.⁴ The current treatment regimen includes acetylcholine-esterase inhibitors (AChEI) comprising of donepezil, rivastigmine and galantamine as well as N-methyl-d-aspartate (NMDA)-receptor antagonist, memantine. These provide only symptomatic relief to the patient. Most of the therapeutics that are currently being tested in clinical trials couldn''t proceed beyond phase II and phase III clinical trials due to lower efficacy in elderly patients, multiple side effects and limitations in their pharmacokinetic and pharmacodynamic profiles.^5–9 This has created challenges on the societal and economic upfront.Literature analysis reveals that the soluble oligomeric Aβ species is the culprit for neurotoxicity. It interrupts normal physiological functioning of the human brain. The central hydrophobic fragment Aβ_16–22 (KLVFFAE) and the C-terminus region fragment Aβ_31–42 (IIGLMVGGVVIA) are responsible for controlling the aggregation kinetics of the monomeric species, wherein the later still remains relatively less explored.^8,9 Our group is focused on development of peptidomimetic analogues for preventing Aβ aggregation. Studies on a complete peptide scan on the C-terminus region regions has already been published previously.^10–12 In an attempt to enhance the biological efficacy of the previously designed scaffolds,¹² we rationalized the use of sequential amino acid scan by modifying/replacing individual residues, as well as amide protection of the C-terminus on the lead tetrapeptide sequence (Val-Val-Ile-Ala) to enhance the proteolytic stability of the peptides.C-terminus amidated peptides were synthesized by microwave-assisted Fmoc-solid phase peptide synthesis protocol. Scheme 1 shows the general route for the synthesis of peptides employing Rink amide resin (detailed methodology is mentioned in the ESI, Section 1^†). These peptides were characterized using by analytical HPLC, ¹H and ¹³C NMR, APCI/ESI-MS and HRMS.Open in a separate windowScheme 1Synthesis of tetrapeptide 12c using MW-assisted Fmoc-solid phase peptide synthesis protocol employing Rink amide resin. Reaction conditions: (i) 20% piperidine in DMF (7 mL), MW (40 W), 60 °C, 2 cycles – 1.5 & 3 min; (ii) 2, 4, 6, 8 (4 equiv.), TBTU (4 equiv.), HoBt (4 equiv.), DIPEA (5 equiv.), DMF (3.5 mL), MW (40 W), 60 °C, 13.5 min; (iii) TFA : TIPS : H₂O (95 : 2.5 : 2.5), rt, 2.5 h; reaction monitoring was done by: UV measurement: Fmoc deprotection-dibenzofulvene adduct, Kaiser test: 1° amines; acetaldehyde test: 2° amines.Aggregation of Aβ₄₂ results in accumulation of toxic species, which interact with neurons and hinder their functioning, leading to loss of memory and cognition. Inhibiting the process of Aβ₄₂ aggregation would alleviate the neurotoxicity imparted in PC-12 cells; this was evaluated by MTT cell viability assay.¹³ Viability of untreated cells is considered 100%. Upon treatment with 2 μM of Aβ₄₂, only 74% cells were found to be viable. Out of the total tested peptides, seven tetrapeptides 12a, 12c, 12f, 13e, 14b, 15b and 15f showed complete inhibition of Aβ₄₂-induced toxicity by restoring the cell viability to 100%, at respective concentrations. Results for cell viability assay along with Thioflavin-T fluorescence assay for all the synthesized tetrapeptides has been summarized in

Atomistic investigation of an Iowa Amyloid-β trimer in aqueous solution

The self-assembly of Amyloid beta (Aβ) peptides are widely accepted to associate with Alzheimer''s disease (AD) via several proposed mechanisms. Because Aβ oligomers exist in a complicated environment consisting of various forms of Aβ, including oligomers, protofibrils, and fibrils, their structure has not been well understood. The negatively charged residue D23 is one of the critical residues of the Aβ peptide as it is located in the central hydrophobic domain of the Aβ N-terminal and forms a salt-bridge D23-K28, which helps stabilize the loop domain. In the familial Iowa (D23N) mutant, the total net charge of Aβ oligomers decreases, resulting in the decrease of electrostatic repulsion between D23N Aβ monomers and thus the increase in their self-aggregation rate. In this work, the impact of the D23N mutation on 3Aβ_11–40 trimer was characterized utilizing temperature replica exchange molecular dynamics (REMD) simulations. Our simulation reveals that D23N mutation significantly enhances the affinity between the constituting chains in the trimer, increases the β-content (especially in the sequence 21–23), and shifts the β-strand hydrophobic core from crossing arrangement to parallel arrangement, which is consistent with the increase in self-aggregation rate. Molecular docking indicates that the Aβ fibril-binding ligands bind to the D23N and WT forms at different poses. These compounds prefer to bind to the N-terminal β-strand of the D23N mutant trimer, while they mostly bind to the N-terminal loop region of the WT. It is important to take into account the difference in the binding of ligands to mutant and wild type Aβ peptides in designing efficient inhibitors for various types of AD.

