Effects of Electron-Withdrawing and Electron-Donating Groups on Aromaticity in Cyclic Conjugated Polyenes.

Determining the aromaticity of various fluorinated benzenes is challenging as easily obtained experimental aromaticity [Δδ(Houter - Hinner)] necessitates the chemical shifts of inner and outer protons. This issue was addressed in porphyrinoids by replacing the electron-withdrawing (E.W.) groups at the meso-positions of porphyrins and allyliporphyrins. Electronic effects on aromaticity in porphyrinoids have not been thoroughly examined in the literature. In porphyrins, the effect of E.W. groups is minimal, making it difficult to establish a clear relationship between the aromaticity strength and E.W. groups. Conversely, in allyliporphyrins, stronger E.W. groups, such as indandione (IND) derivatives, significantly reduce the aromaticity of the parent structure. The IND derivatives disrupted the aromatic pathway of allyliporphyrin more effectively than those attached to porphyrins. This is attributed to the absence of ß-carbons in allyliporphyrins. The effect of electron-donating (E.D.) groups on porphyrins and allyliporphyrins was further investigated. Contrary to the initial assumption that the E.D. groups might enhance aromaticity owing to their ability to increase electron density, as the strength of the E.D. groups increased, the aromaticity of the porphyrinoids decreased. Despite the modest reduction in aromaticity, any form of electron perturbation reduces aromaticity. The aromaticity of various fluorinated benzenes is expected to parallel our observations of porphyrinoids as representative aromatic polyenes.

Neuroprotective Effects of Davallia mariesii Roots and Its Active Constituents on Scopolamine-Induced Memory Impairment in In Vivo and In Vitro Studies.

Beta-amyloid (Aß) proteins, major contributors to Alzheimer's disease (AD), are overproduced and accumulate as oligomers and fibrils. These protein accumulations lead to significant changes in neuronal structure and function, ultimately resulting in the neuronal cell death observed in AD. Consequently, substances that can inhibit Aß production and/or accumulation are of great interest for AD prevention and treatment. In the course of an ongoing search for natural products, the roots of Davallia mariesii T. Moore ex Baker were selected as a promising candidate with anti-amyloidogenic effects. The ethanol extract of D. mariesii roots, along with its active constituents, not only markedly reduced Aß production by decreasing ß-secretase expression in APP-CHO cells (Chinese hamster ovary cells which stably express amyloid precursor proteins), but also exhibited the ability to diminish Aß aggregation while enhancing the disaggregation of Aß aggregates, as determined through the Thioflavin T (Th T) assay. Furthermore, in an in vivo study, the extract of D. mariesii roots showed potential (a tendency) for mitigating scopolamine-induced memory impairment, as evidenced by results from the Morris water maze test and the passive avoidance test, which correlated with reduced Aß deposition. Additionally, the levels of acetylcholine were significantly elevated, and acetylcholinesterase levels significantly decreased in the brains of mice (whole brains). The treatment with the extract of D. mariesii roots also led to upregulated brain-derived neurotrophic factor (BDNF) and phospho-cAMP response element-binding protein (p-CREB) in the hippocampal region. These findings suggest that the extract of D. mariesii roots, along with its active constituents, may offer neuroprotective effects against AD. Consequently, there is potential for the development of the extract of D. mariesii roots and its active constituents as effective therapeutic or preventative agents for AD.

Anti-Amyloidogenic Effects of Metasequoia glyptostroboides Fruits and Its Active Constituents.

Alzheimer's disease (AD) is a serious neurodegenerative brain disease that interferes with daily life. The accumulation of beta-amyloid (Aß), along with oxidative stress-inducing neurocellular apoptosis, has been considered one of the causes of AD. Thus, the purpose of this study is to find natural products that can reduce Aß accumulation. The ethanol extract of Metasequoia glyptostroboides Hu & Cheng fruits (Cupressaceae) significantly reduced the aggregation of Aß into oligomers and fibrils determined by Thioflavin T (ThT) assay. The solvent-partitioned ethyl acetate layer was further separated based on the bioassay-guided isolation method combined with the ThT assay. As a result, five compounds were isolated and elucidated as taxoquinone (1), sugiol (2), suginal (3), sandaracopimarinol (4), and sandaracopimaradien-19-ol (5) by comparing NMR data with references. All the compounds significantly reduced the aggregation of Aß and enhanced the disaggregation of pre-formed Aß aggregates in a dose-dependent manner. Furthermore, the inhibition of Aß aggregation by the compounds protected PC12 cells from Aß aggregate-induced toxicity. Among the five compounds, sandaracopimarinol (4) and sandaracopimaradien-19-ol (5) were the most effective. These results suggest that M. glyptostroboides and isolated five compounds have a potential for further study to be developed as anti-AD agents.