Amyloid beta peptide oligomers are believed to play key roles in Alzheimer''s disease pathogenesis. D23N mutation significantly changes their structure and how they bind potential inhibitors.     

Decarboxylative aldol reaction of α,α-difluoro-β-ketocarboxylate salt: a facile method for generation of difluoroenolate

We developed a decarboxylative aldol reaction using α,α-difluoro-β-ketocarboxylate salt, carbonyl compounds, and ZnCl₂/N,N,N′,N′-tetramethylethylenediamine. The generation of difluoroenolate proceeded smoothly under mild heating to provide α,α-difluoro-β-hydroxy ketones in good to excellent yield (up to 99%). The α,α-difluoro-β-ketocarboxylate salt was bench stable and easy to handle under air, which realizes a convenient and environmentally friendly methodology for synthesis of difluoromethylene compounds.

A ZnCl₂/N,N,N′,N′-tetramethylethylenediamine complex promoted decarboxylative aldol reaction of α,α-difluoro-β-ketocarboxylate salt with carbonyl compounds has been developed.     

Development of an MRI contrast agent for both detection and inhibition of the amyloid-β fibrillation process

A curcumin derivative conjugated with Gd-DO3A (Gd-DO3A-Comp.B) was synthesised as an MRI contrast agent for detecting the amyloid-β (Aβ) fibrillation process. Gd-DO3A-Comp.B inhibited Aβ aggregation significantly and detected the fibril growth at 20 μM of Aβ with 10 μM of probe concentration by T₁-weighted MR imaging.

A curcumin derivative conjugated with Gd-DO3A (Gd-DO3A-Comp.B) was developed to significantly inhibit the amyloid-β (Aβ) aggregation and detect the fibril growth by T₁-weighted MR imaging.

A significant increase of Alzheimer''s disease (AD) patients urges the development of therapeutic and diagnostic technology.¹ As with the therapeutic development, diagnostic technology also faces several obstacles. To date, the definite diagnosis of AD relies on the histopathological data of post-mortem.^2,3 The non-invasive imaging technology targeting AD biomarkers such as amyloid β (Aβ) could provide phenotypical diagnostics, although the development of Aβ probes still remains challenging. Several contrast agents for single photon emission computed tomography (SPECT) and positron emission tomography (PET) such as Florbetapir-¹⁸F and Pittsburgh compound-B ([¹¹C]PiB) were developed as efficient tracers in mild cognitive impairment patients.^4,5 However, PET- and SPECT-based diagnostics require injection of radioactive probes, which cannot be measured frequently due to radiation exposure and limited availability of facilities. They also provide limited information on the anatomic profile of biomarkers due to their low spatial resolution and imprecise microscopic localization.⁶ In contrast, magnetic resonance imaging (MRI) contrast agents could quantify the Aβ accumulation in the anatomic brain image.⁷Several reported MRI contrast agents using gadolinium (Gd) complexes demonstrate potential use of Aβ detection. A clinically approved contrast agent, Gd(iii) diethylenetriaminepentaacetic acid (Gd-DTPA) complex accumulates in brain after opening the blood–brain barrier (BBB) by using mannitol and detects Aβ deposits in the mice AD-model.⁸ To improve the selectivity, Gd complexes were conjugated with compounds binding to Aβ such as Pittsburgh compound B (Gd-DO3A-PiB) which also serves as an approach for increasing MRI sensitivity.^9,10 An α,β-unsaturated ketone compound curcumin has been widely reported as an Aβ probe due to its ability to bind the hydrophobic site of Aβ.^11,12 Allen et al. firstly reported the direct conjugation of curcumin with Gd-DTPA which binds to Aβ with four times higher relaxivity than free Gd-DTPA.¹³ Furthermore, a polymalic acid-based nanoparticle covalently linked with curcumin and Gd-DOTA could also detect Aβ in human brain specimen by MRI.¹⁴ These previous studies demonstrate that the curcumin structure has significant potential for the development of MRI contrast agents for AD diagnosis.Previously, we reported a curcumin derivative, compound B, possesses 100-times stronger inhibitory activity of Aβ aggregation than curcumin on the basis of thioflavin T (ThT) competitive binding assay.^15,16 According to this result, we designed curcumin-based Gd probes for the detection and inhibition of Aβ (Fig. 1A–C). We hypothesized that these probes could accelerate proton longitudinal relaxation depending on the fibrillation stage of Aβ, because molecular tumbling rate of the Gd complexes becomes slower (Fig. 1A).¹⁷ As a result, the probes permit the detection of Aβ by longitudinal relaxation time (T₁)-weighted imaging. This mechanism could also be utilized to estimate the inhibitory activity of the probes by T₁-based analysis (Fig. 1B). The curcumin and compound B were directly conjugated with the macrocyclic DO3A ligand through the propylamine linker to obtain Gd-DO3A-Cur and Gd-DO3A-Comp.B, respectively (Fig. 1C).Open in a separate windowFig. 1(A) A probe concept that produces T₁ in a dependent manner of Aβ fibrillation process. (B) Inhibitor-based probes that cause moderate T₁ decreases due to inhibitory activity of fibrillation. (C) The chemical structures of the synthesized Gd probes for Aβ detection and inhibition.Gd-DO3A-Cur and Gd-DO3A-Comp.B were synthesized according to Scheme 1 (detail in Scheme S1, ESI^†). The compound 5a and 5b, which have asymmetric curcumin derivatives containing carboxylic acid group, were synthesized by three step reactions. Amide bond formation with DO3A(tBu)₃-propylamine ligand¹⁸ by condensation reaction afforded compound 7a and 7b. The tert-butyl groups were deprotected by trifluoroacetic acid producing compound 8a and 8b. The complexation was performed with GdCl₃·6H₂O by adjusting the reaction pH to 7, giving 43 and 41% yields of Gd-DO3A-Cur and Gd-DO3A-Comp.B, respectively. The T₁ relaxivities (r₁) of the curcumin-based Gd probes were estimated by T₁ measurement using a 1 tesla NMR relaxometry (Fig. S1, ESI^†). For the comparison, we synthesized Gd-DO3A-Chal which is a reported probe for Aβ.¹⁹ The r₁ of Gd-DO3A-Comp.B, Gd-DO3A-Cur, and Gd-DO3A-Chal were 7.1, 6.1 and 5.3 mM⁻¹ s⁻¹, respectively. These r₁ values are higher than that of clinically approved Gd-DOTA (3.9 mM⁻¹ s⁻¹).²⁰ The molecular weight of Gd-DO3A-Comp.B and Gd-DO3A-Cur is almost two times larger than that of Gd-DOTA. Because the r₁ increases approximately linearly with molecular weight in low magnetic field,¹⁷ the high r₁ values of Gd-DO3A-Comp.B and Gd-DO3A-Cur might be mainly attributed to their high rotational correlation time, rather than the high number of coordinated water molecules. The r₁ of Gd-DO3A-Chal was comparable to the value reported previously.¹⁹Open in a separate windowScheme 1Synthetic scheme of Gd-DO3A-Cur and Gd-DO3A-Comp.B. (a) B(OH)₃, morpholine, DMF, 100 °C, 10 min. (b) 3a/3b, B(OH)₃, morpholine, DMF, 100 °C, 10 min. (c) TFA, DCM. (d) DO3A(tBu)₃-propylamine ligand, PyBOP, HOBt, Et₃N, DMF. (e) 7a/7b, TFA, DCM. (f) GdCl₃·6H₂O, NaOH, H₂O.We evaluated the inhibitory effect of three probes toward Aβ aggregation by Congo red assay.²¹ After 24 h incubation of 20 μM Aβ with 10 μM probe, Gd-DO3A-Comp.B showed the lowest fluorescence intensity, indicating the strongest inhibitory activity followed by Gd-DO3A-Cur (Fig. 2A). As the comparison, the reported MRI agents, Gd-DO3A-Chal showed slight inhibitory activity. The inhibitory effect was further evaluated by transmission electron microscopy (TEM) with negative staining (Fig. 2B). In the absence of the probes, Aβ formed huge and massive fibril similar to the typical morphology of Aβ fibril.²² The TEM images of Aβ with Gd-DO3A-Comp.B showed the presence of white spheres below 10 nm, demonstrating that Gd-DO3A-Comp.B strongly inhibits Aβ aggregation. In fact, the fibril growth stopped at a stage of oligomer formation. Lower inhibitory activity of Gd-DO3A-Cur was also found to provide a shortened worm-like fibril, which is the typical morphology of Aβ exposed to curcumin.²³ In contrast, the small amount of white spheres and partial fibril disruption were found in the image of Aβ with Gd-DO3A-Chal. In comparison with a reported Gd-DTPA-curcumin possessing inhibitory activity starting at 50 μM, Gd-DO3A-Comp.B possessed stronger inhibition of Aβ aggregation at 10 μM.²⁴ The MTT assay using Neuro 2a cells showed that IC₅₀ of Gd-DO3A-Cur and Gd-DO3A-Comp.B. were more than 500 μM, indicating that these compounds did not possess significant cytotoxicity (Fig. S2, ESI^†).Open in a separate windowFig. 2Inhibitory effect of the Gd probes toward Aβ aggregation measured by Congo red assay (A) and negative staining TEM images (B). The Gd probes were co-incubated with monomeric Aβ for 24 h in PBS at pH 7.4. [Gd] = 10 μM, [Aβ] = 20 μM. Scale bars = 100 nm.To detect fibrillation process by NMR relaxometry, we measured T₁ of the probe mixture with Aβ which were pre-incubated for 1, 3, 6, 12, and 24 h to make it form the fibrils of different growth stages (Fig. 3A and B). The T₁ of Gd-DO3A-Comp.B solution decreased with pre-incubation time of Aβ, demonstrating that the Gd-DO3A-Comp.B can detect Aβ fibril depending on the growth stage (Fig. 3B). Lower T₁ involved with Aβ growth could be caused by the reduction in tumbling rate of the Gd complex.²⁵ We also co-incubated the probes with the Aβ monomer and monitored T₁ changes over the incubation time (Fig. 3A, B and S3, ESI^†). Interestingly, the Gd-DO3A-Comp.B did not cause significant T₁ decreases even after 24 hours co-incubation with Aβ monomers, demonstrating that Gd-DO3A-Comp.B has a strong inhibitory effect on fibril formation and the inhibition can be monitored by T₁ measurement (Fig. 3B). The inhibitory effect was consistent with the results of Congo red assay and TEM (Fig. 2). On the other hand, the time-dependent increases of T₁ were observed in Gd-DO3A-Chal and Gd-DO3A-Cur. This might be because these two probes were buried in the hydrophobic pocket as Aβ fibril grew up and fewer water molecules permitted access to the Gd ions. It is also possible that these probes have lower binding affinity, especially for matured fibril, and require higher concentrations to produce significant T₁ changes.²⁶ These probe did not produce the significant ΔT₁ between monomer and fibril samples (Fig. 3B and S3, ESI^†), although they showed little inhibition in Congo red assay and TEM (Fig. 2).Open in a separate windowFig. 3(A) Experimental design of T₁-based detection of Aβ fibrillation and inhibition by using the Gd probes. (B) T₁ changes of the Gd probe solutions with pre-incubated fibrils and monomers in PBS at pH 7.4 (mean ± SEM, n = 3). [Gd] = 10 μM, [Aβ] = 20 μM.The feasibility of the Gd probes was further evaluated by in vitro MRI measurement using a 1 tesla scanner. The T₁-weighted images showed that Gd-DO3A-Comp.B produced slight T₁ signal increases with Aβ monomers for 2 and 24 h (Fig. 4A and B). More significant signal increases were observed in the Gd-DO3A-Comp.B with Aβ fibril pre-incubated for 24 h (Fig. 4C). In contrast, Gd-DO3A-Chal and Gd-DO3A-Cur did not show significant signal changes in the presence of Aβ monomers or fibrils (Fig. 4A–C). These results were mostly consistent with the T₁ profile measured by NMR (Fig. 3). Compared to the previously reported Gd-DO3A-Chal that required 100 μM of the probe concentration to detect the equimolar Aβ,¹⁹ Gd-DO3A-Comp.B could detect five-times lower concentration of Aβ (20 μM) with ten-times lower probe concentration (10 μM). Therefore, Gd-DO3A-Comp.B could be promising to further develop highly sensitive diagnostic MRI contrast agents of AD.Open in a separate windowFig. 4 T ₁-weighted images of the Gd probe solutions in the presence of monomeric Aβ at 2 h incubation (A), monomeric Aβ at 24 h incubation (B), and Aβ fibrils pre-incubated for 24 h (C). Incubation was conducted in PBS at pH 7.4.In conclusion, we synthesized the curcumin-based Gd probes which enabled the detection and inhibition of Aβ fibril formation. Gd-DO3A-Comp.B allowed for the highly sensitive detection of Aβ fibril by the T₁ measurement. Moreover, the inhibitory activity could be estimated by T₁ measurement, because Gd-DO3A-Comp.B decreased T₁ depending on the growth stage of Aβ fibril formation. Such unique modality would be useful not only for the diagnostics but also for the direct evaluation of the therapeutic efficacy in vivo. For the future application, it would be important to combine with BBB penetration methods targeting the brain such as transient opening of the BBB using focused ultrasound or mannitol injection.^27,28     