Synthesis of Dioxa-1,7-naphthicorrole and Its Oxidized Porphyrinoid as a Potential Built-In Linker for Biomolecules.

The first aromatic benzicorrole termed naphthicorrole was synthesized with a carbon donor containing more than six members. Its oxidized (enedione-embedded) porphyrinoid was also obtained using different meso-aryl substitutions under sequential oxidation conditions. The resulting enedione motif of the nonaromatic porphyrinoid was regioselective to the C2 position for S or N nucleophiles. Thus, the oxidized porphyrinoid was tested as a built-in linker for biomolecules. The progress of the reaction was visually monitored due to their different conjugation pathways.

o-(2-Thienyl)vinylarene as an Alternative Synthetic Motif for Porphyrinoids: o-Arene-Connected Porphyrinoids.

o-Arene-connected porphyrinoids were synthesized with o-(2-thienyl)vinylarene motif as a new building block for porphyrinoids. This motif can replace meso-aryl-substituted dipyrromethene and serve as a command key arranging o-connectivity of porphyrinoid. While 6a (benzene version) is very weak, 6b (pyridine version) shows a substantial amount of diatropic ring current due to reduced steric hindrance (without H23) and rigidified Pd-6a became more aromatic than 6b.

Tuned Cd2+ Selectivity: Showcase of Electronic and Regio-Effect of π-Extended Di-2-Picolylamine-Substituted Quinoline-Based Tolans.

π-Extended di-2-picolylamine (DPA)-substituted 8-hydroxyquinoline (8-HQ) tolans (2) were synthesized for testing electronic and regio-effects. The electron-poor CN-tolan (2b) showed clear selectivity for Cd2+ (>>Zn2+) over other metal ions via turn-on fluorescence, while the electron-rich MeO-tolan (2a) displayed no clear metal selectivity. Furthermore, considering that there was no significant energy difference between the Cd2+ complexes of 1 and 2b, the intended regio-effect (7- vs. 5-substituted effect) did not induce steric hindrance. Thus, the regio-effect is mainly electronic. Considering the above, 2a and 2b constitute a complete showcase in which electronic and regio-effects modulate the metal selectivity. The fluorescence titration of 2b (10 mM) with Cd2+ showed that the limit of detection (LOD) of the Cd2+-selective 2b was 158 nM in PBS (phosphate-buffered saline) (10 mM, pH 7.2) containing 50% MeOH.

Carbaporphyrin Dimers That Bear a Rigid Naphthalene Motif as an Internal Strap.

The first fully connected aromatic carbaporphyrin dimer (6) and its bis-Pd complex (6-Pd2) that bear a rigid naphthalene motif as an internal strap were synthesized. These dimers consisted of two aromatic carbaporphyrins that shared a naphthalene motif. The π-electron conjugation of the obtained macrocycles was proposed to have two separated local 22 π-electron pathways and a 34 π-electron pathway. Their weak aromaticity was fully supported by 1H NMR spectroscopy, NICS values, ACID calculations, and ICSS plots.

Systematic Modifications of a Simple Tolan: Another Category of Viscosity Sensor.

The first tolan derivative-based viscosity sensor (5d) has been synthesized, and its fluorescence intensity and lifetime increase when the viscosity of the solvent increases in methanol-glycerol mixtures. Phthalide (5d) was selected among structurally diverse tolan derivatives through systematic modifications of a simple tolan. To test 5d as a viscosity sensor, fluorescence lifetime imaging (FLIM) images of HeLa cells were obtained upon treatment with 5 µM of 5d to map the viscosity of the HeLa cells.

Bond Rotation in an Aromatic Carbaporphyrin: Allyliporphyrin.

Allyliporphyrin is a carbaporphyrin that has replaced one pyrrole with an allyl group. Dynamic behavior (bond rotation) was observed by variable temperature 1 H NMR and 2D-NOESY NMR spectroscopy and theoretically examined by DFT calculations. These studies revealed that well-defined bond rotation was first observed in the limited space of the carbaporphyrin from 2 through cis-2 and the calculated rotational barrier was low enough, with the relative energy level of cis-2 only 0.65 kcal mol-1 higher than 2. The synthesized allyliporphyrin (2) is a strongly aromatic macrocycle as indicated by the chemical shifts of its inner NH and CH signals. However, its palladium complex displayed reduced aromaticity due to the tilted thiophene of Pd-2.

Fluorescent and cooperative ion pair receptor based on tolan for Na+ (or Li+) and HSO4-: logic AND gate.

A tolan derivative was synthesized as a fluorescent and cooperative ion pair receptor. As both Na+ and HSO4- ions were complexed to the receptor, only substantial fluorescence was quenched. Thus, it also acts as a logic AND gate.