A Maitake (Grifola frondosa) polysaccharide ameliorates Alzheimer's disease-like pathology and cognitive impairments by enhancing microglial amyloid-β clearance

Alzheimer''s disease (AD) is characterized by the deposition of amyloid-β (Aβ) plaques, neuronal loss and neurofibrillary tangles. In addition, neuroinflammatory processes are thought to contribute to AD pathophysiology. Maitake (Grifola frondosa), an edible/medicinal mushroom, exhibits high nutritional value and contains a great amount of health-beneficial, bioactive compounds. It has been reported that proteo-β-glucan, a polysaccharide derived from Maitake (PGM), possesses strong immunomodulatory activities. However, whether PGM is responsible for the immunomodulatory and neuroprotection effects on APP_swe/PS1_ΔE9 (APP/PS1) transgenic mice, a widely used animal model of AD, remains unclear. In the present study, the results demonstrated that PGM could improve learning and memory impairment, attenuate neuron loss and histopathological abnormalities in APP/PS1 mice. In addition, PGM treatment could activate microglia and astrocytes and promote microglial recruitment to the Aβ plaques. Also, PGM could enhance Aβ phagocytosis, and thereby alleviate Aβ burden and the pathological changes in the cortex and hippocampus in APP/PS1 mice. Moreover, PGM showed no significant effect on mice body weight. In conclusion, these findings indicated that administration of PGM could improve memory impairment via immunomodulatory action, and dietary supplementation with PGM may provide potential benefits on brain aging related memory dysfunction.

PGM ameliorates AD-like pathology and cognitive impairments by enhancing microglial amyloid-β clearance.     

Synthesis of 1-(β-coumarinyl)-1-(β-indolyl)trifluoroethanols through regioselective Friedel–Crafts alkylation of indoles with β-(trifluoroacetyl)coumarins catalyzed by Sc(OTf)3

A highly efficient Friedel–Crafts alkylation of indole derivatives with β-(trifluoroacetyl)coumarins using Sc(OTf)₃ as a catalyst has been developed, which gives regioselective 1,2-adducts to afford 1-(β-coumarinyl)-1-(β-indolyl)trifluoroethanols. A series of tertiary trifluoroethanols containing different indole and coumarin groups were synthesized in moderate to excellent yields (up to 95%) in the presence of 5 mol% catalyst in a short time (only 2 minutes at least). A mechanism of the reaction, in which the trace amount of water plays the role of proton transfer in catalyzing circulation was proposed and confirmed.

A Friedel–Crafts alkylation of indoles with β-(trifluoroacetyl)coumarins catalyzed by Sc(OTf)₃ to afford 1-(β-coumarinyl)-1-(β-indolyl)trifluoroethanols in a short time and high yield was developed.     

Gene therapy using Aβ variants for amyloid reduction

Numerous aggregation inhibitors have been developed with the goal of blocking or reversing toxic amyloid formation in vivo. Previous studies have used short peptide inhibitors targeting different amyloid β (Aβ) amyloidogenic regions to prevent aggregation. Despite the specificity that can be achieved by peptide inhibitors, translation of these strategies has been thwarted by two key obstacles: rapid proteolytic degradation in the bloodstream and poor transfer across the blood-brain barrier. To circumvent these problems, we have created a minigene to express full-length Aβ variants in the mouse brain. We identify two variants, F20P and F19D/L34P, that display four key properties required for therapeutic use: neither peptide aggregates on its own, both inhibit aggregation of wild-type Aβ in vitro, promote disassembly of pre-formed fibrils, and diminish toxicity of Aβ oligomers. We used intraventricular injection of adeno-associated virus (AAV) to express each variant in APP/PS1 transgenic mice. Lifelong expression of F20P, but not F19D/L34P, diminished Aβ levels, plaque burden, and plaque-associated neuroinflammation. Our findings suggest that AAV delivery of Aβ variants may offer a novel therapeutic strategy for Alzheimer’s disease. More broadly our work offers a framework for identifying and delivering peptide inhibitors tailored to other protein-misfolding diseases.     

Catalyst-free chemoselective α-sulfenylation/β-thiolation for α,β-unsaturated carbonyl compounds

A novel, efficient, catalyst-free and product-controllable strategy has been developed for the chemoselective α-sulfenylation/β-thiolation of α,β-unsaturated carbonyl compounds. An aromatic sulfur group could be chemoselectively introduced at α- or β-position of carbonyls with different sulfur reagents under slightly changed reaction conditions. A series of desired products were obtained in moderate to excellent yields. Mechanistic studies revealed that B₂pin₂ played the key role in activating the transformation towards the β-thiolation of α,β-unsaturated carbonyl compounds. This transition-metal-catalyst-free method provides a convenient and efficient tool for the highly chemoselective preparation of α-thiolation or β-sulfenylation products of α,β-unsaturated carbonyl compounds.

This catalyst-free method provides a useful and efficient tool for the highly chemoselective preparation of α-thiolation or β-sulfenylation products of α,β-unsaturated carbonyl compounds.     

New α-pyrones from an endophytic fungus,Hypoxylon investiens J2

Four new α-pyrones, hypotiens A–D (1–4), were isolated from a fungal endophyte, Hypoxylon investiens J2, harbored in the medicinal plant Blumea balsamifera. Their structures were determined through detailed HRMS and NMR spectroscopic data. Compounds 1–4 are new α-pyrone derivatives containing an unusual dimethyl substitution in the highly unsaturated side chain. Their plausible biosynthetic pathway was discussed. Biological assay indicated that compounds 1–4 showed no antimicrobial, quorum sensing inhibitory, and cytotoxic activities. The specific side chain in α-pyrone derivatives 1–4 might be responsible for the weak pharmacological activities.

Four new α-pyrones, hypotiens A–D (1–4), were isolated from a fungal endophyte, Hypoxylon investiens J2, harbored in the medicinal plant Blumea balsamifera.     

Geniposide attenuates Aβ25–35-induced neurotoxicity via the TLR4/NF-κB pathway in HT22 cells

Alzheimer''s disease (AD), a neurodegenerative disorder, is marked by the accumulation of amyloid-β (Aβ) and neuroinflammation which promote the development of AD. Geniposide, the main ingredient isolated from Chinese herbal medicine Gardenia jasminoides Ellis, has a variety of pharmacological functions such as anti-apoptosis and anti-inflammatory activity. Hence, we estimated the inflammatory cytotoxicity caused by Aβ_25–35 and the neuroprotective effects of geniposide in HT22 cells. In this research, following incubation with Aβ_25–35 (40 μM, 24 h) in HT22 cells, the methylthiazolyl tetrazolium (MTT) and lactate dehydrogenase (LDH) release assays showed that the cell survival rate was significantly decreased. In contrast, the reactive oxygen species (ROS) assay indicated that Aβ_25–35 enhanced ROS accumulation and apoptosis showed in both hoechst 33342 staining and annexin V-FITC/PI double staining. And then, immunofluorescence test revealed that Aβ_25–35 promoted p65 to transfer into the nucleus indicating p65 was activated by Aβ_25–35. Moreover, western blot analysis proved that Aβ_25–35 increased the expression of nitric oxide species (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interleukin-1β (IL-1β). Simultaneously, Aβ_25–35 also promoted the expression of toll-like receptor 4 (TLR4), p-p65 and p-IκB-α accompanied with the increase in the level of beta-secretase 1 (BACE1) and caspase-3 which further supported Aβ_25–35 induced apoptosis and inflammation. Fortunately, this up-regulation was reversed by geniposide. In conclusion, our data suggest that geniposide can alleviate Aβ_25–35-induced inflammatory response to protect neurons, which is possibly involved with the inhibition of the TLR4/NF-κB pathway in HT22 cells. Geniposide may be the latent treatment for AD induced by neuroinflammation and apoptosis.

Alzheimer''s disease (AD), a neurodegenerative disorder, is marked by the accumulation of amyloid-β (Aβ) and neuroinflammation which promote the development of AD.     

Direct β-selectivity of α,β-unsaturated γ-butyrolactam for asymmetric conjugate additions in an organocatalytic manner

The β-selective asymmetric addition of γ-butyrolactam with cyclic imino esters catalyzed by a bifunctional chiral tertiary amine has been developed, which provides an efficient access to optically active β-position functionalized pyrrolidin-2-one derivatives in both high yield and enantioselectivity (up to 78% yield and 95 : 5 er). This is the first catalytic method to access chiral β-functionalized pyrrolidin-2-one via a direct organocatalytic approach.

The asymmetric addition of γ-butyrolactam with cyclic imino esters catalyzed by (DHQD)₂AQN has been developed, which provides an access to β-position functionalized pyrrolidin-2-one derivatives in high levels yield and enantioselectivity.

Metal-free organocatalytic asymmetric transformations have successfully captured considerable enthusiasm of chemists as powerful methods for the synthesis of various kinds of useful chiral compounds ranging from the preparation of biologically important molecules through to novel materials.¹ Chiral pyrrolidin-2-ones have been recognized as important structural motifs that are frequently encountered in a variety of biologically active natural and synthetic compounds.² In particular, the β-position functionalized pyrrolidin-2-one backbones, which can serve as key synthetic precursors for inhibitory neurotransmitters γ-aminobutyric acids (GABA),³ selective GABA_B receptor agonists⁴ as well as antidepressant rolipram analogues,⁵ have attracted a great deal of attention. Therefore, the development of highly efficient, environmentally friendly and convenient asymmetric synthetic methods to access these versatile frameworks is particularly appealing.As a direct precursor to pyrrolidin-2-one derivatives, recently, α,β-unsaturated γ-butyrolactam has emerged as the most attractive reactant in asymmetric organometallic or organocatalytic reactions for the synthesis of chiral γ-position functionalized pyrrolidin-2-ones (Scheme 1). These elegant developments have been achieved in the research area of catalytic asymmetric vinylogous aldol,⁶ Mannich,⁷ Michael⁸ and annulation reactions⁹ in the presence of either metal catalysts or organocatalysts (a, Scheme 1). These well-developed catalytic asymmetric methods have been related to the γ-functionalized α,β-unsaturated γ-butyrolactam to date. However, in sharp contrast, the approaches toward introducing C-3 chirality at the β-position of butyrolactam through a direct catalytic manner are underdeveloped (b, Scheme 1)¹⁰ in spite of the fact that β-selective chiral functionalization of butyrolactam can directly build up α,β-functionalized pyrrolidin-2-one frameworks.Open in a separate windowScheme 1Different reactive position of α,β-unsaturated γ-butyrolactam in catalytic asymmetric reactions.So far, only a few metal-catalytic enantioselective β-selective functionalized reactions have been reported. For examples, a rhodium/diene complex catalyzed efficient asymmetric β-selective arylation^10a and alkenylation^10b have been reported by Lin group (a, Scheme 2). Procter and co-workers reported an efficient Cu(i)–NHC-catalyzed asymmetric silylation of unsaturated lactams (b, Scheme 2).^10c Despite these creative works, considerable challenges still exist in the catalytic asymmetric β-selective functionalization of γ-butyrolactam. First, the scope of nucleophiles is limited to arylboronic acids, potassium alkenyltrifluoroborates and PhMe₂SiBpin reagents. Second, the catalytic system and activation mode is restricted to metal/chiral ligands. To our knowledge, an efficient catalytic method to access chiral β-functionalized pyrrolidin-2-one via a direct organocatalytic approach has not yet been established. Therefore, the development of organocatalytic asymmetric β-selective functionalization of γ-butyrolactam are highly desirable. In conjunction with our continuing efforts in building upon chiral precedents by using chiral tertiary amine catalytic system,¹¹ we rationalized that the activated α,β-unsaturated γ-butyrolactam might serve as a β-position electron-deficient electrophile. This γ-butyrolactam may react with a properly designed electron-rich nucleophile to conduct an expected β-selective functionalized reaction of γ-butyrolactam under a bifunctional organocatalytic fashion, while avoiding the direct γ-selective vinylogous addition reaction or β,γ-selective annulation as outlined in Scheme 2. Herein we report the β-selective asymmetric addition of γ-butyrolactam with cyclic imino esters¹² catalyzed by a bifunctional chiral tertiary amine, which provides an efficient and facile access to optically active β-position functionalized pyrrolidin-2-one derivatives with both high diastereoselectivity and enantioselectivity.Open in a separate windowScheme 2β-Selective functionalization of γ-butyrolactam via metal- (previous work) or organo- (this work) catalytic approach.To begin our initial investigation, several bifunctional organocatalysts¹³ were firstly screened to evaluate their ability to promote the β-selective asymmetric addition of γ-butyrolactam 2a with cyclic imino ester 3a in the presence of 15 mol% of catalyst loading at room temperature in CH₂Cl₂ (entries 1–6, EntryCat.SolventYield^eer^f11aCH₂Cl₂70%40 : 6021bCH₂Cl₂<5%57 : 4331cCH₂Cl₂70%65 : 3541dCH₂Cl₂68%70 : 3051eCH₂Cl₂58%63 : 4761fCH₂Cl₂71%77 : 2371fDCE72%80 : 2081fCHCl₃70%80 : 2091fMTBE68%79 : 21101fToluene63%78 : 22111fTHF45%76 : 24121fMeOH32%62 : 3813^b1fDCE : MTBE75%87 : 1314^c1fDCE : MTBE72%87 : 1315^d1fDCE : MTBE70%85 : 15Open in a separate window^aReaction conditions: unless specified, a mixture of 2a (0.2 mmol), 3a (0.3 mmol) and a catalyst (15 mmol%) in a solvent (2.0 mL) was stirred at rt. for 48 h.^bThe reaction was carried out in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1).^cThe reaction was carried out in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1) for 24 h.^dThe reaction was carried out in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1) and 10 mol% of catalyst was used.^eIsolated yields.^fDetermined by chiral HPLC, the product was observed with >99 : 1 dr by ¹H NMR and HPLC. Configuration was assigned by X-ray crystal data of 4a.The results of experiments under the optimized conditions that probed the scope of the reaction are summarized in Scheme 3. The catalytic β-selective asymmetric addition of γ-butyrolactam 2a with cyclic imino esters 3a in the presence of 15 mol% (DHQD)₂AQN 1f was performed. A variety of phenyl-substituted cyclic imino esters including those bearing electron-withdrawing and electron-donating substituents on the aryl ring, heterocyclic were also examined. The electron-neutral, electron-rich, or electron-deficient groups on the para-position of phenyl ring of the cyclic imino esters afforded the products 4a–4m in 57–75% yields and 82 : 18 to 95 : 5 er values. It appears that either an electron-withdrawing or an electron-donating at the meta- or ortho-position of the aromatic ring had little influence on the yield and stereoselectivity. Similar results on the yield and enantioselectivities were obtained with 3,5-dimethoxyl substituted cyclic imino ester (71% yield and 91 : 9 er). It was notable that the system also demonstrated a good tolerance to naphthyl substituted imino ester (78% yield and 92 : 8 er value). The 2-thienyl substituted cyclic imino ester proceeded smoothly under standard conditions as well, which gave the desired product 4p in good enantioselectivity (88 : 12 er), although yield was slightly lower. However, attempts to extend this methodology to aliphatic-substituted product proved unsuccessful due to the low reactivity of the substrate 3q. It is worth noting that the replacement of Boc group with 9-fluorenylmethyl, tosyl or benzyl group as the protection, no reaction occurred. The absolute and relative configurations of the products were unambiguously determined by X-ray crystallography (4a, see the ESI^†).Open in a separate windowScheme 3Substrate scope of the asymmetric reaction of α,β-unsaturated γ-butyrolactam 2 to cyclic imino esters 3.^{a a}Reaction conditions: unless specified, a mixture of 2 (0.2 mmol), 3 (0.3 mmol) and 1f (15.0 mmol%) in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1) was stirred at rt. ^bIsolated yields. ^cDetermined by chiral HPLC, all products were observed with >99 : 1 dr by ¹H NMR and HPLC. Configuration was assigned by comparison of HPLC data and X-ray crystal data of 4a.We then examined the substrate scope of the imide derivatives (Scheme 4). Investigations with maleimides 4r–4u gave 48–61% yield of corresponding products as lower er and dr values than most of γ-butyrolactams. As for methyl substituted maleimides, the reaction failed to give any product.Open in a separate windowScheme 4Substrate scope of the asymmetric reaction of maleimides to cyclic imino esters.^{a a}Reaction conditions: unless specified, a mixture of 2 (0.2 mmol), 3 (0.3 mmol) and 1f (15.0 mmol%) in 2.2 mL a mixture of dichloroethane and methyl tert-butyl ether (volume ratio = 10 : 1) was stirred at rt. ^bIsolated yields. ^cDetermined by ¹H NMR and chiral HPLC.The chloride product 4a ((R)-tert-butyl 4-((R)-3-((E)-(4-chlorobenzylidene)amino)-2-oxotetra hydrofuran-3-yl)-2-oxopyrrolidine-1-carboxylate) was recrystallized and the corresponding single crystal was subjected to X-ray analysis to determine the absolute structure. Based on this result and our previous work, a plausible catalytic mechanism involving multisite interactions was assumed to explain the high stereoselectivity of this process (Fig. 1). Similar to the conformation reported for the dihydroxylation and the asymmetric direct aldol reaction, the transition state structure of the substrate/catalyst complexes might be presumably in the open conformation. The acidic α-carbon atom of cyclic imino ester 3a could be activated by interaction between the tertiary amine moiety of the catalyst and the enol of 3avia a hydrogen bonding. Moreover, the enolate of 3a in the transition state might be in part stabilized through the π–π stacking between the phenyl ring of 3a and the quinoline moiety. Consequently, the Re-face of the enolate is blocked by the left half of the quinidine moiety. The steric hindrance between the Boc group of 2a and the right half of the quinidine moiety make the Re-face of 2a face to the enolate of 3a. Subsequently, the attack of the incoming nucleophiles forms the Si-face of enolate of 3a to Re-face of 2a takes place, which is consistent with the experimental results.Open in a separate windowFig. 1Proposed transition state for the reaction.In conclusion, we have disclosed the β-selective asymmetric addition of γ-butyrolactam with cyclic imino esters catalyzed by a bifunctional chiral tertiary amine, which provides an efficient and facile access to optically active β-position functionalized pyrrolidin-2-one derivatives with high diastereoselectivity and enantioselectivity. To our knowledge, this is the first catalytic method to access chiral β-functionalized pyrrolidin-2-one via a direct organocatalytic approach. Current efforts are in progress to apply this new methodology to synthesize biologically active products.     

N α-arylsulfonyl histamines as selective β-glucosidase inhibitors

N ^α-benzenesulfonylhistamine, a new semi-synthetic β-glucosidase inhibitor, was obtained by bioactivity-guided isolation from a chemically engineered extract of Urtica urens L. prepared by reaction with benzenesulfonyl chloride. In order to identify better β-glucosidase inhibitors, a new series of N^α,N^τ-di-arylsulfonyl and N^α-arylsulfonyl histamine derivatives was prepared. Biological studies revealed that the β-glucosidase inhibition was in a micromolar range for several N^α-arylsulfonyl histamine compounds of the series, N^α-4-fluorobenzenesulfonyl histamine being the most powerful compound. Besides, this reversible and competitive inhibitor presented a good selectivity for β-glucosidase with respect to other target enzymes including α-glucosidase.

A selective β-glucosidase inhibitor was discovered using the chemically engineered extracts approach.     

Structural and electronic properties of α-, β-, γ-, and 6,6,18-graphdiyne sheets and nanotubes

α-, β-, γ- and 6,6,18-graphdiyne (GDYs) sheets, as well as the corresponding nanotubes (GDYNTs) are investigated systematically by using the self-consistent-field crystal orbital method. The calculations show that the GDYs and GDYNTs with different structures have different electronic properties. The α-GDY sheet is a conductor, while 2D β-, γ- and 6,6,18-GDYs are semiconductors. The carrier mobilities of β- and γ-GDY sheets in different directions are almost the same, indicating the isotropic transport characteristics. In addition, the electron mobility is in the order of 10⁶ cm² V⁻¹ s⁻¹ and it is two orders of magnitude larger than the hole mobility of 2D γ-GDY. However, α- and 6,6,18-GDY sheets have anisotropic mobilities, which are different along different directions. For the 1D tubes, the order of stability is γ-GDYNTs > 6,6,18-GDYNTs > β-GDYNTs > α-GDYNTs and is independent of the tube chirality and size. β- and γ-GDYNTs as well as zigzag α- and 6,6,18-GDYNTs are semiconductors with direct bandgaps, while armchair α-GDYNTs are metals, and armchair 6,6,18-GDYNTs change from semiconductors to metals with increasing tube size. The armchair β- and γ-GDYNTs are more favourable to transport holes, while the corresponding zigzag tubes prefer to transport electrons.

Theoretical investigation of α-, β-, γ- and 6,6,18-graphdiyne sheets as well as their corresponding nanotubes.